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Yu F, Gong Z, Li Y, Naseem DF, Li C, Wen M, Zhao B, Xu Z, Zhang S, Zang R, Wu A, Han Q, Wu S, Li H, Song Y. Association of SIRT6 Expression With Risk of Pneumonitis Induced by Radiotherapy in Cancer Patients. Mol Carcinog 2025; 64:1104-1118. [PMID: 40170513 PMCID: PMC12074565 DOI: 10.1002/mc.23900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/06/2025] [Accepted: 02/18/2025] [Indexed: 04/03/2025]
Abstract
Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients in this study, 124 developed NSRP, and 46 experienced SRP. The univariate analysis showed that SIRT6 expression (cOR, 0.33, 95%CI, 0.18-0.97 before RT and 0.31, 0.19-0.98 after RT), clinical factors, dosimetric parameters and haematological/serological parameters were associated with SRP before and after RT. Our multivariable logistic regression showed that SIRT6 expression was significantly associated with risk of SRP before (aOR, 0.32, 95%CI, 0.15-0.96) and after RT (aOR, 0.32, 95%CI, 0.18-0.99) after adjustment with other confounders. Moreover, the receiver operating characteristic curve analysis revealed that the combined multivariable model exhibited superior predictive capability compared to any single predictor (overall AUC, 0.93, 95%CI, 0.90-0.97 before RT and AUC, 0.91, 95%CI, 0.87-0.96 after RT). The expression of SIRT6 alone or in combination with other risk factors was associated with an increased risk of SRP, suggesting a novel approach for the prevention and treatment of radiation pneumonitis in clinical practice.
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Affiliation(s)
- Fengyuan Yu
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Zheng Gong
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Yuan Li
- Department of RadiologyAffiliated Hospital of Nanjing University of Chinese MedicineNanjingPR China
| | - Danial F. Naseem
- Department of Head and Neck SurgeryMD Anderson Cancer CenterHoustonTexasUSA
| | - Chen Li
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Miaowei Wen
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Bingying Zhao
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Zhezhe Xu
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Shanshan Zhang
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Rukun Zang
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Ailu Wu
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Qingxin Han
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Shuhui Wu
- Department of OtorhinolaryngologyBaoshan Hospital Affiliated with Shanghai University of Traditional Chinese MedicineShanghaiPR China
| | - Hongwei Li
- Department of RadiotherapyQingdao UniversityQingdaoChina
| | - Yipeng Song
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
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Li X, Chen W, Jia Z, Xiao Y, Shi A, Ma X. Mitochondrial Dysfunction as a Pathogenesis and Therapeutic Strategy for Metabolic-Dysfunction-Associated Steatotic Liver Disease. Int J Mol Sci 2025; 26:4256. [PMID: 40362504 PMCID: PMC12072025 DOI: 10.3390/ijms26094256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/28/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD) has emerged as a significant public health concern, attributed to its increasing prevalence and correlation with metabolic disorders, including obesity and type 2 diabetes. Recent research has highlighted that mitochondrial dysfunction can result in the accumulation of lipids in non-adipose tissues, as well as increased oxidative stress and inflammation. These factors are crucial in advancing the progression of MASLD. Despite advances in the understanding of MASLD pathophysiology, challenges remain in identifying effective therapeutic strategies targeting mitochondrial dysfunction. This review aims to consolidate current knowledge on how mitochondrial imbalance affects the development and progression of MASLD, while addressing existing research gaps and potential avenues for future research. This review was conducted after a systematic search of comprehensive academic databases such as PubMed, Embase, and Web of Science to gather information on mitochondrial dysfunction as well as mitochondrial-based treatments for MASLD.
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Affiliation(s)
- Xiangqiong Li
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Wenling Chen
- The First Clinical College of Yunnan University of Chinese Medicine, Kunming 650500, China;
| | - Zhuangzhuang Jia
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Yahui Xiao
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Anhua Shi
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Xuan Ma
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
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Gupta S, Kishore A, Rishi V, Aggarwal A. Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies. Funct Integr Genomics 2025; 25:26. [PMID: 39849126 DOI: 10.1007/s10142-025-01530-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/04/2025] [Accepted: 01/08/2025] [Indexed: 01/25/2025]
Abstract
Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca2+) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca2+ homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca2+ regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.
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Affiliation(s)
- Shiwangi Gupta
- National Agri-Food and Biomanufacturing Institute, Sector-81, SAS Nagar, Knowledge City, Punjab, India
- Department of Biotechnology, Sector-25, Panjab University, BMS block I, Chandigarh, India
| | - Abhinoy Kishore
- Indian Institute of Science, Bengaluru, India
- Chandigarh Group of Colleges, Landran, Punjab, India
| | - Vikas Rishi
- National Agri-Food and Biomanufacturing Institute, Sector-81, SAS Nagar, Knowledge City, Punjab, India
| | - Aanchal Aggarwal
- National Agri-Food and Biomanufacturing Institute, Sector-81, SAS Nagar, Knowledge City, Punjab, India.
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De Benedittis G, Latini A, Morgante C, Perricone C, Ceccarelli F, Novelli G, Novelli L, Ciccacci C, Borgiani P. The dysregulation of mitochondrial homeostasis-related genes could be involved in the decrease of mtDNA copy number in systemic lupus erythematosus patients. Immunol Res 2024; 72:1384-1392. [PMID: 39230799 PMCID: PMC11618193 DOI: 10.1007/s12026-024-09535-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/29/2024] [Indexed: 09/05/2024]
Abstract
Systemic lupus erythematosus (SLE) is a chronic multifactorial autoimmune disease. It is now widely demonstrated that oxidative stress (OS) plays an important role in the modulation of the pathogenesis of this disease. Mitochondrial DNA (mtDNA) is highly vulnerable to OS and it is known a decrease of mtDNA copy number in SLE patients. However, to date, it has not been investigated if this decrease is associated with a dysregulation of mitochondrial homeostasis genes. Our aim is to evaluate the amount of mtDNA copy number and the expression of the genes more involved in the mitochondrial homeostasis pathways, in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls. We analysed the amount of mtDNA in PBMCs of 72 SLE patients and 61 healthy controls by qPCR. Then, we investigated the expression variability of TFAM and SIRT1 (biogenesis), MFN1 and MFF (fusion/fission) and PRKN2 (mitophagy) genes in a subgroup of SLE patients and healthy controls. Interestingly, we have observed a highly significant decrease in mtDNA copies in SLE patients compared to healthy controls (P < 0.0001). In addition, we have shown that the expression levels of SIRT1, MFN1 and PRKN2 genes were significantly decreased in SLE patients with respect to healthy controls (P = 0.00001 for SIRT1, P = 0.0150 for MFN1 and P = 0.0009 for PRKN2). Lastly, we have reported a positive correlation between PRKN2 expression level and mtDNA copy number (P = 0.019, r = 0.475). In conclusion, our data confirm the impairment of mtDNA copy number in the disease and show for the first time a dysregulation of the mitochondrial homeostasis genes. These results could provide additional support to the important role of mitochondria in SLE development.
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Affiliation(s)
- Giada De Benedittis
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Andrea Latini
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Chiara Morgante
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Fulvia Ceccarelli
- Lupus Clinic, Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, Italy
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, USA
| | - Lucia Novelli
- UniCamillus, Saint Camillus International University of Health Sciences, 00131, Rome, Italy
| | - Cinzia Ciccacci
- UniCamillus, Saint Camillus International University of Health Sciences, 00131, Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133, Rome, Italy
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Sun M, Wei C, Gao Y, Chen X, Zhong K, Li Y, Yang Z, Gao Y, Wang H. TSG Extends the Longevity of Caenorhabditis elegans by Targeting the DAF-16/SKN-1/SIR-2.1-Mediated Mitochondrial Quality Control Process. Antioxidants (Basel) 2024; 13:1086. [PMID: 39334745 PMCID: PMC11428426 DOI: 10.3390/antiox13091086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/25/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
The improvement of mitochondrial function is described as a strategy for alleviating oxidative stress and intervening in the aging process. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the major bioactive components isolated from Polygonum multiflorum Thunb, and it exhibits multiple activities, including antioxidant and anti-inflammatory effects. In this study, we found that 200 μM TSG significantly extended the mean lifespan of Caenorhabditis elegans by 16.48% and improved health status by delaying age-associated physiological decline in worms. The longevity prolongation effect of TSG depended on the regulation of the mitochondrial quality control process mediated by DAF-16/FOXO, SKN-1/Nrf2 and SIR-2.1/SIRT1 to improve mitochondrial function. Moreover, TSG treatment obviously alleviated the proteotoxicity of β-amyloid and tau proteins in worms. Our findings indicated that TSG is a promising natural product for preventing aging and treating aging-associated neurodegenerative diseases by regulating the mitochondrial quality control process to improve mitochondrial function.
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Affiliation(s)
- Menglu Sun
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Congmin Wei
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yehui Gao
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xinyan Chen
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Kaixin Zhong
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yingzi Li
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Zhou Yang
- Tongji Alpha Natural Medicine Research Institute, Tongji University, Shanghai 200070, China
| | - Yihuai Gao
- Tongji Alpha Natural Medicine Research Institute, Tongji University, Shanghai 200070, China
| | - Hongbing Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
- Tongji Alpha Natural Medicine Research Institute, Tongji University, Shanghai 200070, China
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Kim MB, Lee J, Lee JY. Targeting Mitochondrial Dysfunction for the Prevention and Treatment of Metabolic Disease by Bioactive Food Components. J Lipid Atheroscler 2024; 13:306-327. [PMID: 39355406 PMCID: PMC11439752 DOI: 10.12997/jla.2024.13.3.306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/21/2024] [Accepted: 05/13/2024] [Indexed: 10/03/2024] Open
Abstract
Dysfunctional mitochondria have been linked to the pathogenesis of obesity-associated metabolic diseases. Excessive energy intake impairs mitochondrial biogenesis and function, decreasing adenosine-5'-triphosphate production and negatively impacting metabolically active tissues such as adipose tissue, skeletal muscle, and the liver. Compromised mitochondrial function disturbs lipid metabolism and increases reactive oxygen species production in these tissues, contributing to the development of insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease. Recent studies have demonstrated the therapeutic potential of bioactive food components, such as resveratrol, quercetin, coenzyme Q10, curcumin, and astaxanthin, by enhancing mitochondrial function. This review provides an overview of the current understanding of how these bioactive compounds ameliorate mitochondrial dysfunction to mitigate obesity-associated metabolic diseases.
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Affiliation(s)
- Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Jaeeun Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
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Russo C, Valle MS, D’Angeli F, Surdo S, Malaguarnera L. Resveratrol and Vitamin D: Eclectic Molecules Promoting Mitochondrial Health in Sarcopenia. Int J Mol Sci 2024; 25:7503. [PMID: 39062745 PMCID: PMC11277153 DOI: 10.3390/ijms25147503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Sarcopenia refers to the progressive loss and atrophy of skeletal muscle function, often associated with aging or secondary to conditions involving systemic inflammation, oxidative stress, and mitochondrial dysfunction. Recent evidence indicates that skeletal muscle function is not only influenced by physical, environmental, and genetic factors but is also significantly impacted by nutritional deficiencies. Natural compounds with antioxidant properties, such as resveratrol and vitamin D, have shown promise in preventing mitochondrial dysfunction in skeletal muscle cells. These antioxidants can slow down muscle atrophy by regulating mitochondrial functions and neuromuscular junctions. This review provides an overview of the molecular mechanisms leading to skeletal muscle atrophy and summarizes recent advances in using resveratrol and vitamin D supplementation for its prevention and treatment. Understanding these molecular mechanisms and implementing combined interventions can optimize treatment outcomes, ensure muscle function recovery, and improve the quality of life for patients.
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Affiliation(s)
- Cristina Russo
- Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy;
| | - Maria Stella Valle
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
| | - Floriana D’Angeli
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Sofia Surdo
- Italian Center for the Study of Osteopathy (CSDOI), 95124 Catania, Italy;
| | - Lucia Malaguarnera
- Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy;
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Cook NE, McGovern MR, Zaman T, Lundin PM, Vaughan RA. Effect of mTORC Agonism via MHY1485 with and without Rapamycin on C2C12 Myotube Metabolism. Int J Mol Sci 2024; 25:6819. [PMID: 38999929 PMCID: PMC11241331 DOI: 10.3390/ijms25136819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 07/14/2024] Open
Abstract
The mechanistic target of rapamycin complex (mTORC) regulates protein synthesis and can be activated by branched-chain amino acids (BCAAs). mTORC has also been implicated in the regulation of mitochondrial metabolism and BCAA catabolism. Some speculate that mTORC overactivation by BCAAs may contribute to insulin resistance. The present experiments assessed the effect of mTORC activation on myotube metabolism and insulin sensitivity using the mTORC agonist MHY1485, which does not share structural similarities with BCAAs. METHODS C2C12 myotubes were treated with MHY1485 or DMSO control both with and without rapamycin. Gene expression was assessed using qRT-PCR and insulin sensitivity and protein expression by western blot. Glycolytic and mitochondrial metabolism were measured by extracellular acidification rate and oxygen consumption. Mitochondrial and lipid content were analyzed by fluorescent staining. Liquid chromatography-mass spectrometry was used to assess extracellular BCAAs. RESULTS Rapamycin reduced p-mTORC expression, mitochondrial content, and mitochondrial function. Surprisingly, MHY1485 did not alter p-mTORC expression or cell metabolism. Neither treatment altered indicators of BCAA metabolism or extracellular BCAA content. CONCLUSION Collectively, inhibition of mTORC via rapamycin reduces myotube metabolism and mitochondrial content but not BCAA metabolism. The lack of p-mTORC activation by MHY1485 is a limitation of these experiments and warrants additional investigation.
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Affiliation(s)
- Norah E. Cook
- Department of Health and Human Performance, High Point University, High Point, NC 27262-3598, USA; (N.E.C.); (M.R.M.)
| | - Macey R. McGovern
- Department of Health and Human Performance, High Point University, High Point, NC 27262-3598, USA; (N.E.C.); (M.R.M.)
| | - Toheed Zaman
- Department of Chemistry, High Point University, High Point, NC 27262-3598, USA; (T.Z.); (P.M.L.)
| | - Pamela M. Lundin
- Department of Chemistry, High Point University, High Point, NC 27262-3598, USA; (T.Z.); (P.M.L.)
| | - Roger A. Vaughan
- Department of Health and Human Performance, High Point University, High Point, NC 27262-3598, USA; (N.E.C.); (M.R.M.)
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Wu X, Zhou Y, Xi Y, Zhou H, Tang Z, Xiong L, Qin D. Polyphenols: Natural Food-Grade Biomolecules for the Treatment of Nervous System Diseases from a Multi-Target Perspective. Pharmaceuticals (Basel) 2024; 17:775. [PMID: 38931442 PMCID: PMC11206395 DOI: 10.3390/ph17060775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/08/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Polyphenols are the most prevalent naturally occurring phytochemicals in the human diet and range in complexity from simple molecules to high-molecular-weight polymers. They have a broad range of chemical structures and are generally categorized as "neuroprotective", "anti-inflammatory", and "antioxidant" given their main function of halting disease onset and promoting health. Research has shown that some polyphenols and their metabolites can penetrate the blood-brain barrier and hence increase neuroprotective signaling and neurohormonal effects to provide anti-inflammatory and antioxidant effects. Therefore, multi-targeted modulation of polyphenols may prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for difficult-to-treat neuropsychiatric disorders. Therefore, multi-target modulation of polyphenols has the potential to prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for such nervous system diseases. Herein, we review the therapeutic benefits of polyphenols on autism-spectrum disorders, anxiety disorders, depression, and sleep disorders, along with in vitro and ex vivo experimental and clinical trials. Although their methods of action are still under investigation, polyphenols are still seldom employed directly as therapeutic agents for nervous system disorders. Comprehensive mechanistic investigations and large-scale multicenter randomized controlled trials are required to properly evaluate the safety, effectiveness, and side effects of polyphenols.
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Affiliation(s)
- Xinchen Wu
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.W.); (Y.Z.); (Y.X.)
| | - Yang Zhou
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.W.); (Y.Z.); (Y.X.)
| | - Yujiang Xi
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.W.); (Y.Z.); (Y.X.)
| | - Haimei Zhou
- School of Basic Medical Science, Yunnan University of Chinese Medicine, Kunming 650500, China; (H.Z.); (Z.T.)
| | - Zhengxiu Tang
- School of Basic Medical Science, Yunnan University of Chinese Medicine, Kunming 650500, China; (H.Z.); (Z.T.)
| | - Lei Xiong
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.W.); (Y.Z.); (Y.X.)
| | - Dongdong Qin
- School of Basic Medical Science, Yunnan University of Chinese Medicine, Kunming 650500, China; (H.Z.); (Z.T.)
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming 650500, China
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10
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Del Bianco D, Gentile R, Sallicandro L, Biagini A, Quellari PT, Gliozheni E, Sabbatini P, Ragonese F, Malvasi A, D’Amato A, Baldini GM, Trojano G, Tinelli A, Fioretti B. Electro-Metabolic Coupling of Cumulus-Oocyte Complex. Int J Mol Sci 2024; 25:5349. [PMID: 38791387 PMCID: PMC11120766 DOI: 10.3390/ijms25105349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/03/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Oocyte-cumulus cell interaction is essential for oocyte maturation and competence. The bidirectional crosstalk network mediated by gap junctions is fundamental for the metabolic cooperation between these cells. As cumulus cells exhibit a more glycolytic phenotype, they can provide metabolic substrates that the oocyte can use to produce ATP via oxidative phosphorylation. The impairment of mitochondrial activity plays a crucial role in ovarian aging and, thus, in fertility, determining the success or failure of assisted reproductive techniques. This review aims to deepen the knowledge about the electro-metabolic coupling of the cumulus-oocyte complex and to hypothesize a putative role of potassium channel modulators in order to improve fertility, promote intracellular Ca2+ influx, and increase the mitochondrial biogenesis and resulting ATP levels in cumulus cells.
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Affiliation(s)
- Diletta Del Bianco
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
| | - Rosaria Gentile
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Laboratorio Interdipartimentale di Fisiopatologia della Riproduzione, Università degli Studi di Perugia, Edificio C, Piano 3 P.zza Lucio Severi, 1, Sant’Andrea delle Fratte, 06132 Perugia, Italy
| | - Luana Sallicandro
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Department of Medicine and Surgery, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy
| | - Andrea Biagini
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Department of Medicine and Surgery, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy
| | - Paola Tiziana Quellari
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Department of Medicine and Surgery, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy
- ASST Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy
| | - Elko Gliozheni
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Department of Medicine and Surgery, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tirana, AL1005 Tirana, Albania
| | - Paola Sabbatini
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
| | - Francesco Ragonese
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Laboratorio Interdipartimentale di Fisiopatologia della Riproduzione, Università degli Studi di Perugia, Edificio C, Piano 3 P.zza Lucio Severi, 1, Sant’Andrea delle Fratte, 06132 Perugia, Italy
| | - Antonio Malvasi
- Department of Biomedical Sciences and Human Oncology, University of Bari, 70121 Bari, Italy;
| | - Antonio D’Amato
- 1st Unit of Obstetrics and Gynecology, University of Bari, 70121 Bari, Italy;
| | | | - Giuseppe Trojano
- Department of Maternal and Child Health, “Madonna delle Grazie” Hospital ASM, 75100 Matera, Italy;
| | - Andrea Tinelli
- Department of Obstetrics and Gynecology and CERICSAL (CEntro di RIcerca Clinico SALentino), Veris delli Ponti Hospital, Via Giuseppina delli Ponti, 73020 Scorrano, Lecce, Italy
| | - Bernard Fioretti
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via dell’Elce di Sotto 8, 06132 Perugia, Italy; (D.D.B.); (R.G.); (L.S.); (A.B.); (P.T.Q.); (E.G.); (P.S.); (F.R.)
- Laboratorio Interdipartimentale di Fisiopatologia della Riproduzione, Università degli Studi di Perugia, Edificio C, Piano 3 P.zza Lucio Severi, 1, Sant’Andrea delle Fratte, 06132 Perugia, Italy
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Hahm JH, Nirmala FS, Ha TY, Ahn J. Nutritional approaches targeting mitochondria for the prevention of sarcopenia. Nutr Rev 2024; 82:676-694. [PMID: 37475189 DOI: 10.1093/nutrit/nuad084] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/22/2023] Open
Abstract
A decline in function and loss of mass, a condition known as sarcopenia, is observed in the skeletal muscles with aging. Sarcopenia has a negative effect on the quality of life of elderly. Individuals with sarcopenia are at particular risk for adverse outcomes, such as reduced mobility, fall-related injuries, and type 2 diabetes mellitus. Although the pathogenesis of sarcopenia is multifaceted, mitochondrial dysfunction is regarded as a major contributor for muscle aging. Hence, the development of preventive and therapeutic strategies to improve mitochondrial function during aging is imperative for sarcopenia treatment. However, effective and specific drugs that can be used for the treatment are not yet approved. Instead studies on the relationship between food intake and muscle aging have suggested that nutritional intake or dietary control could be an alternative approach for the amelioration of muscle aging. This narrative review approaches various nutritional components and diets as a treatment for sarcopenia by modulating mitochondrial homeostasis and improving mitochondria. Age-related changes in mitochondrial function and the molecular mechanisms that help improve mitochondrial homeostasis are discussed, and the nutritional components and diet that modulate these molecular mechanisms are addressed.
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Affiliation(s)
- Jeong-Hoon Hahm
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Farida S Nirmala
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea
| | - Tae Youl Ha
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea
| | - Jiyun Ahn
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea
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12
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Sung JY, Kim SG, Kang YJ, Park SY, Choi HC. SIRT1-dependent PGC-1α deacetylation by SRT1720 rescues progression of atherosclerosis by enhancing mitochondrial function. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159453. [PMID: 38244675 DOI: 10.1016/j.bbalip.2024.159453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/08/2023] [Accepted: 01/15/2024] [Indexed: 01/22/2024]
Abstract
Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis via lipid-mediated mitochondrial dysfunction and oxidative stress. However, the mechanisms of mitochondrial dysfunction and VSMC senescence in atherosclerosis have not been established. Here, we investigated the mechanisms whereby signaling pathways regulated by SRT1720 enhance or regulate mitochondrial functions in atherosclerotic VSMCs to suppress atherosclerosis. Initially, we examined the effect of SRT1720 on oleic acid (OA)-induced atherosclerosis. Atherosclerotic VSMCs exhibited elevated expressions of BODIPY and ADRP (adipose differentiation-related protein) and associated intracellular lipid droplet markers. In addition, the expression of collagen I was upregulated by OA, while the expressions of elastin and α-SMA were downregulated. mtDNA copy numbers, an ATP detection assay, transmission electron microscopy (TEM) imaging of mitochondria, mitochondria membrane potentials (assessed using JC-1 probe), and levels of mitochondrial oxidative phosphorylation (OXPHOS) were used to examine the effects of SRT1720 on OA-induced mitochondrial dysfunction. SRT1720 reduced mtDNA damage and accelerated mitochondria repair in VSMCs with OA-induced mitochondria dysfunction. In addition, mitochondrial reactive oxygen species (mtROS) levels were downregulated by SRT1720 in OA-treated VSMCs. Importantly, SRT1720 significantly increased SIRT1 and PGC-1α expression levels, but VSMCs senescence, inflammatory response, and atherosclerosis phenotypes were not recovered by treating cells with EX527 and SR-18292 before SRT1720. Mechanistically, the upregulations of SIRT1 and PGC-1α deacetylation by SRT1720 restored mitochondrial function, and consequently suppressed VSMC senescence and atherosclerosis-associated proteins and phenotypes. Collectively, this study indicates that SRT1720 can attenuate OA-induced atherosclerosis associated with VSMC senescence and mitochondrial dysfunction via SIRT1-mediated deacetylation of the PGC-1α pathway.
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Affiliation(s)
- Jin Young Sung
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Seul Gi Kim
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Young Jin Kang
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - So-Young Park
- Department of Physiology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Hyoung Chul Choi
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; Senotherapy-based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea.
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13
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Dhiman S, Mannan A, Taneja A, Mohan M, Singh TG. Sirtuin dysregulation in Parkinson's disease: Implications of acetylation and deacetylation processes. Life Sci 2024; 342:122537. [PMID: 38428569 DOI: 10.1016/j.lfs.2024.122537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/16/2024] [Accepted: 02/23/2024] [Indexed: 03/03/2024]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor function and is caused by a gradual decline of dopaminergic neurons in the brain's substantia pars compacta (Snpc) region. Multiple molecular pathways are involved in the pathogenesis, which results in impaired cellular functions and neuronal degeneration. However, the role of sirtuins, a type of NAD+-dependent deacetylase, in the pathogenesis of Parkinson's disease has recently been investigated. Sirtuins are essential for preserving cellular homeostasis because they control a number of biological processes, such as metabolism, apoptosis, and DNA repair. This review shed lights on the dysregulation of sirtuin activity in PD, highlighting the role that acetylation and deacetylation processes play in the development of the disease. Key regulators of protein acetylation, sirtuins have been found to be involved in the aberrant acetylation of vital substrates linked to PD pathology when their balance is out of balance. The hallmark characteristics of PD such as neuroinflammation, oxidative stress, and mitochondrial dysfunction have all been linked to the dysregulation of sirtuin expression and activity. Furthermore, we have also explored how the modulators of sirtuins can be a promising therapeutic intervention in the treatment of PD.
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Affiliation(s)
- Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ayushi Taneja
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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14
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Zhou Y, Suo W, Zhang X, Liang J, Zhao W, Wang Y, Li H, Ni Q. Targeting mitochondrial quality control for diabetic cardiomyopathy: Therapeutic potential of hypoglycemic drugs. Biomed Pharmacother 2023; 168:115669. [PMID: 37820568 DOI: 10.1016/j.biopha.2023.115669] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/23/2023] [Accepted: 10/06/2023] [Indexed: 10/13/2023] Open
Abstract
Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.
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Affiliation(s)
- Yutong Zhou
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China
| | - Wendong Suo
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xinai Zhang
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China
| | - Jiaojiao Liang
- Zhengzhou Shuqing Medical College, Zhengzhou 450064, China
| | - Weizhe Zhao
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing 100105, China
| | - Yue Wang
- Capital Medical University, Beijing 100069, China
| | - Hong Li
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Qing Ni
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China.
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Liao Y, Ke B, Long X, Xu J, Wu Y. Abnormalities in the SIRT1-SIRT3 axis promote myocardial ischemia-reperfusion injury through ferroptosis caused by silencing the PINK1/Parkin signaling pathway. BMC Cardiovasc Disord 2023; 23:582. [PMID: 38012584 PMCID: PMC10683361 DOI: 10.1186/s12872-023-03603-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 11/07/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Myocardial ischemia-reperfusion injury (MIRI) is one of the main reasons for poor prognosis in patients with ischemic cardiomyopathy (ICM). To date, the mechanism remains unknown. As members of the silent information regulator 2 (SIR2) family, both SIRT1 and SIRT3 have been shown to play critical roles in protecting cardiomyocytes against MIRI, but their specific protective mechanism, their interact between the two and their relationship with ferroptosis are still unclear. Hence, in this study, we investigated the interact and specific mechanism of SIRT1 and SIRT3 in protecting cardiomyocytes against MIRI, as well as their association with ferroptosis. METHODS Bioinformatics analysis methods were used to explore the expression of SIRT1 and SIRT3 during MIRI, and then a cell hypoxia/reoxygenation injury model was constructed to verify the results. Then, Pearson correlation analysis was further used to explore the relationship between SIRT1 and SIRT3, whose roles in the regulation of ferroptosis were also analysed by gene knock down, Western Blotting and flow cytometry. Several biomarkers, such as Fe2+ concentration, lipid peroxidation marker MDA and mitochondrial membrane potential (MMP), were used to evaluate changes in ferroptosis. RESULTS The expression of SIRT1 and SIRT3 was abnormal during MIRI, and SIRT1 was significantly negatively correlated with SIRT3 in the SIRT1-SIRT3 axis. Further analysis revealed that the SIRT1-SIRT3 axis was closely correlated with ferroptosis, and its silencing effectively increase the incidence of ferroptosis. Furthermore, SIRT1-SIRT3 axis silencing was accompanied by changes in PINK1, Parkin, P62/SQSTM1 and LC3 expression. PINK1 silencing significantly increased the incidence of ferroptosis, while resveratrol (Res) and/or honokiol (HKL) effectively reversed the outcome. CONCLUSION Abnormalities in the SIRT1-SIRT3 axis promote MIRI through ferroptosis caused by silencing the PINK1/Parkin signaling pathway.
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Affiliation(s)
- Yunfei Liao
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- East China Digital Medical Engineering Research Institute, Shangrao, China
| | - Ben Ke
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaoyan Long
- East China Digital Medical Engineering Research Institute, Shangrao, China
| | - Jianjun Xu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
| | - Yongbing Wu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
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16
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Talib NF, Zhu Z, Kim KS. Vitamin D3 Exerts Beneficial Effects on C2C12 Myotubes through Activation of the Vitamin D Receptor (VDR)/Sirtuins (SIRT)1/3 Axis. Nutrients 2023; 15:4714. [PMID: 38004107 PMCID: PMC10674540 DOI: 10.3390/nu15224714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
The onset of sarcopenia is associated with a decline in vitamin D receptor (VDR) expression, wherein reduced VDR levels contribute to muscle atrophy, while heightened expression promotes muscle hypertrophy. Like VDR, the age-related decline in protein deacetylase sirtuin (SIRT) expression is linked to the development of sarcopenia and age-related muscle dysfunction. This study aimed to investigate whether the VDR agonist 1,25-dihydroxyvitamin D3 (1,25VD3) exerts beneficial effects on muscles through interactions with sirtuins and, if so, the underlying molecular mechanisms. Treatment of 1,25VD3 in differentiating C2C12 myotubes substantially elevated VDR, SIRT1, and SIRT3 expression, enhancing their differentiation. Furthermore, 1,25VD3 significantly enhanced the expression of key myogenic markers, including myosin heavy chain (MyHC) proteins, MyoD, and MyoG, and increased the phosphorylation of AMPK and AKT. Conversely, VDR knockdown resulted in myotube atrophy and reduced SIRT1 and SIRT3 levels. In a muscle-wasting model triggered by IFN-γ/TNF-α in C2C12 myotubes, diminished VDR, SIRT1, and SIRT3 levels led to skeletal muscle atrophy and apoptosis. 1,25VD3 downregulated the increased expression of muscle atrophy-associated proteins, including FoxO3a, MAFbx, and MuRF1 in an IFN-γ/TNF-α induced atrophy model. Importantly, IFN-γ/TNF-α significantly reduced the mtDNA copy number in the C2C12 myotube, whereas the presence of 1,25VD3 effectively prevented this decrease. These results support that 1,25VD3 could serve as a potential preventive or therapeutic agent against age-related muscle atrophy by enhancing the VDR/SIRT1/SIRT3 axis.
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Affiliation(s)
- Nurul Fatihah Talib
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (N.F.T.); (Z.Z.)
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
| | - Zunshu Zhu
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (N.F.T.); (Z.Z.)
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
| | - Kyoung-Soo Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (N.F.T.); (Z.Z.)
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
- East-West Bone & Joint Disease Research Institute, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea
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17
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Smits MAJ, Schomakers BV, van Weeghel M, Wever EJM, Wüst RCI, Dijk F, Janssens GE, Goddijn M, Mastenbroek S, Houtkooper RH, Hamer G. Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction. Hum Reprod 2023; 38:2208-2220. [PMID: 37671592 PMCID: PMC10628503 DOI: 10.1093/humrep/dead177] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 08/16/2023] [Indexed: 09/07/2023] Open
Abstract
STUDY QUESTION Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes? SUMMARY ANSWER We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources. WHAT IS KNOWN ALREADY Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited. STUDY DESIGN, SIZE, DURATION A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid-liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons. MAIN RESULTS AND THE ROLE OF CHANCE Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells. LIMITATIONS, REASONS FOR CAUTION The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences. WIDER IMPLICATIONS OF THE FINDINGS Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Amsterdam UMC. The authors declare to have no competing interests. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Myrthe A J Smits
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Bauke V Schomakers
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Michel van Weeghel
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Eric J M Wever
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Rob C I Wüst
- Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | - Frederike Dijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Georges E Janssens
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands
| | - Mariëtte Goddijn
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
- Center for Reproductive Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Sebastiaan Mastenbroek
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Riekelt H Houtkooper
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Geert Hamer
- Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
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Elgendy O, Kitahara G, Yamada K, Taniguchi S, Osawa T. 5-Aminolevulinic acid/sodium ferrous citrate improves the quality of heat-stressed bovine oocytes by reducing oxidative stress. J Reprod Dev 2023; 69:261-269. [PMID: 37599082 PMCID: PMC10602763 DOI: 10.1262/jrd.2023-038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/26/2023] [Indexed: 08/22/2023] Open
Abstract
A high temperature-humidity index during summer has deleterious effects on mitochondrial function, reducing oocyte developmental competence. 5-Aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) are both known to support mitochondrial function and have strong anti-oxidant and anti-apoptotic activities. This study aimed to determine the mechanism of action of 5-ALA/SFC on oocyte quality. Bovine oocytes were collected from medium-sized follicles during summer (July-September, temperature-humidity index:76.6), cultured with 0, 1, 2, 4, and 8 µM 5-ALA with SFC at a molar ratio of 1:0.125, fertilized, and cultured for 10 days. The addition of 8/1 µM 5-ALA/SFC had a deleterious effect on oocyte cleavage rate in comparison with control oocytes, but did not affect the blastocyst rate, while 1/0.125 µM 5-ALA/SFC had a significantly higher increase in blastocyst rate than 8/1 µM 5-ALA/SFC. The addition of 1/0.125 and 2/0.25 µM 5-ALA/SFC improved oocyte quality by increasing the mitochondrial distribution pattern and metaphase-II oocytes, reducing reactive oxygen species and upregulating nuclear factor erythroid-2-related factor 2, heme oxygenase-1, and superoxide dismutase-1 in oocytes, and nuclear factor erythroid-2-related factor 2 and mitochondrial transcription factor A in cumulus cells. These results indicate that 1/0.125 and 2/0.25 µM 5-ALA/SFC may support oocyte quality and developmental competence and provide anti-oxidant actions in cumulus-oocyte complexes.
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Affiliation(s)
- Omnia Elgendy
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-2192, Japan
- Department of Veterinary Sciences, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
- Department of Theriogenology, Faculty of Veterinary Medicine, Benha University, Qalyobia 13736, Egypt
| | - Go Kitahara
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-2192, Japan
- Department of Veterinary Sciences, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Kentaro Yamada
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-2192, Japan
- Department of Veterinary Sciences, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Shin Taniguchi
- One Health Business Department, Neopharma Japan Co., Ltd., Tokyo 102-0071, Japan
- Present: Hokusatsu Regional Promotion Bureau, Kagoshima pref., Kagoshima, Japan
| | - Takeshi Osawa
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-2192, Japan
- Department of Veterinary Sciences, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
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19
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Song H, Thompson LP. Effects of Gestational Hypoxia on PGC1α and Mitochondrial Acetylation in Fetal Guinea Pig Hearts. Reprod Sci 2023; 30:2996-3009. [PMID: 37138147 PMCID: PMC10556133 DOI: 10.1007/s43032-023-01245-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/20/2023] [Indexed: 05/05/2023]
Abstract
Chronic intrauterine hypoxia is a significant pregnancy complication impacting fetal heart growth, metabolism, and mitochondrial function, contributing to cardiovascular programming of the offspring. PGC1α (peroxisome proliferator-activated receptor γ co-activator 1α) is the master regulator of mitochondrial biogenesis. We investigated the effects of hypoxia on PGC1α expression following exposure at different gestational ages. Time-mated pregnant guinea pigs were exposed to normoxia (NMX, 21% O2) or hypoxia (HPX, 10.5% O2) at either 25-day (early-onset) or 50-day (late-onset) gestation, and all fetuses were extracted at term (term = ~65-day gestation). Expression of nuclear PGC1α, sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and mitochondrial sirtuin 3 (SIRT3) was measured, along with SIRT3 activity and mitochondrial acetylation of heart ventricles of male and female fetuses. Early-onset hypoxia increased (P<0.05) fetal cardiac nuclear PGC1α and had no effect on mitochondrial acetylation of either growth-restricted males or females. Late-onset hypoxia had either no effect or decreased (P<0.05) PCC1α expression in males and females, respectively, but increased (P<0.05) mitochondrial acetylation in both sexes. Hypoxia had variable effects on expression of SIRT1, AMPK, SIRT3, and SIRT3 activity depending on the sex. The capacity of the fetal heart to respond to hypoxia differs depending on the gestational age of exposure and sex of the fetus. Further, the effects of late-onset hypoxia on fetal heart function impose a greater risk to male than female fetuses, which has implications toward cardiovascular programming effects of the offspring.
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Affiliation(s)
- Hong Song
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA
| | - Loren P Thompson
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, School of Medicine, 655 W. Baltimore St., Baltimore, MD, 21201, USA.
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20
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Riegger J, Schoppa A, Ruths L, Haffner-Luntzer M, Ignatius A. Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review. Cell Mol Biol Lett 2023; 28:76. [PMID: 37777764 PMCID: PMC10541721 DOI: 10.1186/s11658-023-00489-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/11/2023] [Indexed: 10/02/2023] Open
Abstract
During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, and proinflammatory cytokines. This detrimental environment triggers cellular stress and subsequent dysfunction, which not only contributes to the development of associated diseases, that is, osteoporosis and osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated stress and reduce the overall tissue damage, cells possess diverse defense mechanisms. However, cellular antioxidative capacities are limited and thus ROS accumulation can lead to aberrant cell fate decisions, which have adverse effects on cartilage and bone homeostasis. In this narrative review, we address oxidative stress as a major driver of pathophysiologic processes in cartilage and bone, including senescence, misdirected differentiation, cell death, mitochondrial dysfunction, and impaired mitophagy by illustrating the consequences on tissue homeostasis and regeneration. Moreover, we elaborate cellular defense mechanisms, with a particular focus on oxidative stress response and mitophagy, and briefly discuss respective therapeutic strategies to improve cell and tissue protection.
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Affiliation(s)
- Jana Riegger
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University Medical Center, 89081, Ulm, Germany.
| | - Astrid Schoppa
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, 89081, Ulm, Germany
| | - Leonie Ruths
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University Medical Center, 89081, Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, 89081, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, 89081, Ulm, Germany
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21
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Cooper ID, Kyriakidou Y, Petagine L, Edwards K, Elliott BT. Bio-Hacking Better Health-Leveraging Metabolic Biochemistry to Maximise Healthspan. Antioxidants (Basel) 2023; 12:1749. [PMID: 37760052 PMCID: PMC10525476 DOI: 10.3390/antiox12091749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD+ to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD+ availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.
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Affiliation(s)
- Isabella D. Cooper
- Ageing Biology and Age-Related Diseases, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK; (Y.K.); (L.P.); (K.E.); (B.T.E.)
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22
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Abdelmaksoud NM, Abulsoud AI, Abdelghany TM, Elshaer SS, Rizk SM, Senousy MA. Mitochondrial remodeling in colorectal cancer initiation, progression, metastasis, and therapy: A review. Pathol Res Pract 2023; 246:154509. [PMID: 37182313 DOI: 10.1016/j.prp.2023.154509] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
Colorectal cancer (CRC) is a major health concern with multifactorial pathophysiology representing intense therapeutic challenges. It is well known that deregulation of spatiotemporally-controlled signaling pathways and their metabolic reprogramming effects play a pivotal role in the development and progression of CRC. As such, the mitochondrial role in CRC initiation gained a lot of attention recently, as it is considered the powerhouse that regulates the bioenergetics in CRC. In addition, the crosstalk between microRNAs (miRNAs) and mitochondrial dysfunction has become a newfangled passion for deciphering CRC molecular mechanisms. This review sheds light on the relationship between different signaling pathways involved in metabolic reprogramming and their therapeutic targets, alterations in mitochondrial DNA content, mitochondrial biogenesis, and mitophagy, and the role of polymorphisms in mitochondrial genes as well as miRNAs regulating mitochondrial proteins in CRC initiation, progression, metastasis, and resistance to various therapies.
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Affiliation(s)
- Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11823, Egypt.
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Sherine Maher Rizk
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt
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23
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Yoon J, Ku D, Lee M, Lee N, Im SG, Kim Y. Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress. Int J Mol Sci 2023; 24:ijms24087403. [PMID: 37108567 PMCID: PMC10138523 DOI: 10.3390/ijms24087403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/31/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington's disease, osteoarthritis, and autoimmune Sjögren's syndrome. Yet, small chemicals that can protect cells from a mt-dsRNA-mediated immune response remain largely unexplored. Here, we investigate the potential of resveratrol (RES), a plant-derived polyphenol with antioxidant properties, on suppressing mt-dsRNA-mediated immune activation. We show that RES can revert the downstream response to immunogenic stressors that elevate mitochondrial RNA expressions, such as stimulation by exogenous dsRNAs or inhibition of ATP synthase. Through high-throughput sequencing, we find that RES can regulate mt-dsRNA expression, interferon response, and other cellular responses induced by these stressors. Notably, RES treatment fails to counter the effect of an endoplasmic reticulum stressor that does not affect the expression of mitochondrial RNAs. Overall, our study demonstrates the potential usage of RES to alleviate the mt-dsRNA-mediated immunogenic stress response.
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Affiliation(s)
- Jimin Yoon
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Doyeong Ku
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Minseok Lee
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Namseok Lee
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Sung Gap Im
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
- KAIST Institute for NanoCentury (KINC), Daejeon 34141, Republic of Korea
| | - Yoosik Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
- KAIST Institute for Health Science and Technology (KIHST), Daejeon 34141, Republic of Korea
- KAIST Institute for BioCentury (KIB), Daejeon 34141, Republic of Korea
- BioProcess Engineering Research Center and BioInformatics Research Center, KAIST, Daejeon 34141, Republic of Korea
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24
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Tiberi J, Cesarini V, Stefanelli R, Canterini S, Fiorenza MT, Rosa PL. Sex differences in antioxidant defence and the regulation of redox homeostasis in physiology and pathology. Mech Ageing Dev 2023; 211:111802. [PMID: 36958540 DOI: 10.1016/j.mad.2023.111802] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/25/2023]
Abstract
Reactive oxygen species (ROS) is a term that defines a group of unstable compounds derived from exogenous sources or endogenous metabolism. Under physiological conditions, low levels of ROS play a key role in the regulation of signal transduction- or transcription-mediated cellular responses. In contrast, excessive and uncontrolled loading of ROS results in a pathological state known as oxidative stress (OS), a leading contributor to aging and a pivotal factor for the onset and progression of many disorders. Evolution has endowed cells with an antioxidant system involved in stabilizing ROS levels to a specific threshold, preserving ROS-induced signalling function and limiting negative side effects. In mammals, a great deal of evidence indicates that females defence against ROS is more proficient than males, determining a longer lifespan and lower incidence of most chronic diseases. In this review, we will summarize the most recent sex-related differences in the regulation of redox homeostasis. We will highlight the peculiar aspects of the antioxidant defence in sex-biased diseases whose onset or progression is driven by OS, and we will discuss the molecular, genetic, and evolutionary determinants of female proficiency to cope with ROS.
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Affiliation(s)
- Jessica Tiberi
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; PhD program in Behavioral Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Valeriana Cesarini
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Roberta Stefanelli
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Sonia Canterini
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Maria Teresa Fiorenza
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Piergiorgio La Rosa
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy.
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25
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Ryanto GRT, Suraya R, Nagano T. Mitochondrial Dysfunction in Pulmonary Hypertension. Antioxidants (Basel) 2023; 12:372. [PMID: 36829931 PMCID: PMC9952650 DOI: 10.3390/antiox12020372] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/21/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Pulmonary hypertension (PH) is a multi-etiological condition with a similar hemodynamic clinical sign and end result of right heart failure. Although its causes vary, a similar link across all the classifications is the presence of mitochondrial dysfunction. Mitochondria, as the powerhouse of the cells, hold a number of vital roles in maintaining normal cellular homeostasis, including the pulmonary vascular cells. As such, any disturbance in the normal functions of mitochondria could lead to major pathological consequences. The Warburg effect has been established as a major finding in PH conditions, but other mitochondria-related metabolic and oxidative stress factors have also been reported, making important contributions to the progression of pulmonary vascular remodeling that is commonly found in PH pathophysiology. In this review, we will discuss the role of the mitochondria in maintaining a normal vasculature, how it could be altered during pulmonary vascular remodeling, and the therapeutic options available that can treat its dysfunction.
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Affiliation(s)
- Gusty Rizky Teguh Ryanto
- Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe 658-8558, Japan
| | - Ratoe Suraya
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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26
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Sharma A, Chabloz S, Lapides RA, Roider E, Ewald CY. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients 2023; 15:nu15020445. [PMID: 36678315 PMCID: PMC9861325 DOI: 10.3390/nu15020445] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.
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Affiliation(s)
- Arastu Sharma
- Laboratory of Extracellular Matrix Regeneration, Department of Health Sciences and Technology, Institute of Translational Medicine, ETH Zürich, 8603 Schwerzenbach, Switzerland
- AVEA Life AG, Bahnhofplatz, 6300 Zug, Switzerland
| | | | - Rebecca A. Lapides
- Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland
- Robert Larner, MD College of Medicine at the University of Vermont, Burlington, VT 05405, USA
| | - Elisabeth Roider
- Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Maximon AG, Bahnhofplatz, 6300 Zug, Switzerland
| | - Collin Y. Ewald
- Laboratory of Extracellular Matrix Regeneration, Department of Health Sciences and Technology, Institute of Translational Medicine, ETH Zürich, 8603 Schwerzenbach, Switzerland
- Correspondence:
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27
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Ye Z, Chai R, Luan Y, Du Y, Xue W, Shi S, Wu H, Wei Y, Zhang L, Hu Y. Trends in mitochondrial unfolded protein response research from 2004 to 2022: A bibliometric analysis. Front Cell Dev Biol 2023; 11:1146963. [PMID: 37035249 PMCID: PMC10079909 DOI: 10.3389/fcell.2023.1146963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/17/2023] [Indexed: 04/11/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is a stress response pathway that regulates the expression of mitochondrial chaperones, proteases, and other proteins involved in protein folding and degradation, thereby ensuring proper mitochondrial function. In addition to this critical function, the UPRmt also plays a role in other cellular processes such as mitochondrial biogenesis, energy metabolism, and cellular signaling. Moreover, the UPRmt is strongly associated with various diseases. From 2004 to 2022, there has been a lot of interest in UPRmt. The present study aims to utilized bibliometric tools to assess the genesis, current areas of focus, and research trends pertaining to UPRmt, thereby highlighting avenues for future research. There were 442 papers discovered to be related to UPRmt, with the overall number of publications rising yearly. International Journal of Molecular Sciences was the most prominent journal in this field. 2421 authors from 1,402 institutions in 184 nations published studies on UPRmt. The United States was the most productive country (197 documents). The top three authors were Johan Auwerx, Cole M Haynes, and Dongryeol Ryu. The early focus of UPRmt is "protein." And then the UPRmt research shifted from Caenorhabditis elegans back to mammals, and its close link to aging and various diseases. The top emerging research hotspots are neurodegenerative diseases and metabolic diseases. These findings provide the trends and frontiers in the field of UPRmt, and valuable information for clinicians and scientists to identify new perspectives with potential collaborators and cooperative countries.
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Affiliation(s)
| | | | | | | | | | | | | | - Yi Wei
- *Correspondence: Yi Wei, ; Limei Zhang, ; Yuanhui Hu,
| | - Limei Zhang
- *Correspondence: Yi Wei, ; Limei Zhang, ; Yuanhui Hu,
| | - Yuanhui Hu
- *Correspondence: Yi Wei, ; Limei Zhang, ; Yuanhui Hu,
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28
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Hinkle JS, Rivera CN, Vaughan RA. Branched-Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary. Mol Nutr Food Res 2022; 66:e2200109. [PMID: 36047448 PMCID: PMC9786258 DOI: 10.1002/mnfr.202200109] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/17/2022] [Indexed: 12/30/2022]
Abstract
Branched-chain amino acids (BCAA) are essential in the diet and promote several vital cell responses which may have benefits for health and athletic performance, as well as disease prevention. While BCAA are well-known for their ability to stimulate muscle protein synthesis, their effects on cell energetics are also becoming well-documented, but these receive less attention. In this review, much of the current evidence demonstrating BCAA ability (as individual amino acids or as part of dietary mixtures) to alter regulators of cellular energetics with an emphasis on mitochondrial biogenesis and related signaling is highlighted. Several studies have shown, both in vitro and in vivo, that BCAA (either individual or as a mixture) may promote signaling associated with increased mitochondrial biogenesis including the upregulation of master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as numerous downstream targets and related function. However, sparse data in humans and the difficulty of controlling variables associated with feeding studies leave the physiological relevance of these findings unclear. Future well-controlled diet studies will be needed to assess if BCAA consumption is associated with increased mitochondrial biogenesis and improved metabolic outcomes in healthy and/or diseased human populations.
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Affiliation(s)
- Jason S. Hinkle
- Department of Exercise ScienceHigh Point UniversityHigh PointNC27262‐3598USA
| | - Caroline N. Rivera
- Department of Exercise ScienceHigh Point UniversityHigh PointNC27262‐3598USA
| | - Roger A. Vaughan
- Department of Exercise ScienceHigh Point UniversityHigh PointNC27262‐3598USA
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29
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Guajardo-Correa E, Silva-Agüero JF, Calle X, Chiong M, Henríquez M, García-Rivas G, Latorre M, Parra V. Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases. Front Cell Dev Biol 2022; 10:968373. [PMID: 36187489 PMCID: PMC9516331 DOI: 10.3389/fcell.2022.968373] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/25/2022] [Indexed: 11/29/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Epidemiological studies indicate that pre-menopausal women are more protected against the development of CVDs compared to men of the same age. This effect is attributed to the action/effects of sex steroid hormones on the cardiovascular system. In this context, estrogen modulates cardiovascular function in physiological and pathological conditions, being one of the main physiological cardioprotective agents. Here we describe the common pathways and mechanisms by which estrogens modulate the retrograde and anterograde communication between the nucleus and mitochondria, highlighting the role of genomic and non-genomic pathways mediated by estrogen receptors. Additionally, we discuss the presumable role of bromodomain-containing protein 4 (BRD4) in enhancing mitochondrial biogenesis and function in different CVD models and how this protein could act as a master regulator of estrogen protective activity. Altogether, this review focuses on estrogenic control in gene expression and molecular pathways, how this activity governs nucleus-mitochondria communication, and its projection for a future generation of strategies in CVDs treatment.
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Affiliation(s)
- Emanuel Guajardo-Correa
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Juan Francisco Silva-Agüero
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Ximena Calle
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago, Chile
- Center of Applied Nanoscience (CANS), Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile
| | - Mario Chiong
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Mauricio Henríquez
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Red para el Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile
| | - Gerardo García-Rivas
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, Mexico
- Tecnológico de Monterrey, The Institute for Obesity Research, Hospital Zambrano Hellion, San Pedro Garza Garcia, Nuevo León, Mexico
| | - Mauricio Latorre
- Laboratorio de Bioingeniería, Instituto de Ciencias de la Ingeniería, Universidad de O’Higgins, Rancagua, Chile
- Laboratorio de Bioinformática y Expresión Génica, INTA, Universidad de Chile, Santiago, Chile
| | - Valentina Parra
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- Red para el Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile
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Shelton MG, Kerns KA, Castora FJ, Coleman RA. Incorporating Mitochondrial Gene Expression Changes Within a Testable Mathematical Model for Alzheimer’s Disease: Stress Response Modulation Predicts Potential Therapeutic Targets. J Alzheimers Dis 2022; 90:109-117. [DOI: 10.3233/jad-220163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background: Alzheimer’s disease is a specific form of dementia characterized by the aggregation of amyloid-β plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of cellular respiration and the production of radical oxygen species. Proteomic data shows that these changes are also related to unique gene expression patterns. Objective: This study is designed to incorporate both proteomic and gene expression data into a testable mathematical model for AD. Manipulation of this new model allows the identification of potential therapeutic targets for AD. Methods: We investigate the impact of these findings on new therapeutic targets via metabolic flux analysis of sirtuin stress response pathways while also highlighting the importance of metabolic enzyme activity in maintaining proper respiratory activity. Results: Our results indicate that protective changes in SIRT1 and AMPK expression are potential avenues for therapeutics. Conclusion: Combining our mitochondrial gene expression analyses with available protein data allowed the construction of a new mathematical model for AD that provides a useful approach to test the efficacy of potential AD therapeutic targets.
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Affiliation(s)
- Morgan G. Shelton
- Department of Chemistry, The College of William and Mary, Williamsburg, VA, USA
| | - Kimberly A. Kerns
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Frank J. Castora
- Department of Physiological Sciences, Division of Biochemistry, Eastern Virginia Medical School, Norfolk, VA, USA
- Department of Neurology, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Randolph A. Coleman
- Department of Chemistry, The College of William and Mary, Williamsburg, VA, USA
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Baskal S, Beckmann B, Stahmer L, Peter C, Bohnhorst B, Das AM, Tsikas D. Possible role of SIRT1 and SIRT3 in post-translational modifications in human breast milk during the neonatal period. Amino Acids 2022; 54:1611-1619. [PMID: 35976439 DOI: 10.1007/s00726-022-03197-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/02/2022] [Indexed: 11/30/2022]
Abstract
We measured free and proteinic concentrations of native and modified amino acids from post-translational modifications (PTMs) and correlated them with the activity of SIRT1 and SIRT3 in the pellet and aqueous phases of human breast milk samples of ten lactating women during the neonatal period. SIRT1 and SIRT3 correlated directly with citrullination, asymmetric dimethylation and glycation of L-arginine, hydroxylation and glycation of L-lysine. SIRT1 and SIRT3 correlated inversely with the hydroxylation of L-proline. SIRT1 and SITR3 tended to correlate inversely with oxidative stress measured as malondialdehyde. Our study suggests that SIRT1 and SIRT3 may modulate PTMs in human breast milk cells.
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Affiliation(s)
- Svetlana Baskal
- Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Bibiana Beckmann
- Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Laura Stahmer
- Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30623, Hannover, Germany
| | - Corinna Peter
- Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30623, Hannover, Germany
| | - Bettina Bohnhorst
- Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30623, Hannover, Germany
| | - Anibh Martin Das
- Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30623, Hannover, Germany
| | - Dimitrios Tsikas
- Institute of Toxicology, Core Unit Proteomics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
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Altınova AE. Beige Adipocyte as the Flame of White Adipose Tissue: Regulation of Browning and Impact of Obesity. J Clin Endocrinol Metab 2022; 107:e1778-e1788. [PMID: 34967396 DOI: 10.1210/clinem/dgab921] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Indexed: 11/19/2022]
Abstract
Beige adipocyte, the third and relatively new type of adipocyte, can emerge in white adipose tissue (WAT) under thermogenic stimulations that is termed as browning of WAT. Recent studies suggest that browning of WAT deserves more attention and therapies targeting browning of WAT can be helpful for reducing obesity. Beyond the major inducers of browning, namely cold and β 3-adrenergic stimulation, beige adipocytes are affected by several factors, and excess adiposity per se may also influence the browning process. The objective of the present review is to provide an overview of recent clinical and preclinical studies on the hormonal and nonhormonal factors that affect the browning of WAT. This review further focuses on the role of obesity per se on browning process.
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Affiliation(s)
- Alev Eroğlu Altınova
- Gazi University Faculty of Medicine, Department of Endocrinology and Metabolism, 06500 Ankara, Turkey
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Rivera ME, Rivera CN, Vaughan RA. Excess branched-chain amino acids alter myotube metabolism and substrate preference which is worsened by concurrent insulin resistance. Endocrine 2022; 76:18-28. [PMID: 34811646 DOI: 10.1007/s12020-021-02939-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/02/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE Branched-chain amino acids (BCAA) have been shown to enhance several cellular signaling pathways including protein synthesis and mitochondrial biogenesis, yet population data demonstrate a correlation between circulating BCAA and severity of insulin resistance which has been hypothesized to be, in part, a byproduct of BCAA inhibition of mitochondrial function. The purpose of this study is to examine the effect of a BCAA mixture on muscle metabolism and related gene expression in vitro. METHODS C2C12 myotubes were treated with a BCAA mixture containing leucine:isoleucine:valine at a ratio of 2:1:1 at 0.2, 2, or 20 mM (based on leucine content) for 6 days. qRT-PCR was used to measure metabolic gene expression. Oxygen consumption and extracellular acidification were used to assess mitochondrial and glycolytic metabolism, respectively. Mitochondrial content was determined via mitochondrial-specific staining. RESULTS Despite significantly elevated mitochondrial staining, 6-day BCAA treatment reduced basal mitochondrial metabolism at a supraphysiological concentration (20 mM) in both insulin sensitive and resistant cells. Peak mitochondrial capacity was also reduced in insulin-resistant (but not insulin sensitive) cells. Conversely, basal glycolytic metabolism was elevated following 20 mM BCAA treatment, regardless of insulin resistance. In addition, insulin-resistant cells treated with 20 mM BCAA exhibited reduced gene expression of Ppargc1a, Cytc, Atp5b, Glut4, and several glycolytic enzymes versus insulin sensitive cells treated with 20 mM BCAA. CONCLUSIONS Collectively, these findings suggest BCAA at supraphysiologically high levels may negatively alter mitochondrial metabolism, and concurrent insulin resistance may also diminish peak mitochondrial capacity, as well as impede molecular adaptations that support a transition to a glycolytic preference/compensation.
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Affiliation(s)
- Madison E Rivera
- Department of Exercise Science, High Point University, High Point, NC, USA
| | - Caroline N Rivera
- Department of Exercise Science, High Point University, High Point, NC, USA
| | - Roger A Vaughan
- Department of Exercise Science, High Point University, High Point, NC, USA.
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Polydatin Attenuates Intra-Uterine Growth Retardation-Induced Liver Injury and Mitochondrial Dysfunction in Weanling Piglets by Improving Energy Metabolism and Redox Balance. Antioxidants (Basel) 2022; 11:antiox11040666. [PMID: 35453351 PMCID: PMC9028342 DOI: 10.3390/antiox11040666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/22/2022] [Accepted: 03/28/2022] [Indexed: 02/08/2023] Open
Abstract
The present study investigated the potential of polydatin to protect against liver injury and the mitochondrial dysfunction of weanling piglets suffering from intra-uterine growth retardation (IUGR). Thirty-six normal birth weight weanling piglets and an equal number of IUGR littermates were given a basal diet with or without polydatin (250 mg/kg) from 21 to 35 d of age. Plasma and liver samples were collected to measure biochemistry parameters at 35 d of age. IUGR caused hepatic apoptosis, mitochondrial dysfunction, and oxidative damage, along with a lower efficiency of energy metabolism and inferior antioxidant ability. Polydatin decreased apoptotic rate, improved the features of mitochondrial damage, inhibited mitochondrial swelling and superoxide anion formation, and preserved mitochondrial membrane potential in the liver. Concurrently, polydatin promoted mitochondrial biogenesis, increased sirtuin 1 activity, and upregulated the expression levels of several genes related to mitochondrial function and fitness. Polydatin also facilitated mitochondrial oxidative metabolism with a beneficial outcome of increased energy production. Furthermore, polydatin mitigated the IUGR-induced reduction in manganese superoxide dismutase activity and prevented the excessive accumulation of oxidative damaging products in the liver. These findings indicate that polydatin confers protection against hepatic injury and mitochondrial dysfunction in the IUGR piglets by improving energy metabolism and redox balance.
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Barcena ML, Aslam M, Pozdniakova S, Norman K, Ladilov Y. Cardiovascular Inflammaging: Mechanisms and Translational Aspects. Cells 2022; 11:cells11061010. [PMID: 35326461 PMCID: PMC8946971 DOI: 10.3390/cells11061010] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/07/2022] [Accepted: 03/15/2022] [Indexed: 12/14/2022] Open
Abstract
Aging is one of the major non-reversible risk factors for several chronic diseases, including cancer, type 2 diabetes, dementia, and cardiovascular diseases (CVD), and it is a key cause of multimorbidity, disability, and frailty (decreased physical activity, fatigue, and weight loss). The underlying cellular mechanisms are complex and consist of multifactorial processes, such as telomere shortening, chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, accumulation of senescent cells, and reduced autophagy. In this review, we focused on the molecular mechanisms and translational aspects of cardiovascular aging-related inflammation, i.e., inflammaging.
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Affiliation(s)
- Maria Luisa Barcena
- Department of Geriatrics and Medical Gerontology, Charité—Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; (S.P.); (K.N.); (Y.L.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
- Correspondence: ; Tel.: +49-30-450-525-359
| | - Muhammad Aslam
- Experimental Cardiology, Department of Internal Medicine I, Justus Liebig University, Aulweg 129, 35392 Giessen, Germany;
- Department of Cardiology, Kerckhoff Clinic GmbH, 61231 Bad Nauheim, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Rhein-Main, 61231 Bad Nauheim, Germany
| | - Sofya Pozdniakova
- Department of Geriatrics and Medical Gerontology, Charité—Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; (S.P.); (K.N.); (Y.L.)
- Barcelona Biomedical Research Park (PRBB), Barcelona Institute for Global Health (ISGlobal), Doctor Aiguader, 88, 08003 Barcelona, Spain
| | - Kristina Norman
- Department of Geriatrics and Medical Gerontology, Charité—Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; (S.P.); (K.N.); (Y.L.)
- Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
- Department of Nutrition & Gerontology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
| | - Yury Ladilov
- Department of Geriatrics and Medical Gerontology, Charité—Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; (S.P.); (K.N.); (Y.L.)
- Department of Cardiovascular Surgery, Heart Center Brandenburg, Brandenburg Medical School Theodor Fontane, University Hospital, Ladeburger Str. 17, 16321 Bernau, Germany
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Peng X, Hou R, Yang Y, Luo Z, Cao Y. Current Studies of Mitochondrial Quality Control in the Preeclampsia. Front Cardiovasc Med 2022; 9:836111. [PMID: 35295266 PMCID: PMC8920482 DOI: 10.3389/fcvm.2022.836111] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/02/2022] [Indexed: 01/22/2023] Open
Abstract
Mitochondria are cellular energy powerhouses that play important roles in regulating cellular processes. Mitochondrial quality control (mQC), including mitochondrial biogenesis, mitophagy, mitochondrial fusion and fission, maintains physiological demand and adapts to changed conditions. mQC has been widely investigated in neurodegeneration, cardiovascular disease and cancer because of the high demand for ATP in these diseases. Although placental implantation and fetal growth similarly require a large amount of energy, the investigation of mQC in placental-originated preeclampsia (PE) is limited. We elucidate mitochondrial morphology and function in different pregnancy stages, outline the role of mQC in cellular homeostasis and PE and summarize the current findings of mQC-related PE studies. This review also provides suggestions on the future investigation of mQC in PE, which will lead to the development of new prevention and therapy strategies for PE.
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Affiliation(s)
- Xiaoqing Peng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China
- School of Pharmacy, Anhui Medical University, Hefei, China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Ruirui Hou
- School of Pharmacy, Anhui Medical University, Hefei, China
- The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, China
| | - Yuanyuan Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhigang Luo
- Department of Cardiovascular, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Zhigang Luo
| | - Yunxia Cao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China
- *Correspondence: Yunxia Cao
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Chung JY, Kim OY, Song J. Role of ketone bodies in diabetes-induced dementia: sirtuins, insulin resistance, synaptic plasticity, mitochondrial dysfunction, and neurotransmitter. Nutr Rev 2021; 80:774-785. [PMID: 34957519 PMCID: PMC8907488 DOI: 10.1093/nutrit/nuab118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Abstract
Patients with type 2 diabetes can have several neuropathologies, such as memory deficits. Recent studies have focused on the association between metabolic imbalance and neuropathological problems, and the associated molecular pathology. Diabetes triggers neuroinflammation, impaired synaptic plasticity, mitochondrial dysfunction, and insulin resistance in the brain. Glucose is a main energy substrate for neurons, but under certain conditions, such as fasting and starvation, ketone bodies can be used as an energy fuel for these cells. Recent evidence has shed new light on the role of ketone bodies in regulating several anti-inflammation cellular pathways and improving glucose metabolism, insulin action, and synaptic plasticity, thereby being neuroprotective. However, very high amount of ketone bodies can be toxic for the brain, such as in ketoacidosis, a dangerous complication that may occur in type 1 diabetes mellitus or alcoholism. Recent findings regarding the relationship between ketone bodies and neuropathogenesis in dementia are reviewed in this article. They suggest that the adequately low amount of ketone bodies can be a potential energy source for the treatment of diabetes-induced dementia neuropathology, considering the multifaceted effects of the ketone bodies in the central nervous system. This review can provide useful information for establishing the therapeutic guidelines of a ketogenic diet for diabetes-induced dementia.
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Affiliation(s)
- Ji Yeon Chung
- Department of Neurology, Chosun University Medical School, Gwangju, Republic of Korea
| | - Oh Yoen Kim
- Department of Food Science and Nutrition and the Department of Health Sciences, Dong-A University, Busan, Republic of Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, Republic of Korea
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Nishigaki A, Tsubokura H, Tsuzuki-Nakao T, Okada H. Hypoxia: Role of SIRT1 and the protective effect of resveratrol in ovarian function. Reprod Med Biol 2021; 21:e12428. [PMID: 34934403 PMCID: PMC8656197 DOI: 10.1002/rmb2.12428] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/09/2021] [Indexed: 12/27/2022] Open
Abstract
Background Ovarian function is closely related to the degree of vascular network development surrounding the ovary. Maternal aging‐related construction defects in this vascular network can cause ovarian hypoxia, which impedes oocyte nutrient supply, leading to physiological changes in the ovaries and oocytes. The anti‐aging gene Sirtuin 1 (SIRT1) senses and adapts to ambient stress and is associated with hypoxic environments and mitochondrial biogenesis. Methods The present study is a literature review focusing on investigations involving the changes in SIRT1 and mitochondrial expression during hypoxia and the cytoprotective effects of the SIRT1 activator, resveratrol. Main findings Hypoxia suppresses SIRT1 and mitochondrial expression. Resveratrol can reverse the hypoxia‐induced decrease in mitochondrial and SIRT1 activity. Resveratrol suppresses the production of hypoxia‐inducible factor‐1α and vascular endothelial growth factor proteins. Conclusion Resveratrol exhibits protective activity against hypoxic stress and may prevent hypoxia‐ or aging‐related mitochondrial dysfunction. Resveratrol treatment may be a potential option for infertility therapy.
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Affiliation(s)
- Akemi Nishigaki
- Department of Obstetrics and Gynecology Kansai Medical University Osaka Japan
| | - Hiroaki Tsubokura
- Department of Obstetrics and Gynecology Kansai Medical University Osaka Japan
| | | | - Hidetaka Okada
- Department of Obstetrics and Gynecology Kansai Medical University Osaka Japan
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Unveiling Metabolic Vulnerability and Plasticity of Human Osteosarcoma Stem and Differentiated Cells to Improve Cancer Therapy. Biomedicines 2021; 10:biomedicines10010028. [PMID: 35052705 PMCID: PMC8773137 DOI: 10.3390/biomedicines10010028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 01/01/2023] Open
Abstract
Defining the metabolic phenotypes of cancer-initiating cells or cancer stem cells and of their differentiated counterparts might provide fundamental knowledge for improving or developing more effective therapies. In this context we extensively characterized the metabolic profiles of two osteosarcoma-derived cell lines, the 3AB-OS cancer stem cells and the parental MG-63 cells. To this aim Seahorse methodology-based metabolic flux analysis under a variety of conditions complemented with real time monitoring of cell growth by impedentiometric technique and confocal imaging were carried out. The results attained by selective substrate deprivation or metabolic pathway inhibition clearly show reliance of 3AB-OS on glycolysis and of MG-63 on glutamine oxidation. Treatment of the osteosarcoma cell lines with cisplatin resulted in additive inhibitory effects in MG-63 cells depleted of glutamine whereas it antagonized under selective withdrawal of glucose in 3AB-OS cells thereby manifesting a paradoxical pro-survival, cell-cycle arrest in S phase and antioxidant outcome. All together the results of this study highlight that the efficacy of specific metabolite starvation combined with chemotherapeutic drugs depends on the cancer compartment and suggest cautions in using it as a generalizable curative strategy.
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Brenmoehl J, Walz C, Caffier C, Brosig E, Walz M, Ohde D, Trakooljul N, Langhammer M, Ponsuksili S, Wimmers K, Zettl UK, Hoeflich A. Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP). Cells 2021; 10:3418. [PMID: 34943926 PMCID: PMC8699648 DOI: 10.3390/cells10123418] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023] Open
Abstract
The somatotropic axis is required for a number of biological processes, including growth, metabolism, and aging. Due to its central effects on growth and metabolism and with respect to its positive effects on muscle mass, regulation of the GH/IGF-system during endurance exercise is of particular interest. In order to study the control of gene expression and adaptation related to physical performance, we used a non-inbred mouse model, phenotype-selected for high running performance (DUhTP). Gene expression of the GH/IGF-system and related signaling cascades were studied in the pituitary gland and muscle of sedentary males of marathon and unselected control mice. In addition, the effects of three weeks of endurance exercise were assessed in both genetic groups. In pituitary glands from DUhTP mice, reduced expression of Pou1f1 (p = 0.002) was accompanied by non-significant reductions of Gh mRNA (p = 0.066). In addition, mRNA expression of Ghsr and Sstr2 were significantly reduced in the pituitary glands from DUhTP mice (p ≤ 0.05). Central downregulation of Pou1f1 expression was accompanied by reduced serum concentrations of IGF1 and coordinated downregulation of multiple GH/IGF-signaling compounds in muscle (e.g., Ghr, Igf1, Igf1r, Igf2r, Irs1, Irs2, Akt3, Gskb, Pik3ca/b/a2, Pten, Rictor, Rptor, Tsc1, Mtor; p ≤ 0.05). In response to exercise, the expression of Igfbp3, Igfbp 4, and Igfbp 6 and Stc2 mRNA was increased in the muscle of DUhTP mice (p ≤ 0.05). Training-induced specific activation of AKT, S6K, and p38 MAPK was found in muscles from control mice but not in DUhTP mice (p ≤ 0.05), indicating a lack of mTORC1 and mTORC2 activation in marathon mice in response to physical exercise. While hormone-dependent mTORC1 and mTORC2 pathways in marathon mice were repressed, robust increases of Ragulator complex compounds (p ≤ 0.001) and elevated sirtuin 2 to 6 mRNA expression were observed in the DUhTP marathon mouse model (p ≤ 0.05). Activation of AMPK was not observed under the experimental conditions of the present study. Our results describe coordinated downregulation of the somatotropic pathway in long-term selected marathon mice (DUhTP), possibly via the pituitary gland and muscle interaction. Our results, for the first time, demonstrate that GH/IGF effects are repressed in a context of superior running performance in mice.
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Affiliation(s)
- Julia Brenmoehl
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Christina Walz
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Caroline Caffier
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
- Department of Neurology, Neuroimmunological Section, University Medicine Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany;
| | - Elli Brosig
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
- Department of Neurology, Neuroimmunological Section, University Medicine Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany;
| | - Michael Walz
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Daniela Ohde
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Nares Trakooljul
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Martina Langhammer
- Lab Animal Facility, Research Institute for Genetics and Biometry, Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany;
| | - Siriluck Ponsuksili
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Klaus Wimmers
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
| | - Uwe K. Zettl
- Department of Neurology, Neuroimmunological Section, University Medicine Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany;
| | - Andreas Hoeflich
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany; (J.B.); (C.W.); (C.C.); (E.B.); (M.W.); (D.O.); (N.T.); (S.P.); (K.W.)
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Hassan FE, Sakr HI, Mohie PM, Suliman HS, Mohamed AS, Attia MH, Eid DM. Pioglitazone improves skeletal muscle functions in reserpine-induced fibromyalgia rat model. Ann Med 2021; 53:1032-1040. [PMID: 34233552 PMCID: PMC8274527 DOI: 10.1080/07853890.2021.1916069] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/24/2021] [Accepted: 04/03/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) is characterized by musculoskeletal pain, fatigue, sleep and memory disturbance. There is no definitive cure yet for FM-related health problems. Peroxisome proliferator-activated receptor's (PPAR's) activation is associated with insulin sensitisation and improved glucose metabolism. PPAR-γ was reported to alleviate FM allodynia. Limited data are discussing its effect on motor disorders. OBJECTIVE To investigate the potential effect of PPAR-γ agonists (pioglitazone, as one member of thiazolidinediones (TZD)) on motor dysfunction in reserpine-induced FM in a rat model. MATERIALS AND METHODS Thirty-six male Wistar rats were divided into negative control (n = 9) and reserpine-induced FM (n = 27) groups. The latter was subdivided into three equal subgroups (n = 9), positive control (untreated FM model), pioglitazone-treated and GW9662-treated. We evaluated muscle functions and activity of chloramphenicol acetyltransferase, superoxide dismutase, malondialdehyde, and serum levels of interleukin-8 and monocyte chemoattractant protein-1. RESULTS Pioglitazone significantly relieved fatigue, improved muscle performance, reduced inflammatory cytokines and enhanced antioxidant's activity, while GW9662, a known PPAR-γ antagonist, aggravated the FM manifestations in the rat model. CONCLUSION PPAR-γ agonists show a promising role against FM-associated motor dysfunctions.
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Affiliation(s)
- Fatma E. Hassan
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Egypt
| | - Hader I. Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Egypt
- Department of Medical Physiology, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Passant M. Mohie
- Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Egypt
| | - Howayda Saeed Suliman
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Egypt
| | | | - Mohamed H. Attia
- Internal Medicine Department, Faculty of Medicine, Ain Shams University, Egypt
| | - Dalia M. Eid
- Department of Biochemistry, Faculty of Medicine, Ain Shams University, Egypt
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Song H, Polster BM, Thompson LP. Chronic hypoxia alters cardiac mitochondrial complex protein expression and activity in fetal guinea pigs in a sex-selective manner. Am J Physiol Regul Integr Comp Physiol 2021; 321:R912-R924. [PMID: 34730023 PMCID: PMC8714812 DOI: 10.1152/ajpregu.00004.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 10/22/2021] [Accepted: 10/22/2021] [Indexed: 11/22/2022]
Abstract
We hypothesize that intrauterine hypoxia (HPX) alters the mitochondrial phenotype in fetal hearts contributing to developmental programming. Pregnant guinea pigs were exposed to normoxia (NMX) or hypoxia (HPX, 10.5% O2), starting at early [25 days (25d), 39d duration] or late gestation (50d, 14d duration). Near-term (64d) male and female fetuses were delivered by hysterotomy from anesthetized sows, and body/organ weights were measured. Left ventricles of fetal hearts were excised and frozen for measurement of expression of complex (I-V) subunits, fusion (Mfn2/OPA1) and fission (DRP1/Fis1) proteins, and enzymatic rates of I and IV from isolated mitochondrial proteins. Chronic HPX decreased fetal body weight and increased relative placenta weight regardless of timing. Early-onset HPX increased I, III, and V subunit levels, increased complex I but decreased IV activities in males but not females (all P < 0.05). Late-onset HPX decreased (P < 0.05) I, III, and V levels in both sexes but increased I and decreased IV activities in males only. Both HPX conditions decreased cardiac mitochondrial DNA content in males only. Neither early- nor late-onset HPX had any effect on Mfn2 levels but increased OPA1 in both sexes. Both HPX treatments increased DRP1/Fis1 levels in males. In females, early-onset HPX increased DRP1 with no effect on Fis1, whereas late-onset HPX increased Fis1 with no effect on DRP1. We conclude that both early- and late-onset HPX disrupts the expression/activities of select complexes that could reduce respiratory efficiency and shifts dynamics toward fission in fetal hearts. Thus, intrauterine HPX disrupts the mitochondrial phenotype predominantly in male fetal hearts, potentially altering cardiac metabolism and predisposing the offspring to heart dysfunction.
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Affiliation(s)
- Hong Song
- Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Brian M Polster
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Loren P Thompson
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, School of Medicine, University of Maryland, Baltimore, Maryland
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AICAR stimulates mitochondrial biogenesis and BCAA catabolic enzyme expression in C2C12 myotubes. Biochimie 2021; 195:77-85. [PMID: 34798200 DOI: 10.1016/j.biochi.2021.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/27/2021] [Accepted: 11/11/2021] [Indexed: 11/21/2022]
Abstract
Type 2 diabetes is characterized by reduced insulin sensitivity, elevated blood metabolites, and reduced mitochondrial metabolism. Insulin resistant populations often exhibit reduced expression of genes governing mitochondrial metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Interestingly, PGC-1α regulates the expression of branched-chain amino acid (BCAA) metabolism, and thus, the consistently observed increased circulating levels of BCAA in diabetics may be partially explained by reduced PGC-1α expression. Conversely, PGC-1α upregulation appears to increase BCAA catabolism. PGC-1α activity is regulated by 5'-AMP-activated protein kinase (AMPK), however, only limited experimental data exists on the effect of AMPK activation in the regulation of BCAA catabolism. The present report examined the effects of the commonly used AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) on the metabolism and expression of several related targets (including BCAA catabolic enzymes) of cultured myotubes. C2C12 myotubes were treated with AICAR at 1 mM for up to 24 h. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via qRT-PCR and western blot, respectively. AICAR treatment significantly increased mitochondrial content and peak mitochondrial capacity. AICAR treatment also increased AMPK activation and mRNA expression of several regulators of mitochondrial biogenesis but reduced glycolytic metabolism and mRNA expression of several glycolytic enzymes. Interestingly, branched-chain alpha-keto acid dehydrogenase a (BCKDHa) protein was significantly increased following AICAR-treatment suggesting increased overall BCAA catabolic capacity in AICAR-treated cells. Together, these experiments demonstrate AICAR/AMPK activation can upregulate BCAA catabolic machinery in a model of skeletal muscle.
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Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy. Chin Med 2021; 16:115. [PMID: 34758848 PMCID: PMC8579168 DOI: 10.1186/s13020-021-00528-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/31/2021] [Indexed: 12/12/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, modulates the activities of several substrates involving in autophagy and energy metabolism. Honokiol (HK) is a natural lignan from the plants of Magnolia genus that exhibits potent liver protective property. Methods AML12 was challenged with 500 μM palmitic acid and 250 μM oleic acid mixture solution to induce lipotoxicity. C57BL/6J mice were fed with a choline-deficient high fat diet (CDHFD) to generate liver steatosis. The expression of autophagy-related and AMP-activated protein kinase (AMPK) pathway proteins was evaluated by Western blotting and immunofluorescence staining. Intracellular lipid accumulation was validated by Nile red staining. Molecular docking analysis was performed on AutoDock 4.2. Results HK (5 and 10 μM) was found to attenuate lipid accumulation through promoting SIRT3-AMPK-mediated autophagy, mainly on lipid droplets. HK had hydrophobic interaction with amino acid residues (PHE294, GLU323 and VAL324) and NAD+. Moreover, HK improved mitochondrial function to enhance lipolysis, through decreasing the acetylated long-chain acyl-CoA dehydrogenase level. In CDHFD-fed mice, HK (2.5 and 10 mg/Kg) treatment obviously prevented lipid accumulation in the liver. And co-treatment of the AMPK inhibitor, Compound C, almost abolished the above changes. Conclusions These results suggest that HK could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK-lipophagy axis, which might be a potential therapeutic agent against NAFLD.
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Li Y, Wang Q, Li J, Shi B, Liu Y, Wang P. SIRT3 affects mitochondrial metabolic reprogramming via the AMPK-PGC-1α axis in the development of benign prostatic hyperplasia. Prostate 2021; 81:1135-1148. [PMID: 34411320 DOI: 10.1002/pros.24208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Sirtuin 3 (SIRT3) has been reported to share an association with mitochondrial metabolic reprogramming. However, the molecular mechanism underlying is not well understood, especially in benign prostatic hyperplasia (BPH). Therefore, the purpose of this study was to research whether SIRT3 can affect the progression of BPH via the regulation of mitochondrial metabolic reprogramming. METHODS Following the development of a rat model of BPH using testosterone propionate (TP), we extracted prostate tissues from sham-operated and BPH rats. Subsequently, bioinformatics prediction was used to screen the genes differentially expressed in BPH. To verify the role played by SIRT3 in BPH, we injected AAV9-SIRT3 into rats, followed by TP treatment. Prostate epithelial cells (PEC) were treated with TP to assess the mitochondrial morphology, mitochondrial membrane potential, and expression of enzymes related to the oxidative phosphorylation pathway after SIRT3 expression alteration. Finally, we examined the expression of AMPK-PGC-1α pathway in tissues and cells. RESULTS SIRT3 was reduced in the prostate tissues of BPH rats. After overexpression of SIRT3, mitochondrial morphology was more stable in prostate tissues of BPH rats and in TP-treated PEC, with significant increases in mitochondrial membrane potential and in the expression of oxidative phosphorylation-related enzymes in the cytoplasm. Moreover, SIRT3 significantly activated the AMPK-PGC-1α signaling pathway, which maintained the stability of mitochondrial membrane potential as well as mitochondrial structure, thus alleviating the symptoms of BPH. CONCLUSION SIRT3 maintained the stability of mitochondrial membrane potential as well as mitochondrial structure by activating the AMPK-PGC-1α pathway, thereby alleviating the symptoms of BPH.
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Affiliation(s)
- Yongzhi Li
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qian Wang
- Key Laboratory of Medical Cell Biology, Ministry of Education, Department of Cell Biology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Jingyu Li
- Department of Urology, Dandong Central Hospital, Dandong, Liaoning, China
| | - Benkang Shi
- Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yili Liu
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ping Wang
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Curry AM, Cohen I, Zheng S, Wohlfahrt J, White DS, Donu D, Cen Y. Profiling sirtuin activity using Copper-free click chemistry. Bioorg Chem 2021; 117:105413. [PMID: 34655842 DOI: 10.1016/j.bioorg.2021.105413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/06/2021] [Accepted: 10/05/2021] [Indexed: 11/16/2022]
Abstract
The mammalian sirtuins are a group of posttranslational modification enzymes that remove acyl modifications from lysine residues in an NAD+-dependent manner. Although initially proposed as histone deacetylases (HDACs), they are now known to target other cellular enzymes and proteins as well. Sirtuin-catalyzed simple amide hydrolysis has profound biological consequences including suppression of gene expression, promotion of DNA damage repair, and regulation of glucose and lipid metabolism. Human sirtuins have been intensively pursued by both academia and industry as potential therapeutic targets for the treatment of diseases such as cancer and neurodegeneration. To gain a better understanding of their roles in various cellular events, innovative chemical probes are highly sought after. This current study focuses on the development of activity-based chemical probes (ABPs) for the profiling of sirtuin activity in biological samples. Cyclooctyne-containing and azido-containing probes were synthesized to enable the subsequent copper-free "click" conjugation to either a fluorophore or biotin. The two groups of structurally related ABPs demonstrated different labeling efficiency and selectivity: the cyclooctyne-containing probes failed to label recombinant sirtuins to any appreciable level, while the azido-containing ABPs showed good isoform selectivity. The azido-containing ABPs were further analyzed for their ability to label an individual sirtuin isoform in protein mixtures and cell lysates. These biocompatible ABPs allow the study of dynamic cellular protein activity change to become possible.
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Affiliation(s)
- Alyson M Curry
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States
| | - Ian Cohen
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, United States
| | - Song Zheng
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, United States
| | - Jessica Wohlfahrt
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, United States
| | - Dawanna S White
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States
| | - Dickson Donu
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States
| | - Yana Cen
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, United States.
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Galvan DL, Mise K, Danesh FR. Mitochondrial Regulation of Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:745279. [PMID: 34646847 PMCID: PMC8502854 DOI: 10.3389/fmed.2021.745279] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022] Open
Abstract
The role and nature of mitochondrial dysfunction in diabetic kidney disease (DKD) has been extensively studied. Yet, the molecular drivers of mitochondrial remodeling in DKD are poorly understood. Diabetic kidney cells exhibit a cascade of mitochondrial dysfunction ranging from changes in mitochondrial morphology to significant alterations in mitochondrial biogenesis, biosynthetic, bioenergetics and production of reactive oxygen species (ROS). How these changes individually or in aggregate contribute to progression of DKD remain to be fully elucidated. Nevertheless, because of the remarkable progress in our basic understanding of the role of mitochondrial biology and its dysfunction in DKD, there is great excitement on future targeted therapies based on improving mitochondrial function in DKD. This review will highlight the latest advances in understanding the nature of mitochondria dysfunction and its role in progression of DKD, and the development of mitochondrial targets that could be potentially used to prevent its progression.
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Affiliation(s)
- Daniel L Galvan
- Section of Nephrology, The University of Texas at MD Anderson Cancer Center, Houston, TX, United States
| | - Koki Mise
- Section of Nephrology, The University of Texas at MD Anderson Cancer Center, Houston, TX, United States.,Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Farhad R Danesh
- Section of Nephrology, The University of Texas at MD Anderson Cancer Center, Houston, TX, United States.,Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, United States
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Bucher M, Montaniel KRC, Myatt L, Weintraub S, Tavori H, Maloyan A. Dyslipidemia, insulin resistance, and impairment of placental metabolism in the offspring of obese mothers. J Dev Orig Health Dis 2021; 12:738-747. [PMID: 33185172 PMCID: PMC8606174 DOI: 10.1017/s2040174420001026] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Obesity is a chronic condition associated with dyslipidemia and insulin resistance. Here, we show that the offspring of obese mothers are dyslipidemic and insulin resistant from the outset.Maternal and cord blood and placental tissues were collected following C-section at term. Patients were grouped as being normal weight (NW, BMI = 18-24.9) or obese (OB, BMI ≥ 30), and separated by fetal sex. We measured plasma lipids, insulin, and glucose in maternal and cord blood. Insulin resistance was quantified using the HOMA-IR. Placental markers of lipid and energy metabolism and relevant metabolites were measured by western blot and metabolomics, respectively.For OB women, total cholesterol was decreased in both maternal and cord blood, while HDL was decreased only in cord blood, independent of sex. In babies born to OB women, cord blood insulin and insulin resistance were increased. Placental protein expression of the energy and lipid metabolism regulators PGC1α, and SIRT3, ERRα, CPT1α, and CPT2 decreased with maternal obesity in a sex-dependent manner (P < 0.05). Metabolomics showed lower levels of acylcarnitines C16:0, C18:2, and C20:4 in OB women's placentas, suggesting a decrease in β-oxidation. Glutamine, glutamate, alpha-ketoglutarate (αKG), and 2-hydroxyglutarate (2-HG) were increased, and the glutamine-to-glutamate ratio decreased (P < 0.05), in OB placentas, suggesting induction of glutamate into αKG conversion to maintain a normal metabolic flux.Newly-born offspring of obese mothers begin their lives dyslipidemic and insulin resistant. If not inherited genetically, such major metabolic perturbations might be explained by abnormal placental metabolism with potential long-term adverse consequences for the offspring's health and wellbeing.
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Affiliation(s)
- Matthew Bucher
- Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA
- Department of OB/GYN, Oregon Health & Science University, Portland, OR, USA
| | - Kim Ramil C. Montaniel
- Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA
- The Graduate Program in Biomedical Sciences (PBMS), Oregon Health & Science University, Portland, OR, USA
| | - Leslie Myatt
- Department of OB/GYN, Oregon Health & Science University, Portland, OR, USA
| | - Susan Weintraub
- Department of Biochemistry, The Metabolomics Core Facility, Institutional Mass Spectrometry Laboratory, University of Texas Health, San Antonio, TX, USA
| | - Hagai Tavori
- Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Alina Maloyan
- Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA
- The Graduate Program in Biomedical Sciences (PBMS), Oregon Health & Science University, Portland, OR, USA
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Chen M, Wang Z, Zhou W, Lu C, Ji T, Yang W, Jin Z, Tian Y, Lei W, Wu S, Fu Q, Wu Z, Wu X, Han M, Fang M, Yang Y. SIRT1/PGC-1α signaling activation by mangiferin attenuates cerebral hypoxia/reoxygenation injury in neuroblastoma cells. Eur J Pharmacol 2021; 907:174236. [PMID: 34116043 DOI: 10.1016/j.ejphar.2021.174236] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 02/08/2023]
Abstract
Ischemia reperfusion injury (IRI) is associated with poor prognoses in the setting of ischemic brain diseases. Silence information regulator 1 (SIRT1) is a member of the third class of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins. Recently, the role of SIRT1/peroxisome proliferators-activated receptor-γ coactivator 1α (PGC-1α) pathway in organ (especially the brain) protection under various pathological conditions has been widely investigated. Mangiferin (MGF), a natural C-glucosyl xanthone polyhydroxy polyphenol, has been shown to be beneficial to several nervous system diseases and the protective effects of MGF can be achieved through the regulation of SIRT1 signaling. This study is designed to investigate the protective effects of MGF treatment in the setting of cerebral IRI and to elucidate the potential mechanisms. We first evaluated the toxicity of MGF and chose the safe concentrations for the following experiments. MGF exerted obvious neuroprotection against hypoxia/reoxygenation (HR)-induced injury, indicated by restored cell viability and cell morphology, decreased lactate dehydrogenase (LDH) release and reactive oxygen species generation. MGF also restored the protein expressions of SIRT1, PGC-1α, Nrf2, NQO1, HO-1, NRF1, UCP2, and Bcl2 down-regulated by HR treatment. However, SIRT1 siRNA could reverse MGF-induced neuroprotection and decrease the expressions of molecules mentioned above. Taken together, our findings suggest that MGF treatment exerts neuroprotection against HR injury via activating SIRT1/PGC-1α signaling. These findings may provide a theoretical basis for the exploitation of MGF as a potential neuroprotective drug candidate, which may be beneficial for the ischemic stroke patients in clinic.
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Affiliation(s)
- Mengfan Chen
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zheng Wang
- Department of Cardiothoracic Surgery, Central Theater Command General Hospital of Chinese People's Liberation Army, 627 Wuluo Road, Wuhan, China
| | - Wenying Zhou
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chenxi Lu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Ting Ji
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Wenwen Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an, China
| | - Ye Tian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Wangrui Lei
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Songdi Wu
- Department of Neurology, Xi'an No.1 Hospital, School of Life Sciences and Medicine, Northwest University, 30 Fenxiang, Xi'an, China
| | - Qi Fu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zhen Wu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Xue Wu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Mengzhen Han
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Minfeng Fang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China.
| | - Yang Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China.
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Deus CM, Pereira SP, Cunha-Oliveira T, Teixeira J, Simões RF, Cagide F, Benfeito S, Borges F, Raimundo N, Oliveira PJ. A mitochondria-targeted caffeic acid derivative reverts cellular and mitochondrial defects in human skin fibroblasts from male sporadic Parkinson's disease patients. Redox Biol 2021; 45:102037. [PMID: 34147843 PMCID: PMC8220403 DOI: 10.1016/j.redox.2021.102037] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/24/2021] [Accepted: 06/03/2021] [Indexed: 12/24/2022] Open
Abstract
Parkinson's Disease (PD) is a neurodegenerative disorder affecting more than 10 million people worldwide. Currently, PD has no cure and no early diagnostics methods exist. Mitochondrial dysfunction is presented in the early stages of PD, and it is considered an important pathophysiology component. We have previously developed mitochondria-targeted hydroxycinnamic acid derivatives, presenting antioxidant and iron-chelating properties, and preventing oxidative stress in several biological models of disease. We have also demonstrated that skin fibroblasts from male sporadic PD patients (sPD) presented cellular and mitochondrial alterations, including increased oxidative stress, hyperpolarized and elongated mitochondria and decreased respiration and ATP levels. We also showed that forcing mitochondrial oxidative phosphorylation (OXPHOS) in sPD fibroblasts uncovers metabolic defects that were otherwise hidden. In this work, we tested the hypothesis that a lead mitochondria-targeted hydroxycinnamic acid derivative would revert the phenotype found in skin fibroblasts from sPD patients. Our results demonstrated that treating human skin fibroblasts from sPD patients with non-toxic concentrations of AntiOxCIN4 restored mitochondrial membrane potential and mitochondrial fission, decreased autophagic flux, and enhanced cellular responses to stress by improving the cellular redox state and decreasing reactive oxygen species (ROS) levels. Besides, fibroblasts from sPD patients treated with AntiOxCIN4 showed increased maximal respiration and metabolic activity, converting sPD fibroblasts physiologically more similar to their sex- and age-matched healthy controls. The positive compound effect was reinforced using a supervised machine learning model, confirming that AntiOxCIN4 treatment converted treated fibroblasts from sPD patients closer to the phenotype of control fibroblasts. Our data points out a possible mechanism of AntiOxCIN4 action contributing to a deeper understanding of how the use of mitochondria-targeted antioxidants based on a polyphenol scaffold can be used as potential drug candidates for delaying PD progression, validating the use of fibroblasts from sPD patients with more active OXPHOS as platforms for mitochondria-based drug development.
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Affiliation(s)
- Cláudia M Deus
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Susana P Pereira
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Research Centre in Physical Activity Health and Leisure (CIAFEL), Faculty of Sports, University of Porto, Porto, Portugal
| | - Teresa Cunha-Oliveira
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - José Teixeira
- CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Rui F Simões
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Fernando Cagide
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernanda Borges
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Nuno Raimundo
- Penn State University College of Medicine, Department of Cellular and Molecular Physiology, Hershey, PA, USA; Multidisciplinary Institute of Ageing (MIA), University of Coimbra, Coimbra, Portugal
| | - Paulo J Oliveira
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal.
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