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Singh S, Singh RK. Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease. Mol Biol Rep 2025; 52:173. [PMID: 39880979 DOI: 10.1007/s11033-025-10297-6] [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: 11/12/2024] [Accepted: 01/23/2025] [Indexed: 01/31/2025]
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive decline. The processes underlying the pathophysiology of AD are still not fully understood despite a great deal of research. Since mitochondrial dysfunction affects cellular energy metabolism, oxidative stress, and neuronal survival, it is becoming increasingly clear that it plays a major role in the development of AD. This review summarizes the recent developments of mitochondrial dysfunction in AD, emphasizing mitochondrial biogenesis, dynamics, axonal transport, interactions between endoplasmic reticulum and mitochondria, mitophagy, and mitochondrial proteostasis. It emphasizes how tau and amyloid-beta (Aβ) proteins worsen mitochondrial and synaptic dysfunction by impairing adenosine triphosphate (ATP) synthesis, causing oxidative stress, and upsetting equilibrium. Additionally, important processes controlling mitochondrial activity and their correlation to the brain health are also discussed. One of the promising therapeutic approaches to lessen neurodegeneration and cognitive decline in AD is to improve mitochondrial activity. This study highlights possible directions for creating focused therapies to impede the advancement of AD through incorporating knowledge of mitochondrial biogenesis and its related mechanisms.
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Affiliation(s)
- Shreya Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli Transit Campus, Bijnour-Sisendi Road, Sarojini Nagar, Lucknow, Uttar Pradesh, 226002, India
| | - Rakesh Kumar Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli Transit Campus, Bijnour-Sisendi Road, Sarojini Nagar, Lucknow, Uttar Pradesh, 226002, India.
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2
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la Torre A, Lo Vecchio F, Angelillis VS, Gravina C, D’Onofrio G, Greco A. Reinforcing Nrf2 Signaling: Help in the Alzheimer's Disease Context. Int J Mol Sci 2025; 26:1130. [PMID: 39940900 PMCID: PMC11818887 DOI: 10.3390/ijms26031130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 02/16/2025] Open
Abstract
Oxidative stress plays a role in various pathophysiological diseases, including neurogenerative diseases, such as Alzheimer's disease (AD), which is the most prevalent neuro-pathology in the aging population. Oxidative stress has been reported to be one of the earliest pathological alterations in AD. Additionally, it was demonstrated that in older adults, there is a loss of free radical scavenging ability. The Nrf2 transcription factor is a key regulator in antioxidant defense systems, but, with aging, both the amount and the transcriptional activity of Nrf2 decrease. With the available treatments for AD being poorly effective, reinforcing the antioxidant defense systems via the Nrf2 pathway may be a way to prevent and treat AD. To highlight the predominant role of Nrf2 signaling in defending against oxidative stress and, therefore, against neurotoxicity, we present an overview of the natural compounds that exert their own neuroprotective roles through the activation of the Nrf2 pathway. This review is an opportunity to promote a holistic approach in the treatment of AD and to highlight the need to further refine the development of new potential Nrf2-targeting drugs.
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Affiliation(s)
- Annamaria la Torre
- Laboratory of Gerontology and Geriatrics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; (F.L.V.); (C.G.)
| | - Filomena Lo Vecchio
- Laboratory of Gerontology and Geriatrics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; (F.L.V.); (C.G.)
| | - Valentina Soccorsa Angelillis
- Complex Unit of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; (V.S.A.); (A.G.)
| | - Carolina Gravina
- Laboratory of Gerontology and Geriatrics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; (F.L.V.); (C.G.)
| | - Grazia D’Onofrio
- Clinical Psychology Service, Health Department, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy;
| | - Antonio Greco
- Complex Unit of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; (V.S.A.); (A.G.)
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Boldyreva LV, Evtushenko AA, Lvova MN, Morozova KN, Kiseleva EV. Underneath the Gut-Brain Axis in IBD-Evidence of the Non-Obvious. Int J Mol Sci 2024; 25:12125. [PMID: 39596193 PMCID: PMC11594934 DOI: 10.3390/ijms252212125] [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: 10/07/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
The gut-brain axis (GBA) plays a pivotal role in human health and wellness by orchestrating complex bidirectional regulation and influencing numerous critical processes within the body. Over the past decade, research has increasingly focused on the GBA in the context of inflammatory bowel disease (IBD). Beyond its well-documented effects on the GBA-enteric nervous system and vagus nerve dysregulation, and gut microbiota misbalance-IBD also leads to impairments in the metabolic and cellular functions: metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton dysregulation. These systemic effects are currently underexplored in relation to the GBA; however, they are crucial for the nervous system cells' functioning. This review summarizes the studies on the particular mechanisms of metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton impairments in IBD. Understanding the involvement of these processes in the GBA may help find new therapeutic targets and develop systemic approaches to improve the quality of life in IBD patients.
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Affiliation(s)
- Lidiya V. Boldyreva
- Scientific-Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia;
| | - Anna A. Evtushenko
- Scientific-Research Institute of Neurosciences and Medicine, 630117 Novosibirsk, Russia;
| | - Maria N. Lvova
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (M.N.L.); (K.N.M.); (E.V.K.)
| | - Ksenia N. Morozova
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (M.N.L.); (K.N.M.); (E.V.K.)
| | - Elena V. Kiseleva
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (M.N.L.); (K.N.M.); (E.V.K.)
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Liang W, Zhang W, Tian J, Zhang X, Lv X, Qu A, Chen J, Wu Z. Advances in carbohydrate-based nanoparticles for targeted therapy of inflammatory bowel diseases: A review. Int J Biol Macromol 2024; 281:136392. [PMID: 39423983 DOI: 10.1016/j.ijbiomac.2024.136392] [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: 05/18/2024] [Revised: 09/13/2024] [Accepted: 10/05/2024] [Indexed: 10/21/2024]
Abstract
The incidence of inflammatory bowel disease (IBD), a chronic gastrointestinal disorder, is rapidly increasing worldwide. Unfortunately, the current therapies for IBD are often hindered by premature drug release and undesirable side effects. With the advancement of nanotechnology, the innovative targeted nanotherapeutics are explored to ensure the accurate delivery of drugs to specific sites in the colon, thereby reducing side effects and improving the efficacy of oral administration. The emphasis of this review is to summarize the potential pathogenesis of IBD and highlight recent breakthroughs in carbohydrate-based nanoparticles for IBD treatment, including their construction, release mechanism, potential targeting ability, and their therapeutic efficacy. Specifically, we summarize the latest knowledge regarding environmental-responsive nano-systems and active targeted nanoparticles. The environmental-responsive drug delivery systems crafted with carbohydrates or other biological macromolecules like chitosan and sodium alginate, exhibit a remarkable capacity to enhance the accumulation of therapeutic drugs in the inflamed regions of the digestive tract. Active targeting strategies improve the specificity and accuracy of oral drug delivery to the colon by modifying carbohydrates such as hyaluronic acid and mannose onto nanocarriers. Finally, we discuss the challenges and provide insight into the future perspectives of colon-targeted delivery systems for IBD treatment.
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Affiliation(s)
- Wenjing Liang
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Wen Zhang
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China; Key Laboratory of Low Carbon Cold Chain for Agricultural Products, Ministry of Agriculture and Rural Affairs, China.
| | - Jiayi Tian
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Xinping Zhang
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Xinyi Lv
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Ao Qu
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Jinyu Chen
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China; Key Laboratory of Low Carbon Cold Chain for Agricultural Products, Ministry of Agriculture and Rural Affairs, China
| | - Zijian Wu
- Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin 300134, China; Key Laboratory of Low Carbon Cold Chain for Agricultural Products, Ministry of Agriculture and Rural Affairs, China.
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Vodičková A, Müller-Eigner A, Okoye CN, Bischer AP, Horn J, Koren SA, Selim NA, Wojtovich AP. Mitochondrial energy state controls AMPK-mediated foraging behavior in C. elegans. SCIENCE ADVANCES 2024; 10:eadm8815. [PMID: 38630817 PMCID: PMC11023558 DOI: 10.1126/sciadv.adm8815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/14/2024] [Indexed: 04/19/2024]
Abstract
Organisms surveil and respond to their environment using behaviors entrained by metabolic cues that reflect food availability. Mitochondria act as metabolic hubs and at the center of mitochondrial energy production is the protonmotive force (PMF), an electrochemical gradient generated by metabolite consumption. The PMF serves as a central integrator of mitochondrial status, but its role in governing metabolic signaling is poorly understood. We used optogenetics to dissipate the PMF in Caenorhabditis elegans tissues to test its role in food-related behaviors. Our data demonstrate that PMF reduction in the intestine is sufficient to initiate locomotor responses to acute food deprivation. This behavioral adaptation requires the cellular energy regulator AMP-activated protein kinase (AMPK) in neurons, not in the intestine, and relies on mitochondrial dynamics and axonal trafficking. Our results highlight a role for intestinal PMF as an internal metabolic cue, and we identify a bottom-up signaling axis through which changes in the PMF trigger AMPK activity in neurons to promote foraging behavior.
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Affiliation(s)
- Anežka Vodičková
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Annika Müller-Eigner
- Research Group Epigenetics, Metabolism and Longevity, Research Institute for Farm Animal Biology (FBN), Dummerstorf 18196, Germany
| | - Chidozie N. Okoye
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Andrew P. Bischer
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Jacob Horn
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Shon A. Koren
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Nada Ahmed Selim
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA
| | - Andrew P. Wojtovich
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, NY, USA
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Wu Y, Li M, Ying H, Gu Y, Zhu Y, Gu Y, Huang L. Mitochondrial quality control alterations and placenta-related disorders. Front Physiol 2024; 15:1344951. [PMID: 38390447 PMCID: PMC10883312 DOI: 10.3389/fphys.2024.1344951] [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: 11/27/2023] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Mitochondria are ubiquitous in eukaryotic cells. Normal maintenance of function is the premise and basis for various physiological activities. Mitochondrial dysfunction is commonly observed in a wide range of pathological conditions, such as neurodegenerative, metabolic, cardiovascular, and various diseases related to foetal growth and development. The placenta is a highly energy-dependent organ that acts as an intermediary between the mother and foetus and functions to maintain foetal growth and development. Recent studies have demonstrated that mitochondrial dysfunction is associated with placental disorders. Defects in mitochondrial quality control mechanisms may lead to preeclampsia and foetal growth restriction. In this review, we address the quality control mechanisms of mitochondria and the relevant pathologies of mitochondrial dysfunction in placenta-related diseases, such as preeclampsia and foetal growth restriction. This review also investigates the relation between mitochondrial dysfunction and placental disorders.
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Affiliation(s)
- Yamei Wu
- Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, China
- Wuxi Clinical Medical College of Nanjing Medical University, Wuxi, China
| | - Meng Li
- Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, China
- Wuxi Clinical Medical College of Nanjing Medical University, Wuxi, China
| | - Hao Ying
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ying Gu
- Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, China
- Wuxi Clinical Medical College of Nanjing Medical University, Wuxi, China
| | - Yunlong Zhu
- Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, China
- Wuxi Clinical Medical College of Nanjing Medical University, Wuxi, China
| | - Yanfang Gu
- Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, China
- Wuxi Clinical Medical College of Nanjing Medical University, Wuxi, China
| | - Lu Huang
- Wuxi Maternity and Child Healthcare Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, China
- Wuxi Clinical Medical College of Nanjing Medical University, Wuxi, China
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7
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Atlante A, Valenti D. Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer's Disease: A Critical Review of New and Old Little Regarded Findings. Int J Mol Sci 2023; 24:15951. [PMID: 37958934 PMCID: PMC10650435 DOI: 10.3390/ijms242115951] [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: 10/05/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the main cause of dementia which is characterized by a progressive cognitive decline that severely interferes with daily activities of personal life. At a pathological level, it is characterized by the accumulation of abnormal protein structures in the brain-β-amyloid (Aβ) plaques and Tau tangles-which interfere with communication between neurons and lead to their dysfunction and death. In recent years, research on AD has highlighted the critical involvement of mitochondria-the primary energy suppliers for our cells-in the onset and progression of the disease, since mitochondrial bioenergetic deficits precede the beginning of the disease and mitochondria are very sensitive to Aβ toxicity. On the other hand, if it is true that the accumulation of Aβ in the mitochondria leads to mitochondrial malfunctions, it is otherwise proven that mitochondrial dysfunction, through the generation of reactive oxygen species, causes an increase in Aβ production, by initiating a vicious cycle: there is therefore a bidirectional relationship between Aβ aggregation and mitochondrial dysfunction. Here, we focus on the latest news-but also on neglected evidence from the past-concerning the interplay between dysfunctional mitochondrial complex I, oxidative stress, and Aβ, in order to understand how their interplay is implicated in the pathogenesis of the disease.
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Affiliation(s)
- Anna Atlante
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), Via G. Amendola 122/O, 70126 Bari, Italy;
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Sheng N, Zhang Z, Zheng H, Ma C, Li M, Wang Z, Wang L, Jiang J, Zhang J. Scutellarin Rescued Mitochondrial Damage through Ameliorating Mitochondrial Glucose Oxidation via the Pdk-Pdc Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303584. [PMID: 37750289 PMCID: PMC10646256 DOI: 10.1002/advs.202303584] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/01/2023] [Indexed: 09/27/2023]
Abstract
Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there are no specific potential molecules that have been identified to treat neurological diseases by regulating energy metabolism and repairing mitochondrial damage. Pyruvate dehydrogenase (PDH) complex (PDC), which can be phosphorylated by pyruvate dehydrogenase kinase (PDK), is the gate-keeping enzyme for mitochondrial glucose oxidation. In this study, a small-molecule scutellarin (SG) is discovered that can significantly alleviate the neuropathological changes in hippocampal CA1 of cerebral hypoperfusion model rats, rescued the morphological changes of abnormal mitochondria, and restored mitochondrial homeostasis. Mitochondrial proteomics, energy metabolism monitoring, and 13 C-metabolic flux analysis targeted SG activity on PDK2, thus regulating PDK-PDC-mediated glycolytic metabolism to TCA cycle during mitochondrial OXPHOS damage. The knockdown of PDK2 in the SK-N-SH cells validated that SG could rescue mitochondrial damage via the PDK-PDC axis, promote the MMP level and reduce the mitochondria-dependent apoptosis. Collectively, this study explored the novel therapeutic approach: the PDK-PDC axis for neurological injury and cognitive impairment and uncovered the effect of SG on mitochondrial protection via the PDK-PDC axis and mitochondrial glucose oxidation. The findings indicate that active components ameliorating mitochondrial bioenergetic deficits could be of significant value for neurological disease therapy.
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Affiliation(s)
- Ning Sheng
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Zhihui Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Hao Zheng
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Congyu Ma
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Menglin Li
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Zhe Wang
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Lulu Wang
- Institute of Medicinal BiotechnologyChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Jiandong Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
- Institute of Medicinal BiotechnologyChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
| | - Jinlan Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100050China
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9
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Koren SA, Ahmed Selim N, De la Rosa L, Horn J, Farooqi MA, Wei AY, Müller-Eigner A, Emerson J, Johnson GVW, Wojtovich AP. All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ. Nat Commun 2023; 14:6036. [PMID: 37758713 PMCID: PMC10533892 DOI: 10.1038/s41467-023-41682-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.
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Affiliation(s)
- Shon A Koren
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Nada Ahmed Selim
- University of Rochester Medical Center, Department of Pharmacology and Physiology, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Lizbeth De la Rosa
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Jacob Horn
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - M Arsalan Farooqi
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Alicia Y Wei
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Annika Müller-Eigner
- Research Group Epigenetics, Metabolism and Longevity, Research Institute for Farm Animal Biology (FBN), Dummerstorf, 18196, Germany
| | - Jacen Emerson
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Gail V W Johnson
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Andrew P Wojtovich
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA.
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10
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Del Giudice L, Pontieri P, Aletta M, Calcagnile M. Mitochondrial Neurodegenerative Diseases: Three Mitochondrial Ribosomal Proteins as Intermediate Stage in the Pathway That Associates Damaged Genes with Alzheimer's and Parkinson's. BIOLOGY 2023; 12:972. [PMID: 37508402 PMCID: PMC10376763 DOI: 10.3390/biology12070972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023]
Abstract
Currently, numerous research endeavors are dedicated to unraveling the intricate nature of neurodegenerative diseases. These conditions are characterized by the gradual and progressive impairment of specific neuronal systems that exhibit anatomical or physiological connections. In particular, in the last twenty years, remarkable efforts have been made to elucidate neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. However, despite extensive research endeavors, no cure or effective treatment has been discovered thus far. With the emergence of studies shedding light on the contribution of mitochondria to the onset and advancement of mitochondrial neurodegenerative disorders, researchers are now directing their investigations toward the development of therapies. These therapies include molecules designed to protect mitochondria and neurons from the detrimental effects of aging, as well as mutant proteins. Our objective is to discuss and evaluate the recent discovery of three mitochondrial ribosomal proteins linked to Alzheimer's and Parkinson's diseases. These proteins represent an intermediate stage in the pathway connecting damaged genes to the two mitochondrial neurological pathologies. This discovery potentially could open new avenues for the production of medicinal substances with curative potential for the treatment of these diseases.
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Affiliation(s)
- Luigi Del Giudice
- Istituto di Bioscienze e BioRisorse-UOS Napoli-CNR c/o Dipartimento di Biologia, Sezione di Igiene, 80134 Napoli, Italy
| | - Paola Pontieri
- Istituto di Bioscienze e BioRisorse-UOS Napoli-CNR c/o Dipartimento di Biologia, Sezione di Igiene, 80134 Napoli, Italy
| | | | - Matteo Calcagnile
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali, Università del Salento, 73100 Lecce, Italy
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11
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Caicedo A, Singh KK. Advancing mitochondria as a therapeutic agent. Mitochondrion 2023; 69:33-35. [PMID: 36657505 DOI: 10.1016/j.mito.2023.01.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 01/10/2023] [Indexed: 01/19/2023]
Abstract
This article intends to provide an update of the needs in the field working in the artificial mitochondrial transfer/transplant (AMT/T), and an overview of the highlights from the articles in the special issue "Advances of Mitochondria as a therapeutic agent". In the last 4 decades, scientists have developed innovative therapeutic applications based on the AMT/T, inspired by the natural transfer of mitochondria between cells to repair cellular damage or treat diseases. The clinical application of AMT has become the priority for the field involving the replacement or augmentation of healthy mitochondria in the harmed tissue, especially in the treatment of organ ischemia-reperfusion injury. However, we remark in our article that key questions remain to be answered such as which one is the best isolation protocol, tissue or cell source for isolation, and others of great importance to move the field forward.
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Affiliation(s)
- Andrés Caicedo
- Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina iBioMed, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador; Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador; Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Keshav K Singh
- Departments of Genetics, Dermatology and Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
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12
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Associations of genes of DNA repair systems with Parkinson’s disease. ACTA BIOMEDICA SCIENTIFICA 2022. [DOI: 10.29413/abs.2022-7.6.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background. Approximately 5–10 % of cases of Parkinson’s disease (PD) are monogenic, in other cases the pathology has a multifactorial etiology. One of recognized pathogenetic pathways of PD is mitochondrial dysfunction, in particular the accumulation of damage in mitochondrial DNA. Hence, the genes of DNA repair proteins are promising candidate genes for multifactorial forms of PD.The aim. To study the involvement of genes of DNA repair proteins in the development of Parkinson’s disease.Materials and methods. The associative analysis was carried out while comparing a group of patients with PD (n = 133) with a Tomsk population sample (n = 344). SNaPshot analysis was used to study 8 SNPs in genes of DNA repair proteins (rs560191 (TP53BP1); rs1805800 and rs709816 (NBN); rs473297 (MRE11A); rs1189037 and rs1801516 (ATM); rs1799977 (MLH1); rs1805321 (PMS2)).Results. Common alleles and homozygous rs1801516 genotypes in the ATM gene predispose the development of PD (odds ratio (OR) – 3.27 (p = 0.000004) and OR = 3.46 (p = 0.00008) for risk alleles and genotype respectively) and rs1799977 in the MLH1 gene (OR = 1.88 (p = 0.0004) and OR = 2.42 (p = 0.00007) respectively); heterozygotes have a protective effect (OR = 0.33 (p = 0.0007) and OR = 0.46 (p = 0.0007) for ATM and MLH1, respectively). The rare rs1805800 allele in the NBN gene (OR = 1.62 (p = 0.019)) and a homozygous genotype for it (OR = 2.28 (p = 0.016)) also predispose to PD. Associations with PD of the ATM, MLH1, NBN genes were revealed for the first time.Conclusion. Mitochondrial dysfunction is one of the key factors in the pathogenesis of PD, while at least two of the three protein products of associated genes are involved in the development of mitochondrial dysfunction. Accordingly, it can be assumed that associated genes are involved in the pathogenesis of PD precisely through mitochondrial dysfunction.
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Chen Y, Wang Q, Luo H, Deng S, Tian Y, Wang S. Mechanisms of the ethanol extract of Gelidium amansii for slow aging in high-fat male Drosophila by metabolomic analysis. Food Funct 2022; 13:10110-10120. [PMID: 36102920 DOI: 10.1039/d2fo02116a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Gelidium amansii (GA) is a kind of red alga homologous to medicine and food and is distributed all over the world. Studies on GA are mainly focused on its polysaccharides, with little research on the ethanol extract. The ethanol extract of Gelidium amansii (GAE) was subjected to a reverse-phase column to obtain 7 components. Among them, 100% methanol solution (GAM), enriched with phytene-1,2-diol, exhibited the strongest DPPH free radical scavenging activity (IC50 = 0.17 mg mL-1). Subsequently, high-fat male flies (HMFs) were used as a model to explore the antioxidant and anti-aging effects of GAM in vivo. Studies showed that GAM can effectively prolong the lifespan of HMFs. When GAM concentrations were 0.2 and 1.0 mg mL-1, the average lifespan of HMFs was increased by 28.7 and 40.7%, respectively, while the longest lifespan of HMFs was increased by 20.55% and 32.88%, respectively. Further research revealed that GAM can significantly downregulate the levels of malondialdehyde (MDA) and protein carbonyl (PCO), and can significantly upregulate the levels of catalase (CAT) and total superoxide dismutase (T-SOD). In addition, by analyzing differential metabolites, we found that GAM relieves aging caused by oxidative stress by regulating amino acid, lipid, sugar, and energy metabolism. The GAM group significantly regulated the levels of adenine, cholic acid, glutamate, L-proline, niacin, and stachyose which tend to recover to the levels of the normal diet male fly (NMF) group. In general, our research provides ideas for the high-value utilization of GA and provides a lead compound for the research and development of anti-aging food or medicine.
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Affiliation(s)
- Yushi Chen
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China.
| | - Qishen Wang
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China.
| | - Haitao Luo
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China.
| | - Shanggui Deng
- College of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, Zhejiang 316022, China
| | - Yongqi Tian
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China.
| | - Shaoyun Wang
- College of Chemical Engineering, Fuzhou University, Fuzhou 350108, China.
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Moos WH, Faller DV, Glavas IP, Harpp DN, Kamperi N, Kanara I, Kodukula K, Mavrakis AN, Pernokas J, Pernokas M, Pinkert CA, Powers WR, Sampani K, Steliou K, Tamvakopoulos C, Vavvas DG, Zamboni RJ, Chen X. Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury. Biochem Pharmacol 2022; 203:115168. [PMID: 35835206 DOI: 10.1016/j.bcp.2022.115168] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 11/19/2022]
Abstract
Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
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Affiliation(s)
- Walter H Moos
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.
| | - Douglas V Faller
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Cancer Research Center, Boston University School of Medicine, Boston, MA, USA
| | - Ioannis P Glavas
- Department of Ophthalmology, New York University School of Medicine, New York, NY, USA
| | - David N Harpp
- Department of Chemistry, McGill University, Montreal, QC, Canada
| | - Natalia Kamperi
- Center for Clinical, Experimental Surgery and Translational Research Pharmacology-Pharmacotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | | | | | - Anastasios N Mavrakis
- Department of Medicine, Tufts University School of Medicine, St. Elizabeth's Medical Center, Boston, MA, USA
| | - Julie Pernokas
- Advanced Dental Associates of New England, Woburn, MA, USA
| | - Mark Pernokas
- Advanced Dental Associates of New England, Woburn, MA, USA
| | - Carl A Pinkert
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA
| | - Whitney R Powers
- Department of Health Sciences, Boston University, Boston, MA, USA; Department of Anatomy, Boston University School of Medicine, Boston, MA, USA
| | - Konstantina Sampani
- Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Kosta Steliou
- Cancer Research Center, Boston University School of Medicine, Boston, MA, USA; PhenoMatriX, Inc., Natick, MA, USA
| | - Constantin Tamvakopoulos
- Center for Clinical, Experimental Surgery and Translational Research Pharmacology-Pharmacotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Demetrios G Vavvas
- Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
| | - Robert J Zamboni
- Department of Chemistry, McGill University, Montreal, QC, Canada
| | - Xiaohong Chen
- Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
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