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Bradshaw PC, Aldridge JL, Jamerson LE, McNeal C, Pearson AC, Frasier CR. The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration. Mol Neurobiol 2025; 62:7022-7040. [PMID: 39557801 DOI: 10.1007/s12035-024-04630-6] [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: 05/03/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.
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Affiliation(s)
- Patrick C Bradshaw
- Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Box 70582, Johnson City, TN, 37614, USA
| | - Jessa L Aldridge
- Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Box 70582, Johnson City, TN, 37614, USA
| | - Leah E Jamerson
- Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Box 70582, Johnson City, TN, 37614, USA
| | - Canah McNeal
- Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Box 70582, Johnson City, TN, 37614, USA
| | - A Catherine Pearson
- Department of Biological Sciences, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Chad R Frasier
- Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Box 70582, Johnson City, TN, 37614, USA.
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Schweitzer-Stenner R. Order-to-Disorder and Disorder-to-Order Transitions of Proteins upon Binding to Phospholipid Membranes: Common Ground and Dissimilarities. Biomolecules 2025; 15:198. [PMID: 40001501 PMCID: PMC11852466 DOI: 10.3390/biom15020198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 02/27/2025] Open
Abstract
Cytochrome c is one of the most prominent representatives of peripheral membrane proteins. Besides functioning as an electron transfer carrier in the mitochondrial respiratory chain, it can acquire peroxidase capability, promote the self-assembly of α-synuclein, and function as a scavenger of superoxide. An understanding of its function requires knowledge of how the protein interacts with the inner membrane of mitochondria. The first part of this article provides an overview of a variety of experiments that were aimed at exploring the details of cytochrome c binding to anionic lipid liposomes, which serve as a model system for the inner membrane. While cytochrome c binding involves a conformational change from a folded into a partially disordered state, α-synuclein is intrinsically disordered in solution and subjected to a partial coil -> helix transition on membranes. Depending on the solution conditions and the surface density of α-synuclein, the protein facilitates the self-assembly into oligomers and fibrils. As for cytochrome c, results of binding experiments are discussed. In addition, the article analyzes experiments that explored α-synuclein aggregation. Similarities and differences between cytochrome c and α-synuclein binding are highlighted. Finally, the article presents a brief account of the interplay between cytochrome c and α-synuclein and its biological relevance.
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Foda BM, Baker AE, Joachimiak Ł, Mazur M, Neubig RR. Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: implications for the involvement of pirin. Front Pharmacol 2025; 16:1505000. [PMID: 39917624 PMCID: PMC11799239 DOI: 10.3389/fphar.2025.1505000] [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: 10/01/2024] [Accepted: 01/08/2025] [Indexed: 02/09/2025] Open
Abstract
Aim Overcoming therapy resistance is critical for effective melanoma control. Upregulation of Rho/MRTF signaling in human and mouse melanomas causes resistance to targeted therapies. Inhibition of this pathway by MRTFi, CCG-257081 resensitized resistant melanomas to BRAF and MEK inhibitors. It also prevented the development of resistance to vemurafenib (Vem). Here, we investigate the role of apoptosis and the protein pirin in CCG-257081-mediated suppression of drug resistance. Methods Using naïve and resistant mouse YUMMER melanoma cells, we studied the effect of the BRAF inhibitor Vem with or without CCG-257081 on real-time growth and apoptosis (activation of caspase, Propidium iodide (PI) staining, and PARP cleavage). The effects of CCG-257081 on proliferation (Ki67) and caspase-3 activation were assessed in resistant YUMMER_R tumors in vivo. Finally, two CCG-257081 enantiomers were tested for pirin binding, inhibition of the Rho/MRTF-mediated activation of ACTA2 gene expression in fibroblasts, and the prevention of Vem resistance development by YUMMER_P cells. Results Vem reduced growth of parental but not resistant cells, while CCG-257081 inhibited both. The combination was more effective than Vem alone. CCG-257081, but not Vem, induced activation of caspase-3 and -7 in resistant cells and increased PARP cleavage and PI staining. CCG-257081 reduced proliferation and activated caspase-3 in YUMMER_R melanoma tumors. Both CCG-257081 enantiomers robustly suppressed development of Vem-resistant colonies with the S isomer being more potent (1 μM IC50). Conclusion CCG-257081 appears to target pre-resistant cells and Vem-induced resistant cells through enhanced apoptosis. Inhibition of pirin or the Rho/MRTF pathway can be employed to prevent melanoma resistance.
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Affiliation(s)
- Bardees M. Foda
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
- Molecular Genetics and Enzymology Department, National Research Centre, Dokki, Egypt
| | - Annika E. Baker
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
- School of Health, Pre-Medicine, Calvin University, Grand Rapids, MI, United States
- School of Science Technology, Engineering, and Math, Biochemistry, Calvin University, Grand Rapids, MI, United States
| | | | | | - Richard R. Neubig
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
- Molecure SA, Warsaw, Poland
- Nicholas V. Perricone M.D. Division of Dermatology, Department of Medicine, Michigan State University, East Lansing, MI, United States
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Theofilis P, Vlachakis PK, Oikonomou E, Drakopoulou M, Karakasis P, Apostolos A, Pamporis K, Tsioufis K, Tousoulis D. Cancer Therapy-Related Cardiac Dysfunction: A Review of Current Trends in Epidemiology, Diagnosis, and Treatment. Biomedicines 2024; 12:2914. [PMID: 39767820 PMCID: PMC11673750 DOI: 10.3390/biomedicines12122914] [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: 11/23/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Cancer therapy-related cardiac dysfunction (CTRCD) has emerged as a significant concern with the rise of effective cancer treatments like anthracyclines and targeted therapies such as trastuzumab. While these therapies have improved cancer survival rates, their unintended cardiovascular side effects can lead to heart failure, cardiomyopathy, and arrhythmias. The pathophysiology of CTRCD involves oxidative stress, mitochondrial dysfunction, and calcium dysregulation, resulting in irreversible damage to cardiomyocytes. Inflammatory cytokines, disrupted growth factor signaling, and coronary atherosclerosis further contribute to this dysfunction. Advances in cardio-oncology have led to the early detection of CTRCD using cardiac biomarkers like troponins and imaging techniques such as echocardiography and cardiac magnetic resonance (CMR). These tools help identify asymptomatic patients at risk of cardiac events before the onset of clinical symptoms. Preventive strategies, including the use of cardioprotective agents like beta-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors have shown promise in reducing the incidence of CTRCD. This review summarizes the mechanisms, detection methods, and emerging treatments for CTRCD, emphasizing the importance of interdisciplinary collaboration between oncologists and cardiologists to optimize care and improve both cancer and cardiovascular outcomes.
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Affiliation(s)
- Panagiotis Theofilis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
| | - Panayotis K. Vlachakis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital Sotiria, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Maria Drakopoulou
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
| | - Paschalis Karakasis
- 2nd Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
| | - Anastasios Apostolos
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
| | - Konstantinos Pamporis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
| | - Konstantinos Tsioufis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (P.K.V.); (M.D.); (A.A.); (K.P.); (K.T.)
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Meng X, Song Q, Liu Z, Liu X, Wang Y, Liu J. Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction-the trigger for PANoptosis in neurons. Front Aging Neurosci 2024; 16:1400544. [PMID: 38808033 PMCID: PMC11130508 DOI: 10.3389/fnagi.2024.1400544] [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: 03/13/2024] [Accepted: 04/29/2024] [Indexed: 05/30/2024] Open
Abstract
As the global population ages, the incidence of elderly patients with dementia, represented by Alzheimer's disease (AD), will continue to increase. Previous studies have suggested that β-amyloid protein (Aβ) deposition is a key factor leading to AD. However, the clinical efficacy of treating AD with anti-Aβ protein antibodies is not satisfactory, suggesting that Aβ amyloidosis may be a pathological change rather than a key factor leading to AD. Identification of the causes of AD and development of corresponding prevention and treatment strategies is an important goal of current research. Following the discovery of soluble oligomeric forms of Aβ (AβO) in 1998, scientists began to focus on the neurotoxicity of AβOs. As an endogenous neurotoxin, the active growth of AβOs can lead to neuronal death, which is believed to occur before plaque formation, suggesting that AβOs are the key factors leading to AD. PANoptosis, a newly proposed concept of cell death that includes known modes of pyroptosis, apoptosis, and necroptosis, is a form of cell death regulated by the PANoptosome complex. Neuronal survival depends on proper mitochondrial function. Under conditions of AβO interference, mitochondrial dysfunction occurs, releasing lethal contents as potential upstream effectors of the PANoptosome. Considering the critical role of neurons in cognitive function and the development of AD as well as the regulatory role of mitochondrial function in neuronal survival, investigation of the potential mechanisms leading to neuronal PANoptosis is crucial. This review describes the disruption of neuronal mitochondrial function by AβOs and elucidates how AβOs may activate neuronal PANoptosis by causing mitochondrial dysfunction during the development of AD, providing guidance for the development of targeted neuronal treatment strategies.
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Affiliation(s)
| | | | | | | | | | - Jinyu Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun, China
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Patyal P, Zhang X, Verma A, Azhar G, Wei JY. Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function. Cells 2024; 13:392. [PMID: 38474356 PMCID: PMC10931493 DOI: 10.3390/cells13050392] [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: 12/30/2023] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics.
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Affiliation(s)
| | | | | | | | - Jeanne Y. Wei
- Donald W. Reynolds Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (P.P.); (X.Z.); (A.V.); (G.A.)
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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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Huang F, Ding Z, Chen J, Guo B, Wang L, Liu C, Zhang C. Contribution of mitochondria to postmortem muscle tenderization: a review. Crit Rev Food Sci Nutr 2023; 65:30-46. [PMID: 37819615 DOI: 10.1080/10408398.2023.2266767] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Postmortem meat tenderization is a process mediated by a series of biochemical reactions related to muscle cell death. Cell death is considered a sign that muscle has started to transform into meat. Mitochondria play a significant role in regulating and executing cell death, as they are an aggregation point for many cell death signals and are also the primary target organelle damaged by tissue anoxia. Mitochondrial damage is likely to have an expanded role in postmortem meat tenderization. This review presents current findings on mitochondrial damage induced by the accumulation of reactive oxygen species during postmortem anaerobic metabolism and on the impact of mitochondrial damage on proteolysis and discusses how this leads to improved tenderness during aging. The underlying mechanisms of mitochondrial regulation of postmortem muscle tenderization likely focus on the mitochondria's role in postmortem cell death and energy metabolism. The death process of postmortem skeletal muscle cells may exhibit multiple types, possibly involving transformation from autophagy to apoptosis and, ultimately, necroptosis or necrosis. Mitochondrial characteristics, especially membrane integrity and ATP-related compound levels, are closely related to the transformation of multiple types of dead postmortem muscle cells. Finally, a possible biochemical regulatory network in postmortem muscle tenderization is proposed.
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Affiliation(s)
- Feng Huang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing, China
| | - Zhenjiang Ding
- Beijing Key Laboratory of the Innovative Development of Functional Staple and Nutritional Intervention for Chronic Diseases, China National Research Institute of Food and Fermentation Industries, Beijing, China
| | - Jinsong Chen
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing, China
| | - Bing Guo
- Adisseo Asia Pacific Pte Ltd, Singapore, Singapore
| | - Linlin Wang
- College of Food Science and Technology, Southwest Minzu University, Chengdu, Sichuan, China
| | - Chunmei Liu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing, China
| | - Chunhui Zhang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Processing, Ministry of Agriculture, Beijing, China
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Hayward JA, Makota FV, Cihalova D, Leonard RA, Rajendran E, Zwahlen SM, Shuttleworth L, Wiedemann U, Spry C, Saliba KJ, Maier AG, van Dooren GG. A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites. PLoS Pathog 2023; 19:e1011517. [PMID: 37471441 PMCID: PMC10403144 DOI: 10.1371/journal.ppat.1011517] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/04/2023] [Accepted: 06/28/2023] [Indexed: 07/22/2023] Open
Abstract
Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture 'Pathogen Box' for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC in T. gondii, at least four of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Qi) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.
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Affiliation(s)
- Jenni A. Hayward
- Research School of Biology, Australian National University, Canberra, Australia
| | - F. Victor Makota
- Research School of Biology, Australian National University, Canberra, Australia
| | - Daniela Cihalova
- Research School of Biology, Australian National University, Canberra, Australia
| | - Rachel A. Leonard
- Research School of Biology, Australian National University, Canberra, Australia
| | - Esther Rajendran
- Research School of Biology, Australian National University, Canberra, Australia
| | - Soraya M. Zwahlen
- Research School of Biology, Australian National University, Canberra, Australia
| | - Laura Shuttleworth
- Research School of Biology, Australian National University, Canberra, Australia
| | - Ursula Wiedemann
- Research School of Biology, Australian National University, Canberra, Australia
| | - Christina Spry
- Research School of Biology, Australian National University, Canberra, Australia
| | - Kevin J. Saliba
- Research School of Biology, Australian National University, Canberra, Australia
| | - Alexander G. Maier
- Research School of Biology, Australian National University, Canberra, Australia
| | - Giel G. van Dooren
- Research School of Biology, Australian National University, Canberra, Australia
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Balakrishnan R, Azam S, Kim IS, Choi DK. Neuroprotective Effects of Black Pepper and Its Bioactive Compounds in Age-Related Neurological Disorders. Aging Dis 2023; 14:750-777. [PMID: 37191428 PMCID: PMC10187688 DOI: 10.14336/ad.2022.1022] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/22/2022] [Indexed: 11/18/2022] Open
Abstract
Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders whose risk increases with age. The main pathological hallmarks of ANDs include behavioral changes, excessive oxidative stress, progressive functional declines, impaired mitochondrial function, protein misfolding, neuroinflammation, and neuronal cell death. Recently, efforts have been made to overcome ANDs because of their increased age-dependent prevalence. Black pepper, the fruit of Piper nigrum L. in the family Piperaceae, is an important food spice that has long been used in traditional medicine to treat various human diseases. Consumption of black pepper and black pepper-enriched products is associated with numerous health benefits due to its antioxidant, antidiabetic, anti-obesity, antihypertensive, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective properties. This review shows that black pepper's major bioactive neuroprotective compounds, such as piperine, effectively prevent AND symptoms and pathological conditions by modulating cell survival signaling and death. Relevant molecular mechanisms are also discussed. In addition, we highlight how recently developed novel nanodelivery systems are vital for improving the efficacy, solubility, bioavailability, and neuroprotective properties of black pepper (and thus piperine) in different experimental AND models, including clinical trials. This extensive review shows that black pepper and its active ingredients have therapeutic potential for ANDs.
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Affiliation(s)
- Rengasamy Balakrishnan
- Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea.
- Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea.
| | - Shofiul Azam
- Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea.
| | - In-Su Kim
- Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea.
| | - Dong-Kug Choi
- Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea.
- Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea.
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Goicoechea L, Conde de la Rosa L, Torres S, García-Ruiz C, Fernández-Checa JC. Mitochondrial cholesterol: Metabolism and impact on redox biology and disease. Redox Biol 2023; 61:102643. [PMID: 36857930 PMCID: PMC9989693 DOI: 10.1016/j.redox.2023.102643] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/10/2023] [Accepted: 02/22/2023] [Indexed: 02/26/2023] Open
Abstract
Cholesterol is a crucial component of membrane bilayers by regulating their structural and functional properties. Cholesterol traffics to different cellular compartments including mitochondria, whose cholesterol content is low compared to other cell membranes. Despite the limited availability of cholesterol in the inner mitochondrial membrane (IMM), the metabolism of cholesterol in the IMM plays important physiological roles, acting as the precursor for the synthesis of steroid hormones and neurosteroids in steroidogenic tissues and specific neurons, respectively, or the synthesis of bile acids through an alternative pathway in the liver. Accumulation of cholesterol in mitochondria above physiological levels has a negative impact on mitochondrial function through several mechanisms, including the limitation of crucial antioxidant defenses, such as the glutathione redox cycle, increased generation of reactive oxygen species and consequent oxidative modification of cardiolipin, and defective assembly of respiratory supercomplexes. These adverse consequences of increased mitochondrial cholesterol trafficking trigger the onset of oxidative stress and cell death, and, ultimately, contribute to the development of diverse diseases, including metabolic liver diseases (i.e. fatty liver disease and liver cancer), as well as lysosomal disorders (i.e. Niemann-Pick type C disease) and neurodegenerative diseases (i.e. Alzheimer's disease). In this review, we summarize the metabolism and regulation of mitochondrial cholesterol and its potential impact on liver and neurodegenerative diseases.
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Affiliation(s)
- Leire Goicoechea
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain
| | - Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain
| | - Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain
| | - Carmen García-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain; Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
| | - José C Fernández-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBEREHD), Barcelona, Spain; Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
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12
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Aissia E, Blier PU, Fadhlaoui M, Couture P. Thermal modulation of mitochondrial function is affected by environmental nickel in rainbow trout (Oncorhynchus mykiss). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 257:106451. [PMID: 36868082 DOI: 10.1016/j.aquatox.2023.106451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 02/17/2023] [Accepted: 02/19/2023] [Indexed: 06/18/2023]
Abstract
In this study, we investigated the combined effects of temperature and nickel (Ni) contamination on liver mitochondria electron transport system (ETS) enzymes, citrate synthase (CS), phospholipid fatty acid composition and lipid peroxidation in rainbow trout (Oncorhynchus mykiss). Juvenile trout were acclimated for two weeks to two different temperatures (5˚C and 15˚C) and exposed to nickel (Ni; 520 μg/L) for three weeks. Using ratios of ETS enzymes and CS activities, our data suggest that Ni and an elevated temperature acted synergistically to induce a higher capacity for reduction status of the ETS. The response of phospholipid fatty acid profiles to thermal variation was also altered under nickel exposure. In control conditions, the proportion of saturated fatty acids (SFA) was higher at 15˚C than at 5˚C, while the opposite was observed for monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). However, in nickel contaminated fish, the proportion of SFA was higher at 5˚C than at 15˚C, while PUFA and MUFA followed the opposite direction. A higher PUFA ratio is associated with higher vulnerability to lipid peroxidation. Thiobarbituric Acid Reactive Substances (TBARS) content was higher when the PUFA were in higher proportions, except for Ni-exposed, warm-acclimated fish, in which we reported the lowest level of TBARS but the highest proportion of PUFA. We suspect that the interaction of nickel and temperature on lipid peroxidation is due to their synergistic effects on aerobic energy metabolism, as supported by the decrease in the activity of complex IV of the ETS enzyme activity in those fish, or on antioxidant enzymes and pathways. Overall, our study demonstrates that Ni exposure in heat-challenged fish can lead to the remodelling of the mitochondrial phenotype and potentially stimulate alternative antioxidant mechanisms.
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Affiliation(s)
- Elyas Aissia
- Institut National de la Recherche Scientifique - Centre Eau Terre Environment, Québec, Québec, Canada
| | - Pierre U Blier
- Université du Québec à Rimouski, Rimouski, Québec, Canada
| | - Mariem Fadhlaoui
- Institut National de la Recherche Scientifique - Centre Eau Terre Environment, Québec, Québec, Canada
| | - Patrice Couture
- Institut National de la Recherche Scientifique - Centre Eau Terre Environment, Québec, Québec, Canada.
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Abdul-Rahman T, Dunham A, Huang H, Bukhari SMA, Mehta A, Awuah WA, Ede-Imafidon D, Cantu-Herrera E, Talukder S, Joshi A, Sundlof DW, Gupta R. Chemotherapy Induced Cardiotoxicity: A State of the Art Review on General Mechanisms, Prevention, Treatment and Recent Advances in Novel Therapeutics. Curr Probl Cardiol 2023; 48:101591. [PMID: 36621516 DOI: 10.1016/j.cpcardiol.2023.101591] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 01/03/2023] [Indexed: 01/08/2023]
Abstract
As medicine advances to employ sophisticated anticancer agents to treat a vast array of oncological conditions, it is worth considering side effects associated with several chemotherapeutics. One adverse effect observed with several classes of chemotherapy agents is cardiotoxicity which leads to reduced ejection fraction (EF), cardiac arrhythmias, hypertension and Ischemia/myocardial infarction that can significantly impact the quality of life and patient outcomes. Research into possible mechanisms has elucidated several mechanisms, such as ROS generation, calcium overload and apoptosis. However, there is a relative scarcity of literature detailing the relationship between the exact mechanism of cardiotoxicity for each anticancer agent and observed clinical effects. This review comprehensively describes cardiotoxicity associated with various classes of anticancer agents and possible mechanisms. Further research exploring possible mechanisms for cardiotoxicity observed with anticancer agents could provide valuable insight into susceptibility for developing symptoms and management guidelines. Chemotherapeutics are associated with several side effects. Several classes of chemotherapy agents cause cardiotoxicity leading to a reduced ejection fraction (EF), cardiac arrhythmias, hypertension, and Ischemia/myocardial infarction. Research into possible mechanisms has elucidated several mechanisms, such as ROS generation, calcium overload, and apoptosis. However, there is a relative scarcity of literature detailing the relationship between the exact mechanism of cardiotoxicity for each anticancer agent and observed clinical effects. This review describes cardiotoxicity associated with various classes of anticancer agents and possible mechanisms. Further research exploring mechanisms for cardiotoxicity observed with anticancer agents could provide insight that will guide management.
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Affiliation(s)
| | - Alden Dunham
- University of South Florida Morsani College of Medicine, FL
| | - Helen Huang
- Royal College of Surgeons in Ireland, University of Medicine and Health Science, Dublin, Ireland
| | | | - Aashna Mehta
- University of Debrecen-Faculty of Medicine, Debrecen, Hungary
| | - Wireko A Awuah
- Sumy State University, Toufik's World Medical Association, Ukraine
| | | | - Emiliano Cantu-Herrera
- Department of Clinical Sciences, Division of Health Sciences, University of Monterrey, San Pedro Garza García, Nuevo León, México
| | | | - Amogh Joshi
- Department of Cardiology, Lehigh Valley Health Network, Allentown, PA
| | - Deborah W Sundlof
- Department of Cardiology, Lehigh Valley Health Network, Allentown, PA
| | - Rahul Gupta
- Department of Cardiology, Lehigh Valley Health Network, Allentown, PA.
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14
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Karadayian AG, Paez B, Bustamante J, Lores-Arnaiz S, Czerniczyniec A. Mitochondrial dysfunction due to in vitro exposure to atrazine and its metabolite in striatum. J Biochem Mol Toxicol 2023; 37:e23232. [PMID: 36181348 DOI: 10.1002/jbt.23232] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 07/28/2022] [Accepted: 09/16/2022] [Indexed: 01/18/2023]
Abstract
Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) has been described as a potential toxic for dopaminergic metabolism both in vivo and in vitro. Its main metabolite diamino-chloro triazine (DACT) has been shown to achieve higher levels in brain tissue than atrazine. The aim of this study was to evaluate the in vitro effects of atrazine and DACT on striatal mitochondrial function, active oxygen species generation, and nitric oxide (NO) content. Incubation of mitochondria with atrazine (10 µM) was not able to modify oxygen consumption. However, a 50% increase in malate-glutamate state 4 respiratory rates was observed after DACT treatment (100 µM) without changes in respiratory state 3. Atrazine was able to inhibit complex I-III activity by 30% and DACT induced a tendency to decrease by 17% in the striatum. Regarding reactive oxygen species (ROS), DACT increased H2 O2 production by 43%. Also, superoxide anion levels were higher (14%) after atrazine exposure than in control mitochondria. Incubation of striatal mitochondria with atrazine and DACT induced membrane depolarization by 15% and 19%, respectively. Also, atrazine increased NO content by 10% but no significant changes were observed after exposure of mitochondria to DACT. Glutathione peroxidase activity was inhibited (56%) by DACT and atrazine inhibited superoxide dismutase activity by 60%. Also, cardiolipin oxidation (15%) was observed after atrazine treatment. Summing up, the obtained results suggest that in vitro atrazine and DACT induce ROS production affecting striatal mitochondrial function. The atrazine effects would be attributed to a direct effect on the mitochondrial respiratory chain and superoxide dismutase activity while DACT appears to disturb glutathione-related enzyme system.
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Affiliation(s)
- Analía G Karadayian
- Facultad de Farmacia y Bioquímica, Fisicoquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Bioquímica y Medicina Molecular (IBIMOL), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Bárbara Paez
- Facultad de Farmacia y Bioquímica, Fisicoquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juanita Bustamante
- Facultad de Farmacia y Bioquímica, Fisicoquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Silvia Lores-Arnaiz
- Facultad de Farmacia y Bioquímica, Fisicoquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Bioquímica y Medicina Molecular (IBIMOL), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Analía Czerniczyniec
- Facultad de Farmacia y Bioquímica, Fisicoquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto de Bioquímica y Medicina Molecular (IBIMOL), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
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15
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Nesterov SV, Yaguzhinsky LS, Vasilov RG, Kadantsev VN, Goltsov AN. Contribution of the Collective Excitations to the Coupled Proton and Energy Transport along Mitochondrial Cristae Membrane in Oxidative Phosphorylation System. ENTROPY (BASEL, SWITZERLAND) 2022; 24:1813. [PMID: 36554218 PMCID: PMC9778164 DOI: 10.3390/e24121813] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 06/17/2023]
Abstract
The results of many experimental and theoretical works indicate that after transport of protons across the mitochondrial inner membrane (MIM) in the oxidative phosphorylation (OXPHOS) system, they are retained on the membrane-water interface in nonequilibrium state with free energy excess due to low proton surface-to-bulk release. This well-established phenomenon suggests that proton trapping on the membrane interface ensures vectorial lateral transport of protons from proton pumps to ATP synthases (proton acceptors). Despite the key role of the proton transport in bioenergetics, the molecular mechanism of proton transfer in the OXPHOS system is not yet completely established. Here, we developed a dynamics model of long-range transport of energized protons along the MIM accompanied by collective excitation of localized waves propagating on the membrane surface. Our model is based on the new data on the macromolecular organization of the OXPHOS system showing the well-ordered structure of respirasomes and ATP synthases on the cristae membrane folds. We developed a two-component dynamics model of the proton transport considering two coupled subsystems: the ordered hydrogen bond (HB) chain of water molecules and lipid headgroups of MIM. We analytically obtained a two-component soliton solution in this model, which describes the motion of the proton kink, corresponding to successive proton hops in the HB chain, and coherent motion of a compression soliton in the chain of lipid headgroups. The local deformation in a soliton range facilitates proton jumps due to water molecules approaching each other in the HB chain. We suggested that the proton-conducting structures formed along the cristae membrane surface promote direct lateral proton transfer in the OXPHOS system. Collective excitations at the water-membrane interface in a form of two-component soliton ensure the coupled non-dissipative transport of charge carriers and elastic energy of MIM deformation to ATP synthases that may be utilized in ATP synthesis providing maximal efficiency in mitochondrial bioenergetics.
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Affiliation(s)
- Semen V. Nesterov
- Kurchatov Complex of NBICS-Technologies, National Research Center Kurchatov Institute, 123182 Moscow, Russia
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | - Lev S. Yaguzhinsky
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
- Department of Bioenergetics, Institute of Cytochemistry and Molecular Pharmacology, 115404 Moscow, Russia
- Belozersky Research Institute for Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Raif G. Vasilov
- Kurchatov Complex of NBICS-Technologies, National Research Center Kurchatov Institute, 123182 Moscow, Russia
| | - Vasiliy N. Kadantsev
- Institute for Artificial Intelligence, Russian Technological University (MIREA), 119454 Moscow, Russia
| | - Alexey N. Goltsov
- Institute for Artificial Intelligence, Russian Technological University (MIREA), 119454 Moscow, Russia
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16
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Sun F, Zhao W, Shen H, Fan N, Zhang J, Liu Q, Xu C, Luo J, Zhao M, Chen Y, Lam KWK, Yang X, Kwok RTK, Lam JWY, Sun J, Zhang H, Tang BZ. Design of Smart Aggregates: Toward Rapid Clinical Diagnosis of Hyperlipidemia in Human Blood. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2207671. [PMID: 36134528 DOI: 10.1002/adma.202207671] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/10/2022] [Indexed: 06/16/2023]
Abstract
Molecular aggregates with environmental responsive properties are desired for their wide practical applications such as bioprobes. Here, a series of smart near-infrared (NIR) luminogens for hyperlipidemia (HLP) diagnosis is reported. The aggregates of these molecules exhibit a twisted intramolecular charge-transfer effect in aqueous media, but aggregation-induced emission in highly viscous media due to the restriction of the intramolecular motion. These aggregates, which can autonomously respond to different environments via switching the aggregation state without changing their chemical structures are described, as "smart aggregates". Intriguingly, these luminogens demonstrate NIR-II and NIR-III luminescence with ultralarge Stokes shifts (>950 nm). Both in vitro detection and in vivo imaging of HLP can be realized in a mouse model. Linear relationships exist between the emission intensity and multiple pathological parameters in blood samples of HLP patients. Thus, the design of smart aggregate facilitates rapid and accurate detection of HLP and provides a promising attempt in aggregate science.
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Affiliation(s)
- Feiyi Sun
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Wei Zhao
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Hanchen Shen
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Ni Fan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, 999077, P. R. China
| | - Jianyu Zhang
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Qingqing Liu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, 999077, P. R. China
| | - Changhuo Xu
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Jiaming Luo
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Mengying Zhao
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Yuyang Chen
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Kristy W K Lam
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Xueqin Yang
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Ryan T K Kwok
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Jacky W Y Lam
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Jianwei Sun
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
| | - Hongfei Zhang
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Ben Zhong Tang
- Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Guangdong-Hong Kong-Macau Joint Laboratory of Optoelectronic and Magnetic Functional Materials, Division of Life Science, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 999077, P. R. China
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen, 518172, P. R. China
- Center of Aggregation-Induced Emission, South China University of Technology, Guangzhou, 510640, P. R. China
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17
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Mackert O, Wirth EK, Sun R, Winkler J, Liu A, Renko K, Kunz S, Spranger J, Brachs S. Impact of metabolic stress induced by diets, aging and fasting on tissue oxygen consumption. Mol Metab 2022; 64:101563. [PMID: 35944898 PMCID: PMC9418990 DOI: 10.1016/j.molmet.2022.101563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Alterations in mitochondrial function play an important role in the development of various diseases, such as obesity, insulin resistance, steatohepatitis, atherosclerosis and cancer. However, accurate assessment of mitochondrial respiration ex vivo is limited and remains highly challenging. Using our novel method, we measured mitochondrial oxygen consumption (OCR) and extracellular acidification rate (ECAR) of metabolically relevant tissues ex vivo to investigate the impact of different metabolic stressors on mitochondrial function. METHODS Comparative analyses of OCR and ECAR were performed in tissue biopsies of young mice fed 12 weeks standard-control (STD), high-fat (HFD), high-sucrose (HSD), or western diet (WD), matured mice with HFD, and 2year-old mice aged on STD with and without fasting. RESULTS While diets had only marginal effects on mitochondrial respiration, respiratory chain complexes II and IV were reduced in adipose tissue (AT). Moreover, matured HFD-fed mice showed a decreased hepatic metabolic flexibility and prolonged aging increased OCR in brown AT. Interestingly, fasting boosted pancreatic and hepatic OCR while decreasing weight of those organs. Furthermore, ECAR measurements in AT could indicate its lipolytic capacity. CONCLUSION Using ex vivo tissue measurements, we could extensively analyze mitochondrial function of liver, AT, pancreas and heart revealing effects of metabolic stress, especially aging.
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Affiliation(s)
- Olena Mackert
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
| | - Eva Katrin Wirth
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany
| | - Rongwan Sun
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany
| | - Jennifer Winkler
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
| | - Aoxue Liu
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany
| | - Kostja Renko
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Berlin, Germany
| | - Séverine Kunz
- Technology Platform for Electron Microscopy at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Joachim Spranger
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany.
| | - Sebastian Brachs
- Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany
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18
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Zhang J, Shi Y. In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases. Cells 2022; 11:cells11121906. [PMID: 35741033 PMCID: PMC9221202 DOI: 10.3390/cells11121906] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/08/2022] [Accepted: 06/10/2022] [Indexed: 12/15/2022] Open
Abstract
Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mtDNA bioenergetics, and mitophagy. The depletion or abnormal acyl composition of CL causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and age-related disorders. However, the molecular mechanisms by which mitochondrial dysfunction causes age-related diseases remain poorly understood. Recent development in the field has identified acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase upregulated by oxidative stress, as a key enzyme that promotes mitochondrial dysfunction in age-related diseases. ALCAT1 catalyzes CL remodeling with very-long-chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL becomes a new source of ROS in the form of lipid peroxides, leading to a vicious cycle of oxidative stress, CL depletion, and mitochondrial dysfunction. Consequently, ablation or the pharmacological inhibition of ALCAT1 have been shown to mitigate obesity, type 2 diabetes, heart failure, cardiomyopathy, fatty liver diseases, neurodegenerative diseases, and cancer. The findings suggest that age-related disorders are one disease (aging) manifested by different mitochondrion-sensitive tissues, and therefore should be treated as one disease. This review will discuss a unified hypothesis on CL remodeling by ALCAT1 as the common denominator of mitochondrial dysfunction, linking mitochondrial dysfunction to the development of age-related diseases.
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Affiliation(s)
| | - Yuguang Shi
- Correspondence: ; Tel.: +1-210-450-1363; Fax: +1-210-562-6150
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19
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Fang Y, Zhan Y, Xie Y, Du S, Chen Y, Zeng Z, Zhang Y, Chen K, Wang Y, Liang L, Ding Y, Wu D. Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC. Hepatology 2022; 75:1386-1401. [PMID: 34580888 PMCID: PMC9299851 DOI: 10.1002/hep.32177] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 08/26/2021] [Accepted: 09/24/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC). APPROACH AND RESULTS Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio-resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling-mediated translational control of hypoxia inducible factor-1α (HIF-1α) and sterol regulatory element-binding protein-1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. CONCLUSIONS We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.
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Affiliation(s)
- Yuan Fang
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Yizhi Zhan
- Department of PathologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong ProvinceChina
- Guangdong Province Key Laboratory of Molecular Tumor PathologyGuangzhouGuangdong ProvinceChina
| | - Yuwen Xie
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Shisuo Du
- Department of Radiation OncologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Yuhan Chen
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Zhaochong Zeng
- Department of Radiation OncologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Yaowei Zhang
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Keli Chen
- Huiqiao Medical CenterNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Yongjia Wang
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Li Liang
- Department of PathologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong ProvinceChina
- Guangdong Province Key Laboratory of Molecular Tumor PathologyGuangzhouGuangdong ProvinceChina
| | - Yi Ding
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
| | - Dehua Wu
- Department of Radiation OncologyNanfang Hospital, Southern Medical UniversityGuangzhouGuangdong ProvinceChina
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20
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Awad K, Sayed A, Banach M. Coenzyme Q10 Reduces Infarct Size in Animal Models of Myocardial Ischemia-Reperfusion Injury: A Meta-Analysis and Summary of Underlying Mechanisms. Front Cardiovasc Med 2022; 9:857364. [PMID: 35498032 PMCID: PMC9053645 DOI: 10.3389/fcvm.2022.857364] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/15/2022] [Indexed: 01/14/2023] Open
Abstract
Objective Effective interventions that might limit myocardial ischemia-reperfusion (I/R) injury are still lacking. Coenzyme Q10 (CoQ10) may exert cardioprotective actions that reduce myocardial I/R injury. We conducted this meta-analysis to assess the potential cardioprotective effect of CoQ10 in animal models of myocardial I/R injury. Methods We searched PubMed and Embase databases from inception to February 2022 to identify animal studies that compared the effect of CoQ10 with vehicle treatment or no treatment on myocardial infarct size in models of myocardial I/R injury. Means and standard deviations of the infarct size measurements were pooled as the weighted mean difference with 95% confidence interval (CI) using the random-effects model. Subgroup analyses were also conducted according to animals' species, models' type, and reperfusion time. Results Six animal studies (4 in vivo and 2 ex vivo) with 116 animals were included. Pooled analysis suggested that CoQ10 significantly reduced myocardial infarct size by −11.36% (95% CI: −16.82, −5.90, p < 0.0001, I2 = 94%) compared with the control group. The significance of the pooled effect estimate was maintained in rats, Hartley guinea pigs, and Yorkshire pigs. However, it became insignificant in the subgroup of rabbits −5.29% (95% CI: −27.83, 17.26; I2 = 87%). Furthermore, CoQ10 significantly reduced the myocardial infarct size regardless of model type (either in vivo or ex vivo) and reperfusion time (either ≤ 4 h or >4 h). Conclusion Coenzyme Q10 significantly decreased myocardial infarct size by 11.36% compared with the control group in animal models of myocardial I/R injury. This beneficial action was retained regardless of model type and reperfusion time.
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Affiliation(s)
- Kamal Awad
- Faculty of Medicine, Zagazig University, Zagazig, Egypt
- Zagazig University Hospitals, Zagazig, Egypt
- *Correspondence: Kamal Awad
| | - Ahmed Sayed
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Chair of Nephrology and Hypertension, Medical University of Lodz (MUL), Lodz, Poland
- Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
- Maciej Banach
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21
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Hosseinzadeh A, Mehrzadi S, Rezaei M, Badavi M, Nesari A, Goudarzi M. Lovastatin attenuates glyoxal-induced toxicity on rat liver mitochondria. Hum Exp Toxicol 2021; 40:2215-2222. [PMID: 34165024 DOI: 10.1177/09603271211027939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Alpha-dicarbonyls such as glyoxal (GO) trigger mitochondrial dysfunction resulting in the development of different diabetic complications. The present study investigated the effects of lovastatin against GO-induced toxicity on rat liver mitochondria. The rat liver mitochondria (0.5 mg protein/mL) were treated with various concentrations of lovastatin (1, 5, 10 µM) at 37°C for 30 min and then exposed to GO (3 mM) at 37°C for 30 min. Oxidative stress markers including MDA, reactive oxygen species (ROS), glutathione (GSH) and protein carbonylation (PC) level were measured. Mitochondrial complex II activity and mitochondrial membrane potential (MMP) were assessed for evaluating mitochondrial function. Glyoxal significantly increased the level of ROS, PC and MDA. This effect was associated with the reduction of MMP, complex II activity and GSH content. Pre-treatment with lovastatin potentially reversed GO-induced mitochondrial toxicity. These results suggest that lovastatin have a protective effect against GO-induced toxicity in isolated rat liver mitochondria.
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Affiliation(s)
- A Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - S Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - M Rezaei
- Research center of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - M Badavi
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - A Nesari
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - M Goudarzi
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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22
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Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms222111682. [PMID: 34769112 PMCID: PMC8584226 DOI: 10.3390/ijms222111682] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/20/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic inflammation within the gastrointestinal (GI) tract. Despite the significant progress in understanding the etiology and development of treatment strategies, IBD remain incurable for thousands of patients. Metabolic deregulation is indicative of IBD, including substantial shifts in lipid metabolism. Recent data showed that changes in some phospholipids are very common in IBD patients. For instance, phosphatidylcholine (PC)/phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC)/PC ratios are associated with the severity of the inflammatory process. Composition of phospholipids also changes upon IBD towards an increase in arachidonic acid and a decrease in linoleic and a-linolenic acid levels. Moreover, an increase in certain phospholipid metabolites, such as lysophosphatidylcholine, sphingosine-1-phosphate and ceramide, can result in enhanced intestinal inflammation, malignancy, apoptosis or necroptosis. Because some phospholipids are associated with pathogenesis of IBD, they may provide a basis for new strategies to treat IBD. Current attempts are aimed at controlling phospholipid and fatty acid levels through the diet or via pharmacological manipulation of lipid metabolism.
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23
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Pacheco R, Quezada SA, Kalergis AM, Becker MI, Ferreira J, De Ioannes AE. Allergens of the urushiol family promote mitochondrial dysfunction by inhibiting the electron transport at the level of cytochromes b and chemically modify cytochrome c 1. Biol Res 2021; 54:35. [PMID: 34711292 PMCID: PMC8554850 DOI: 10.1186/s40659-021-00357-z] [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: 07/09/2021] [Accepted: 10/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8+ effector T-cells and downregulated by CD4+ T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms by which urushiols initiate the allergic response. Results Electron microscopy observations of mouse ears exposed to litreol (3-n-pentadecyl-10-enyl-catechol]) showed keratinocytes containing swollen mitochondria with round electron-dense inclusion bodies in the matrix. Biochemical analyses of sub-mitochondrial fractions revealed an inhibitory effect of urushiols on electron flow through the mitochondrial respiratory chain, which requires both the aliphatic and catecholic moieties of these allergens. Moreover, urushiols extracted from poison ivy/oak (mixtures of 3-n-pentadecyl-8,11,13 enyl/3-n-heptadecyl-8,11 enyl catechol) exerted a higher inhibitory effect on mitochondrial respiration than did pentadecyl catechol or litreol, indicating that the higher number of unsaturations in the aliphatic chain, stronger the allergenicity of urushiols. Furthermore, the analysis of radioactive proteins isolated from mitochondria incubated with 3H-litreol, indicated that this urushiol was bound to cytochrome c1. According to the proximity of cytochromes c1 and b, functional evidence indicated the site of electron flow inhibition was within complex III, in between cytochromes bL (cyt b566) and bH (cyt b562). Conclusion Our data provide functional and molecular evidence indicating that the interruption of the mitochondrial electron transport chain constitutes an important mechanism by which urushiols initiates the allergic response. Thus, mitochondria may constitute a source of cellular targets for generating neoantigens involved in the T-cell mediated allergy induced by urushiols. Supplementary Information The online version contains supplementary material available at 10.1186/s40659-021-00357-z.
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Affiliation(s)
- Rodrigo Pacheco
- Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Santiago, Chile. .,Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile.
| | - Sergio A Quezada
- Cancer Immunology Unit, University College London (UCL) Cancer Institute, London, England, UK
| | - Alexis M Kalergis
- Instituto Milenio de Inmunología e Inmunoterapia, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
| | - María Inés Becker
- Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago, Chile.,Department of Research and Development, Biosonda Corporation, Santiago, Chile.,Faculty of Physical and Mathematical Sciences, Department of Chemical Engineering, Biotechnology and Materials, Universidad de Chile, Santiago, Chile
| | - Jorge Ferreira
- Faculty of Medicine, Institute of Biomedical Sciences, Molecular and Clinical Pharmacology Program, Universidad de Chile, Santiago, Chile
| | - Alfredo E De Ioannes
- Department of Research and Development, Biosonda Corporation, Santiago, Chile.,Faculty of Physical and Mathematical Sciences, Department of Chemical Engineering, Biotechnology and Materials, Universidad de Chile, Santiago, Chile.,Faculty of Medicine, Institute of Biomedical Sciences, Molecular and Clinical Pharmacology Program, Universidad de Chile, Santiago, Chile
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24
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Wang ST, Ning HQ, Feng LH, Wang YY, Li YQ, Mo HZ. Oxidative phosphorylation system as the target of glycinin basic peptide against Aspergillus niger. Lebensm Wiss Technol 2021. [DOI: 10.1016/j.lwt.2021.111977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Sedlák E, Žár T, Varhač R, Musatov A, Tomášková N. Anion-Specific Effects on the Alkaline State of Cytochrome c. BIOCHEMISTRY (MOSCOW) 2021; 86:59-73. [PMID: 33705282 DOI: 10.1134/s0006297921010065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Specific effects of anions on the structure, thermal stability, and peroxidase activity of native (state III) and alkaline (state IV) cytochrome c (cyt c) have been studied by the UV-VIS absorbance spectroscopy, intrinsic tryptophan fluorescence, and circular dichroism. Thermal and isothermal denaturation monitored by the tryptophan fluorescence and circular dichroism, respectively, implied lower stability of cyt c state IV in comparison with the state III. The pKa value of alkaline isomerization of cyt c depended on the present salts, i.e., kosmotropic anions increased and chaotropic anions decreased pKa (Hofmeister effect on protein stability). The peroxidase activity of cyt c in the state III, measured by oxidation of guaiacol, showed clear dependence on the salt position in the Hofmeister series, while cyt c in the alkaline state lacked the peroxidase activity regardless of the type of anions present in the solution. The alkaline isomerization of cyt c in the presence of 8 M urea, measured by Trp59 fluorescence, implied an existence of a high-affinity non-native ligand for the heme iron even in a partially denatured protein conformation. The conformation of the cyt c alkaline state in 8 M urea was considerably modulated by the specific effect of anions. Based on the Trp59 fluorescence quenching upon titration to alkaline pH in 8 M urea and molecular dynamics simulation, we hypothesize that the Lys79 conformer is most likely the predominant alkaline conformer of cyt c. The high affinity of the sixth ligand for the heme iron is likely a reason of the lack of peroxidase activity of cyt c in the alkaline state.
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Affiliation(s)
- Erik Sedlák
- Department of Biochemistry, Faculty of Science, P. J. Šafárik University in Košice, Košice, 04154, Slovakia. .,Centre for Interdisciplinary Biosciences, P. J. Šafárik University in Košice, Košice, 04154, Slovakia
| | - Tibor Žár
- Centre for Interdisciplinary Biosciences, P. J. Šafárik University in Košice, Košice, 04154, Slovakia.
| | - Rastislav Varhač
- Department of Biochemistry, Faculty of Science, P. J. Šafárik University in Košice, Košice, 04154, Slovakia.
| | - Andrej Musatov
- Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Košice, 040 01, Slovakia.
| | - Nataša Tomášková
- Department of Biochemistry, Faculty of Science, P. J. Šafárik University in Košice, Košice, 04154, Slovakia.
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Rezaei M, Kalantari H, Mehrzadi S, Goudarzi M. Synergy Effects of Metformin and Berberine on Glyoxal-induced Carbonyl Stress in Isolated Rat Liver Mitochondria. CURRENT DRUG THERAPY 2021. [DOI: 10.2174/1574885515666200214122055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective:
Carbonyl stress, resulting from toxic effects of alpha-dicarbonyls such as
glyoxal (GO), plays an important role in mitochondrial dysfunction and subsequent development of
diabetic complications. This study evaluated the ability of metformin (MET), berberine (BBR), and
their combination to prevent GO-induced carbonyl stress in isolated rat liver mitochondria.
Methods:
Mitochondria (0.5 mg protein/mL) were isolated from the Wistar rat liver and incubated
with various concentrations of GO (1, 2.5, 5, 7.5, and 10 mM) for 30 minutes and IC50 for GO was
calculated. The suspensions of mitochondria were incubated with various concentrations of MET
(2.5, 5, 10, and 20 mM) or BBR (2.5, 5, 10, and 20 μM) for 30 min and then GO in a dose of IC50
at 37 ºC for 30 min. Mitochondrial complex II activity, mitochondrial membrane potential (MMP),
MDA level, reactive oxygen species (ROS) formation, reduced glutathione (GSH) content, and
protein carbonylation were assessed. The combination index and isobologram of MET and BBR on
GO toxicity were calculated.
Results:
IC50 of GO was assigned approximately 3 mM. GO disrupted the electron transfer chain
and significantly increased mitochondrial ROS formation, protein carbonylation, and MDA level.
GO decreased mitochondrial viability, MMP, and GSH content. Pre-treatment with MET and BBR
could potentially reverse GO-induced deleterious effects in a concentration-dependent manner.
Results of the drug combination indicated that CI for Fa 0.5 (Effect 50 %) was 0.83.
Conclusion:
These results suggest that BBR in combination with MET has a moderate synergistic
effect on GO-induced carbonyl stress in isolated rat liver mitochondria.
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Affiliation(s)
- Mohsen Rezaei
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Heibatullah Kalantari
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Goudarzi
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Tu C, Xiong H, Hu Y, Wang W, Mei G, Wang H, Li Y, Zhou Z, Meng F, Zhang P, Mei Z. Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation. Hepatology 2020; 72:1949-1967. [PMID: 32096565 DOI: 10.1002/hep.31202] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 01/18/2020] [Accepted: 02/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. APPROACH AND RESULTS Here, we discovered that CRLS1 was significantly down-regulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA-mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocyte-specific Crls1-knockout (Crls1-HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol diet-induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. CONCLUSIONS In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3.
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Affiliation(s)
- Chuyue Tu
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Hui Xiong
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yufeng Hu
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wen Wang
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Gui Mei
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Hua Wang
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Ya Li
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Zelin Zhou
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Fengping Meng
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Peng Zhang
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhinan Mei
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
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28
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Western Diet Causes Obesity-Induced Nonalcoholic Fatty Liver Disease Development by Differentially Compromising the Autophagic Response. Antioxidants (Basel) 2020; 9:antiox9100995. [PMID: 33076261 PMCID: PMC7602470 DOI: 10.3390/antiox9100995] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by the development of steatosis, which can ultimately compromise liver function. Mitochondria are key players in obesity-induced metabolic disorders; however, the distinct role of hypercaloric diet constituents in hepatic cellular oxidative stress and metabolism is unknown. Male mice were fed either a high-fat (HF) diet, a high-sucrose (HS) diet or a combined HF plus HS (HFHS) diet for 16 weeks. This study shows that hypercaloric diets caused steatosis; however, the HFHS diet induced severe fibrotic phenotype. At the mitochondrial level, lipidomic analysis showed an increased cardiolipin content for all tested diets. Despite this, no alterations were found in the coupling efficiency of oxidative phosphorylation and neither in mitochondrial fatty acid oxidation (FAO). Consistent with unchanged mitochondrial function, no alterations in mitochondrial-induced reactive oxygen species (ROS) and antioxidant capacity were found. In contrast, the HF and HS diets caused lipid peroxidation and provoked altered antioxidant enzyme levels/activities in liver tissue. Our work provides evidence that hepatic oxidative damage may be caused by augmented levels of peroxisomes and consequently higher peroxisomal FAO-induced ROS in the early NAFLD stage. Hepatic damage is also associated with autophagic flux impairment, which was demonstrated to be diet-type dependent. The HS diet induced a reduction in autophagosomal formation, while the HF diet reduced levels of cathepsins. The accumulation of damaged organelles could instigate hepatocyte injuries and NAFLD progression.
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29
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Webb M, Sideris DP. Intimate Relations-Mitochondria and Ageing. Int J Mol Sci 2020; 21:ijms21207580. [PMID: 33066461 PMCID: PMC7589147 DOI: 10.3390/ijms21207580] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction.
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Affiliation(s)
- Michael Webb
- Mitobridge Inc., an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA
| | - Dionisia P Sideris
- Mitobridge Inc., an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA
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30
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Toth A, Aufschnaiter A, Fedotovskaya O, Dawitz H, Ädelroth P, Büttner S, Ott M. Membrane-tethering of cytochrome c accelerates regulated cell death in yeast. Cell Death Dis 2020; 11:722. [PMID: 32892209 PMCID: PMC7474732 DOI: 10.1038/s41419-020-02920-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/18/2022]
Abstract
Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome c into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome c release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome c release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome c with a transmembrane segment to the inner mitochondrial membrane of the yeast Saccharomyces cerevisiae, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome c retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome c from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome c within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome.
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Affiliation(s)
- Alexandra Toth
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Svante Arrheniusväg 16, 106 91, Stockholm, Sweden
| | - Andreas Aufschnaiter
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Svante Arrheniusväg 16, 106 91, Stockholm, Sweden
- Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50, 8010, Graz, Austria
| | - Olga Fedotovskaya
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Svante Arrheniusväg 16, 106 91, Stockholm, Sweden
| | - Hannah Dawitz
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Svante Arrheniusväg 16, 106 91, Stockholm, Sweden
| | - Pia Ädelroth
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Svante Arrheniusväg 16, 106 91, Stockholm, Sweden
| | - Sabrina Büttner
- Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50, 8010, Graz, Austria.
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 106 91, Stockholm, Sweden.
| | - Martin Ott
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Svante Arrheniusväg 16, 106 91, Stockholm, Sweden.
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31
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Yan J, Jiang J, He L, Chen L. Mitochondrial superoxide/hydrogen peroxide: An emerging therapeutic target for metabolic diseases. Free Radic Biol Med 2020; 152:33-42. [PMID: 32160947 DOI: 10.1016/j.freeradbiomed.2020.02.029] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 02/22/2020] [Accepted: 02/27/2020] [Indexed: 12/11/2022]
Abstract
Mitochondria are well known for their roles as energy and metabolic factory. Mitochondrial reactive oxygen species (mtROS) refer to superoxide anion radical (•O2-) and hydrogen peroxide (H2O2). They are byproducts of electron transport in mitochondrial respiratory chain and are implicated in the regulation of physiological and pathological signal transduction. Especially when mitochondrial •O2-/H2O2 production is disturbed, this disturbance is closely related to the occurrence and development of metabolic diseases. In this review, the sources of mitochondrial •O2-/H2O2 as well as mitochondrial antioxidant mechanisms are summarized. Furthermore, we particularly emphasize the essential role of mitochondrial •O2-/H2O2 in metabolic diseases. Specifically, perturbed mitochondrial •O2-/H2O2 regulation aggravates the progression of metabolic diseases, including diabetes, gout and nonalcoholic fatty liver disease (NAFLD). Given the deleterious effect of mitochondrial •O2-/H2O2 in the development of metabolic diseases, antioxidants targeting mitochondrial •O2-/H2O2 might be an attractive therapeutic approach for the prevention and treatment of metabolic diseases.
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Affiliation(s)
- Jialong Yan
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China
| | - Jinyong Jiang
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China
| | - Lu He
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, China.
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China.
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Functional Mechanisms of Mitochondrial Respiratory Chain Supercomplex Assembly Factors and Their Involvement in Muscle Quality. Int J Mol Sci 2020; 21:ijms21093182. [PMID: 32365950 PMCID: PMC7246575 DOI: 10.3390/ijms21093182] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/23/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022] Open
Abstract
Impairment of skeletal muscle function causes disabilities in elderly people. Therefore, in an aged society, prevention and treatment of sarcopenia are important for expanding healthy life expectancy. In addition to aging, adipose tissue disfunction and inflammation also contribute to the pathogenesis of sarcopenia by causing the combined state called ‘sarcopenic obesity’. Muscle quality as well as muscle mass contributes to muscle strength and physical performance. Mitochondria in the skeletal muscles affect muscle quality by regulating the production of energy and reactive oxygen species. A certain portion of the mitochondrial respiratory chain complexes form a higher-order structure called a “supercomplex”, which plays important roles in efficient energy production, stabilization of respiratory chain complex I, and prevention of reactive oxygen species (ROS) generation. Several molecules including phospholipids, proteins, and certain chemicals are known to promote or stabilize mitochondrial respiratory chain supercomplex assembly directly or indirectly. In this article, we review the distinct mechanisms underlying the promotion or stabilization of mitochondrial respiratory chain supercomplex assembly by supercomplex assembly factors. Further, we introduce regulatory pathways of mitochondrial respiratory chain supercomplex assembly and discuss the roles of supercomplex assembly factors and regulatory pathways in skeletal muscles and adipose tissues, believing that this will lead to discovery of potential targets for prevention and treatment of muscle disorders such as sarcopenia.
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33
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Chen G, Kroemer G, Kepp O. Mitophagy: An Emerging Role in Aging and Age-Associated Diseases. Front Cell Dev Biol 2020; 8:200. [PMID: 32274386 PMCID: PMC7113588 DOI: 10.3389/fcell.2020.00200] [Citation(s) in RCA: 238] [Impact Index Per Article: 47.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/09/2020] [Indexed: 12/15/2022] Open
Abstract
Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA (mtDNA) mutations, increased production of mitochondrial reactive oxygen species (ROS) and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies.
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Affiliation(s)
- Guo Chen
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Guido Kroemer
- Gustave Roussy Cancer Campus, Villejuif, France
- INSERM, UMR 1138, Centre de Recherche des Cordeliers, Paris, France
- Equipe 11 Labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université de Paris, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Sorbonne Université, Paris, France
- Université Paris-Saclay, Faculté de Médecine, Kremlin-Bicêtre, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China
- Karolinska Institute, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden
| | - Oliver Kepp
- Gustave Roussy Cancer Campus, Villejuif, France
- INSERM, UMR 1138, Centre de Recherche des Cordeliers, Paris, France
- Equipe 11 Labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- Université de Paris, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Sorbonne Université, Paris, France
- Université Paris-Saclay, Faculté de Médecine, Kremlin-Bicêtre, France
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34
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The Role of Cardiolipin and Mitochondrial Damage in Kidney Transplant. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3836186. [PMID: 31885786 PMCID: PMC6899302 DOI: 10.1155/2019/3836186] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/27/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023]
Abstract
Chronic kidney disease (CKD) is highly incident and prevalent in the world. The death of patients with CKD is primarily due to cardiovascular disease. Renal transplantation (RT) emerges as the best management alternative for patients with CKD. However, the incidence of acute renal graft dysfunction is 11.8% of the related living donor and 17.4% of the cadaveric donor. Anticardiolipin antibodies (ACAs) or antiphospholipid antibodies (APAs) are important risk factors for acute renal graft dysfunction. The determination of ACA or APA to candidates for RT could serve as prognostic markers of early graft failure and would indicate which patients could benefit from anticoagulant therapy. Cardiolipin is a fundamental molecule that plays an important role in the adequate conformation of the mitochondrial cristae and the correct assembly of the mitochondrial respiratory supercomplexes and other proteins essential for proper mitochondrial function. Cardiolipin undergoes a nonrandom oxidation process by having pronounced specificity unrelated to the polyunsaturation pattern of its acyl groups. Accumulation of hydroxyl derivatives and cardiolipin hydroperoxides has been observed in the affected tissues, and recent studies showed that oxidation of cardiolipin is carried out by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. Cardiolipin could be responsible for the proapoptotic production of death signals. Cardiolipin modulates the production of energy and participates in inflammation, mitophagy, and cellular apoptosis. The determination of cardiolipin or its antibodies is an attractive therapeutic, diagnostic target in RT and kidney diseases.
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35
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The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury. Antioxidants (Basel) 2019; 8:antiox8100454. [PMID: 31590423 PMCID: PMC6826663 DOI: 10.3390/antiox8100454] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 09/30/2019] [Accepted: 10/01/2019] [Indexed: 01/11/2023] Open
Abstract
Mitochondria play a critical role in maintaining cellular function by ATP production. They are also a source of reactive oxygen species (ROS) and proapoptotic factors. The role of mitochondria has been established in many aspects of cell physiology/pathophysiology, including cell signaling. Mitochondria may deteriorate under various pathological conditions, including ischemia-reperfusion (IR) injury. Mitochondrial injury can be one of the main causes for cardiac and other tissue injuries by energy stress and overproduction of toxic reactive oxygen species, leading to oxidative stress, elevated calcium and apoptotic and necrotic cell death. However, the interplay among these processes in normal and pathological conditions is still poorly understood. Mitochondria play a critical role in cardiac IR injury, where they are directly involved in several pathophysiological mechanisms. We also discuss the role of mitochondria in the context of mitochondrial dynamics, specializations and heterogeneity. Also, we wanted to stress the existence of morphologically and functionally different mitochondrial subpopulations in the heart that may have different sensitivities to diseases and IR injury. Therefore, various cardioprotective interventions that modulate mitochondrial stability, dynamics and turnover, including various pharmacologic agents, specific mitochondrial antioxidants and uncouplers, and ischemic preconditioning can be considered as the main strategies to protect mitochondrial and cardiovascular function and thus enhance longevity.
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36
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Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects. Cells 2019; 8:cells8070728. [PMID: 31315173 PMCID: PMC6678812 DOI: 10.3390/cells8070728] [Citation(s) in RCA: 283] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/12/2019] [Accepted: 07/14/2019] [Indexed: 12/12/2022] Open
Abstract
In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.
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Affiliation(s)
- Giuseppe Paradies
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.
| | | | - Francesca M Ruggiero
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
| | - Giuseppe Petrosillo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), 70126 Bari, Italy.
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37
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Panchal K, Tiwari AK. Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion 2019; 47:151-173. [PMID: 30408594 DOI: 10.1016/j.mito.2018.11.002] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 10/08/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022]
Abstract
Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well-studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions.
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Affiliation(s)
- Komal Panchal
- Genetics & Developmental Biology Laboratory, School of Biological Sciences & Biotechnology, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar 382426, India
| | - Anand Krishna Tiwari
- Genetics & Developmental Biology Laboratory, School of Biological Sciences & Biotechnology, Institute of Advanced Research (IAR), Koba, Institutional Area, Gandhinagar 382426, India.
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38
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Ait-Aissa K, Blaszak SC, Beutner G, Tsaih SW, Morgan G, Santos JH, Flister MJ, Joyce DL, Camara AKS, Gutterman DD, Donato AJ, Porter GA, Beyer AM. Mitochondrial Oxidative Phosphorylation defect in the Heart of Subjects with Coronary Artery Disease. Sci Rep 2019; 9:7623. [PMID: 31110224 PMCID: PMC6527853 DOI: 10.1038/s41598-019-43761-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 12/06/2018] [Indexed: 12/21/2022] Open
Abstract
Coronary artery disease (CAD) is a leading cause of death worldwide and frequently associated with mitochondrial dysfunction. Detailed understanding of abnormalities in mitochondrial function that occur in patients with CAD is lacking. We evaluated mitochondrial damage, energy production, and mitochondrial complex activity in human non-CAD and CAD hearts. Fresh and frozen human heart tissue was used. Cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA (mtDNA), NAD + and ATP levels, and mitochondrial oxidative phosphorylation capacity were evaluated. Proteins critical to the regulation of mitochondrial metabolism and function were also evaluated in tissue lysates. PCR analysis revealed an increase in mtDNA lesions and the frequency of mitochondrial common deletion, both established markers for impaired mitochondrial integrity in CAD compared to non-CAD patient samples. NAD+ and ATP levels were significantly decreased in CAD subjects compared to Non-CAD (NAD+ fold change: non-CAD 1.00 ± 0.17 vs. CAD 0.32 ± 0.12* and ATP fold change: non-CAD 1.00 ± 0.294 vs. CAD 0.01 ± 0.001*; N = 15, P < 0.005). We observed decreased respiration control index in CAD tissue and decreased activity of complexes I, II, and III. Expression of ETC complex subunits and respirasome formation were increased; however, elevations in the de-active form of complex I were observed in CAD. We observed a corresponding increase in glycolytic flux, indicated by a rise in pyruvate kinase and lactate dehydrogenase activity, indicating a compensatory increase in glycolysis for cellular energetics. Together, these results indicate a shift in mitochondrial metabolism from oxidative phosphorylation to glycolysis in human hearts subjects with CAD.
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Affiliation(s)
- Karima Ait-Aissa
- Cardiovascular Center, Department of Medicine, Med College of Wisconsin, Milwaukee, WI, USA.
| | - Scott C Blaszak
- Cardiovascular Center, Department of Medicine, Med College of Wisconsin, Milwaukee, WI, USA
| | - Gisela Beutner
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA
| | - Shirng-Wern Tsaih
- Department of Physiology, Med College of Wisconsin, Milwaukee, WI, USA
| | - Garrett Morgan
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Janine H Santos
- Genome Integrity and Structural Biology Laboratory, NIHEHS, Raleigh-Durham, NC, USA
| | - Michael J Flister
- Department of Physiology, Med College of Wisconsin, Milwaukee, WI, USA
| | - David L Joyce
- Department of Surgery, Med College of Wisconsin, Milwaukee, WI, USA
| | - Amadou K S Camara
- Department of Physiology, Med College of Wisconsin, Milwaukee, WI, USA.,Department of Anesthesiology, Med College of Wisconsin, Milwaukee, WI, USA
| | - David D Gutterman
- Cardiovascular Center, Department of Medicine, Med College of Wisconsin, Milwaukee, WI, USA
| | - Anthony J Donato
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.,VA Medical Center-Salt Lake City, GRECC, Salt Lake City, Utah, USA
| | - George A Porter
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.,Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.,Department of Medicine (Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Andreas M Beyer
- Cardiovascular Center, Department of Medicine, Med College of Wisconsin, Milwaukee, WI, USA. .,Department of Physiology, Med College of Wisconsin, Milwaukee, WI, USA.
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39
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The role of cardiolipin concentration and acyl chain composition on mitochondrial inner membrane molecular organization and function. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:1039-1052. [PMID: 30951877 DOI: 10.1016/j.bbalip.2019.03.012] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/19/2019] [Accepted: 03/30/2019] [Indexed: 12/28/2022]
Abstract
Cardiolipin (CL) is a key phospholipid of the mitochondria. A loss of CL content and remodeling of CL's acyl chains is observed in several pathologies. Strong shifts in CL concentration and acyl chain composition would presumably disrupt mitochondrial inner membrane biophysical organization. However, it remains unclear in the literature as to which is the key regulator of mitochondrial membrane biophysical properties. We review the literature to discriminate the effects of CL concentration and acyl chain composition on mitochondrial membrane organization. A widely applicable theme emerges across several pathologies, including cardiovascular diseases, diabetes, Barth syndrome, and neurodegenerative ailments. The loss of CL, often accompanied by increased levels of lyso-CLs, impairs mitochondrial inner membrane organization. Modest remodeling of CL acyl chains is not a major driver of impairments and only in cases of extreme remodeling is there an influence on membrane properties.
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40
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Pointer CB, Wenzel TJ, Klegeris A. Extracellular cardiolipin regulates select immune functions of microglia and microglia-like cells. Brain Res Bull 2019; 146:153-163. [PMID: 30625370 DOI: 10.1016/j.brainresbull.2019.01.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/20/2018] [Accepted: 01/03/2019] [Indexed: 12/12/2022]
Abstract
Cardiolipin is a mitochondrial membrane phospholipid with several well-defined metabolic roles. Cardiolipin can be released extracellularly by damaged cells and has been shown to affect peripheral immune functions. We hypothesized that extracellular cardiolipin can also regulate functions of microglia, the resident immune cells of the central nervous system (CNS). We demonstrate that extracellular cardiolipin increases microglial phagocytosis and neurotrophic factor expression, as well as decreases the release of inflammatory mediators and cytotoxins by activated microglia-like cells. These results identify extracellular cardiolipin as a potential CNS intercellular signaling molecule that can regulate key microglial immune functions associated with neurodegenerative diseases.
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Affiliation(s)
- Caitlin B Pointer
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7, Canada
| | - Tyler J Wenzel
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7, Canada
| | - Andis Klegeris
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7, Canada.
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41
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Kappler L, Kollipara L, Lehmann R, Sickmann A. Investigating the Role of Mitochondria in Type 2 Diabetes - Lessons from Lipidomics and Proteomics Studies of Skeletal Muscle and Liver. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1158:143-182. [PMID: 31452140 DOI: 10.1007/978-981-13-8367-0_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mitochondrial dysfunction is discussed as a key player in the pathogenesis of type 2 diabetes mellitus (T2Dm), a highly prevalent disease rapidly developing as one of the greatest global health challenges of this century. Data however about the involvement of mitochondria, central hubs in bioenergetic processes, in the disease development are still controversial. Lipid and protein homeostasis are under intense discussion to be crucial for proper mitochondrial function. Consequently proteomics and lipidomics analyses might help to understand how molecular changes in mitochondria translate to alterations in energy transduction as observed in the healthy and metabolic diseases such as T2Dm and other related disorders. Mitochondrial lipids integrated in a tool covering proteomic and functional analyses were up to now rarely investigated, although mitochondrial lipids might provide a possible lynchpin in the understanding of type 2 diabetes development and thereby prevention. In this chapter state-of-the-art analytical strategies, pre-analytical aspects, potential pitfalls as well as current proteomics and lipidomics-based knowledge about the pathophysiological role of mitochondria in the pathogenesis of type 2 diabetes will be discussed.
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Affiliation(s)
- Lisa Kappler
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany
| | - Laxmikanth Kollipara
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany
| | - Rainer Lehmann
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tuebingen, Tuebingen, Germany.,Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tuebingen, Tuebingen, Germany.,German Center for Diabetes Research (DZD e.V.), Tuebingen, Germany
| | - Albert Sickmann
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany. .,Medical Proteome Centre, Ruhr Universität Bochum, Bochum, Germany. .,Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, UK.
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42
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Gong H, Li J, Xu A, Tang Y, Ji W, Gao R, Wang S, Yu L, Tian C, Li J, Yen HY, Man Lam S, Shui G, Yang X, Sun Y, Li X, Jia M, Yang C, Jiang B, Lou Z, Robinson CV, Wong LL, Guddat LW, Sun F, Wang Q, Rao Z. An electron transfer path connects subunits of a mycobacterial respiratory supercomplex. Science 2018; 362:science.aat8923. [PMID: 30361386 DOI: 10.1126/science.aat8923] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 10/10/2018] [Indexed: 11/02/2022]
Abstract
We report a 3.5-angstrom-resolution cryo-electron microscopy structure of a respiratory supercomplex isolated from Mycobacterium smegmatis. It comprises a complex III dimer flanked on either side by individual complex IV subunits. Complex III and IV associate so that electrons can be transferred from quinol in complex III to the oxygen reduction center in complex IV by way of a bridging cytochrome subunit. We observed a superoxide dismutase-like subunit at the periplasmic face, which may be responsible for detoxification of superoxide formed by complex III. The structure reveals features of an established drug target and provides a foundation for the development of treatments for human tuberculosis.
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Affiliation(s)
- Hongri Gong
- State Key Laboratory of Medicinal Chemical Biology and College of Life Science, Nankai University, Tianjin 300353, China
| | - Jun Li
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.,CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), 320 Yueyang Road, Shanghai 200031, China
| | - Ao Xu
- State Key Laboratory of Medicinal Chemical Biology and College of Life Science, Nankai University, Tianjin 300353, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China
| | - Yanting Tang
- State Key Laboratory of Medicinal Chemical Biology and College of Life Science, Nankai University, Tianjin 300353, China
| | - Wenxin Ji
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ruogu Gao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Shuhui Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.,CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), 320 Yueyang Road, Shanghai 200031, China
| | - Lu Yu
- High Magnetic Field Laboratory, CAS, Hefei 230031, China
| | - Changlin Tian
- High Magnetic Field Laboratory, CAS, Hefei 230031, China.,Hefei National Laboratory of Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Jingwen Li
- Department of Chemistry, University of Oxford, Physical and Theoretical Chemistry Laboratory, South Parks Rd, Oxford, OX1 3QZ, UK
| | - Hsin-Yung Yen
- Department of Chemistry, University of Oxford, Physical and Theoretical Chemistry Laboratory, South Parks Rd, Oxford, OX1 3QZ, UK.,OMass Technologies, Begbroke Science Park, Woodstock Rd, Yarnton, Kidlington OX5 1PF, UK
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, CAS, Beijing 100101, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, CAS, Beijing 100101, China
| | - Xiuna Yang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.,CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), 320 Yueyang Road, Shanghai 200031, China
| | - Yuna Sun
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China
| | - Xuemei Li
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China
| | - Minze Jia
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Life Science, Nankai University, Tianjin 300353, China
| | - Biao Jiang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
| | - Zhiyong Lou
- Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China
| | - Carol V Robinson
- Department of Chemistry, University of Oxford, Physical and Theoretical Chemistry Laboratory, South Parks Rd, Oxford, OX1 3QZ, UK
| | - Luet-Lok Wong
- Department of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Road, Oxford OX1 3QR, UK
| | - Luke W Guddat
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 Queensland, Australia
| | - Fei Sun
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China. .,University of Chinese Academy of Sciences, Beijing, China
| | - Quan Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China.
| | - Zihe Rao
- State Key Laboratory of Medicinal Chemical Biology and College of Life Science, Nankai University, Tianjin 300353, China. .,Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.,CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), 320 Yueyang Road, Shanghai 200031, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS, Beijing 100101, China.,Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China
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43
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Schweitzer-Stenner R. Relating the multi-functionality of cytochrome c to membrane binding and structural conversion. Biophys Rev 2018; 10:1151-1185. [PMID: 29574621 PMCID: PMC6082307 DOI: 10.1007/s12551-018-0409-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 02/23/2018] [Indexed: 12/16/2022] Open
Abstract
Cytochrome c is known as an electron-carrying protein in the respiratory chain of mitochondria. Over the last 20 years, however, alternative functions of this very versatile protein have become the focus of research interests. Upon binding to anionic lipids such as cardiolipin, the protein acquires peroxidase activity. Multiple lines of evidence suggest that this requires a conformational change of the protein which involves partial unfolding of its tertiary structure. This review summarizes the current state of knowledge of how cytochrome c interacts with cardiolipin-containing surfaces and how this affects its structure and function. In this context, we delineate partially conflicting results regarding the affinity of cytochrome c binding to cardiolipin-containing liposomes of different size and its influence on the structure of the protein and the morphology of the membrane.
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44
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Souders CL, Liang X, Wang X, Ector N, Zhao YH, Martyniuk CJ. High-throughput assessment of oxidative respiration in fish embryos: Advancing adverse outcome pathways for mitochondrial dysfunction. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2018; 199:162-173. [PMID: 29631217 DOI: 10.1016/j.aquatox.2018.03.031] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 03/21/2018] [Accepted: 03/26/2018] [Indexed: 06/08/2023]
Abstract
Mitochondrial dysfunction is a prevalent molecular event that can result in multiple adverse outcomes. Recently, a novel high throughput method to assess metabolic capacity in fish embryos following exposure to chemicals has been adapted for environmental toxicology. Assessments of oxygen consumption rates using the Seahorse XF(e) 24/96 Extracellular Flux Analyzer (Agilent Technologies) can be used to garner insight into toxicant effects at early stages of development. Here we synthesize the current state of the science using high throughput metabolic profiling in zebrafish embryos, and present considerations for those wishing to adopt high throughput methods for mitochondrial bioenergetics into their research. Chemicals that have been investigated in zebrafish using this metabolic platform include herbicides (e.g. paraquat, diquat), industrial compounds (e.g. benzo-[a]-pyrene, tributyltin), natural products (e.g. quercetin), and anti-bacterial chemicals (i.e. triclosan). Some of these chemicals inhibit mitochondrial endpoints in the μM-mM range, and reduce basal respiration, maximum respiration, and spare capacity. We present a theoretical framework for how one can use mitochondrial performance data in zebrafish to categorize chemicals of concern and prioritize mitochondrial toxicants. Noteworthy is that our studies demonstrate that there can be considerable variation in basal respiration of untreated zebrafish embryos due to clutch-specific effects as well as individual variability, and basal oxygen consumption rates (OCR) can vary on average between 100 and 300 pmol/min/embryo. We also compare OCR between chorionated and dechorionated embryos, as both models are employed to test chemicals. After 24 h, dechorionated embryos remain responsive to mitochondrial toxicants, although they show a blunted response to the uncoupling agent carbonylcyanide-4-trifluoromethoxyphenylhydrazone (FCCP); dechorionated embryos are therefore a viable option for investigations into mitochondrial bioenergetics. We present an adverse outcome pathway framework that incorporates endpoints related to mitochondrial bioenergetics. High throughput bioenergetics assays conducted using whole embryos are expected to support adverse outcome pathways for mitochondrial dysfunction.
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Affiliation(s)
- Christopher L Souders
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Xuefang Liang
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA; School of Ecology and Environment, Inner Mongolia University, Hohhot, 010021, China
| | - Xiaohong Wang
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA; State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, China
| | - Naomi Ector
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Yuan H Zhao
- State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of Environment, Northeast Normal University, Changchun, Jilin, 130117, China
| | - Christopher J Martyniuk
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA.
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45
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Mishra R, Upadhyay A, Prajapati VK, Mishra A. Proteasome-mediated proteostasis: Novel medicinal and pharmacological strategies for diseases. Med Res Rev 2018; 38:1916-1973. [DOI: 10.1002/med.21502] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/13/2018] [Accepted: 04/04/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Ribhav Mishra
- Cellular and Molecular Neurobiology Unit; Indian Institute of Technology Jodhpur; Rajasthan India
| | - Arun Upadhyay
- Cellular and Molecular Neurobiology Unit; Indian Institute of Technology Jodhpur; Rajasthan India
| | - Vijay Kumar Prajapati
- Department of Biochemistry; School of Life Sciences; Central University of Rajasthan; Rajasthan India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit; Indian Institute of Technology Jodhpur; Rajasthan India
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46
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Chao YJ, Wu WH, Balazova M, Wu TY, Lin J, Liu YW, Hsu YHH. Chlorella diet alters mitochondrial cardiolipin contents differentially in organs of Danio rerio analyzed by a lipidomics approach. PLoS One 2018; 13:e0193042. [PMID: 29494608 PMCID: PMC5832209 DOI: 10.1371/journal.pone.0193042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 02/02/2018] [Indexed: 01/14/2023] Open
Abstract
The zebrafish (Danio rerio) is an important and widely used vertebrate model organism for the study of human diseases which include disorders caused by dysfunctional mitochondria. Mitochondria play an essential role in both energy metabolism and apoptosis, which are mediated through a mitochondrial phospholipid cardiolipin (CL). In order to examine the cardiolipin profile in the zebrafish model, we developed a CL analysis platform by using liquid chromatography-mass spectrometry (LC-MS). Meanwhile, we tested whether chlorella diet would alter the CL profile in the larval fish, and in various organs of the adult fish. The results showed that chlorella diet increased the chain length of CL in larval fish. In the adult zebrafish, the distribution patterns of CL species were similar between the adult brain and eye tissues, and between the heart and muscles. Interestingly, monolyso-cardiolipin (MLCL) was not detected in brain and eyes but found in other examined tissues, indicating a different remodeling mechanism to maintain the CL integrity. While the adult zebrafish were fed with chlorella for four weeks, the CL distribution showed an increase of the species of saturated acyl chains in the brain and eyes, but a decrease in the other organs. Moreover, chlorella diet led to a decrease of MLCL percentage in organs except the non-MLCL-containing brain and eyes. The CL analysis in the zebrafish provides an important tool for studying the mechanism of mitochondria diseases, and may also be useful for testing medical regimens targeting against the Barth Syndrome.
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Affiliation(s)
- Yu-Jen Chao
- Department of Chemistry, Tunghai University, Taichung, Taiwan
| | - Wen-Hsin Wu
- Department of Chemistry, Tunghai University, Taichung, Taiwan
| | - Maria Balazova
- Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ting-Yuan Wu
- Department of Chemistry, Tunghai University, Taichung, Taiwan
| | - Jamie Lin
- Department of Life Science, Tunghai University, Taichung, Taiwan
- Life Science Research Center, Tunghai University, Taichung, Taiwan
| | - Yi-Wen Liu
- Department of Life Science, Tunghai University, Taichung, Taiwan
- Life Science Research Center, Tunghai University, Taichung, Taiwan
- * E-mail: (YWL); (YHH)
| | - Yuan-Hao Howard Hsu
- Department of Chemistry, Tunghai University, Taichung, Taiwan
- Life Science Research Center, Tunghai University, Taichung, Taiwan
- * E-mail: (YWL); (YHH)
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47
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Bown L, Srivastava SK, Piercey BM, McIsaac CK, Tahlan K. Mycobacterial Membrane Proteins QcrB and AtpE: Roles in Energetics, Antibiotic Targets, and Associated Mechanisms of Resistance. J Membr Biol 2017; 251:105-117. [DOI: 10.1007/s00232-017-9997-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 10/20/2017] [Indexed: 02/08/2023]
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48
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Alvarez-Paggi D, Hannibal L, Castro MA, Oviedo-Rouco S, Demicheli V, Tórtora V, Tomasina F, Radi R, Murgida DH. Multifunctional Cytochrome c: Learning New Tricks from an Old Dog. Chem Rev 2017; 117:13382-13460. [DOI: 10.1021/acs.chemrev.7b00257] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Damián Alvarez-Paggi
- Departamento
de Química Inorgánica, Analítica y Química
Física and INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas
y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. 2, piso 1, Buenos Aires C1428EHA, Argentina
| | - Luciana Hannibal
- Department
of Pediatrics, Universitätsklinikum Freiburg, Mathildenstrasse 1, Freiburg 79106, Germany
- Departamento
de Bioquímica and Center for Free Radical and Biomedical Research,
Facultad de Medicina, Universidad de la República, Av.
Gral. Flores 2125, Montevideo 11800, Uruguay
| | - María A. Castro
- Departamento
de Química Inorgánica, Analítica y Química
Física and INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas
y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. 2, piso 1, Buenos Aires C1428EHA, Argentina
| | - Santiago Oviedo-Rouco
- Departamento
de Química Inorgánica, Analítica y Química
Física and INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas
y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. 2, piso 1, Buenos Aires C1428EHA, Argentina
| | - Veronica Demicheli
- Departamento
de Bioquímica and Center for Free Radical and Biomedical Research,
Facultad de Medicina, Universidad de la República, Av.
Gral. Flores 2125, Montevideo 11800, Uruguay
| | - Veronica Tórtora
- Departamento
de Bioquímica and Center for Free Radical and Biomedical Research,
Facultad de Medicina, Universidad de la República, Av.
Gral. Flores 2125, Montevideo 11800, Uruguay
| | - Florencia Tomasina
- Departamento
de Bioquímica and Center for Free Radical and Biomedical Research,
Facultad de Medicina, Universidad de la República, Av.
Gral. Flores 2125, Montevideo 11800, Uruguay
| | - Rafael Radi
- Departamento
de Bioquímica and Center for Free Radical and Biomedical Research,
Facultad de Medicina, Universidad de la República, Av.
Gral. Flores 2125, Montevideo 11800, Uruguay
| | - Daniel H. Murgida
- Departamento
de Química Inorgánica, Analítica y Química
Física and INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas
y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. 2, piso 1, Buenos Aires C1428EHA, Argentina
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49
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Sepuri NBV, Angireddy R, Srinivasan S, Guha M, Spear J, Lu B, Anandatheerthavarada HK, Suzuki CK, Avadhani NG. Mitochondrial LON protease-dependent degradation of cytochrome c oxidase subunits under hypoxia and myocardial ischemia. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2017; 1858:519-528. [PMID: 28442264 PMCID: PMC5507603 DOI: 10.1016/j.bbabio.2017.04.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 04/17/2017] [Accepted: 04/21/2017] [Indexed: 01/08/2023]
Abstract
The mitochondrial ATP dependent matrix protease, Lon, is involved in the maintenance of mitochondrial DNA nucleoids and degradation of abnormal or misfolded proteins. The Lon protease regulates mitochondrial Tfam (mitochondrial transcription factor A) level and thus modulates mitochondrial DNA (mtDNA) content. We have previously shown that hypoxic stress induces the PKA-dependent phosphorylation of cytochrome c oxidase (CcO) subunits I, IVi1, and Vb and a time-dependent reduction of these subunits in RAW 264.7 murine macrophages subjected to hypoxia and rabbit hearts subjected to ischemia/reperfusion. Here, we show that Lon is involved in the preferential turnover of phosphorylated CcO subunits under hypoxic/ischemic stress. Induction of Lon protease occurs at 6 to 12 h of hypoxia and this increase coincides with lower CcO subunit contents. Over-expression of flag-tagged wild type and phosphorylation site mutant Vb and IVi1 subunits (S40A and T52A, respectively) caused marked degradation of wild type protein under hypoxia while the mutant proteins were relatively resistant. Furthermore, the recombinant purified Lon protease degraded the phosphorylated IVi1 and Vb subunits, while the phosphorylation-site mutant proteins were resistant to degradation. 3D structural modeling shows that the phosphorylation sites are exposed to the matrix compartment, accessible to matrix PKA and Lon protease. Hypoxic stress did not alter CcO subunit levels in Lon depleted cells, confirming its role in CcO turnover. Our results therefore suggest that Lon preferentially degrades the phosphorylated subunits of CcO and plays a role in the regulation of CcO activity in hypoxia and ischemia/reperfusion injury.
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Affiliation(s)
- Naresh B V Sepuri
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Rajesh Angireddy
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Satish Srinivasan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Manti Guha
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Joseph Spear
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Bin Lu
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers The State University, New Jersey Medical School, 225 Warren Street, Newark, NJ 17103-3535, USA
| | - Hindupur K Anandatheerthavarada
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Carolyn K Suzuki
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers The State University, New Jersey Medical School, 225 Warren Street, Newark, NJ 17103-3535, USA
| | - Narayan G Avadhani
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
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50
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Karadayian AG, Malanga G, Czerniczyniec A, Lombardi P, Bustamante J, Lores-Arnaiz S. Free radical production and antioxidant status in brain cortex non-synaptic mitochondria and synaptosomes at alcohol hangover onset. Free Radic Biol Med 2017; 108:692-703. [PMID: 28450149 DOI: 10.1016/j.freeradbiomed.2017.04.344] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 04/21/2017] [Accepted: 04/23/2017] [Indexed: 10/19/2022]
Abstract
Alcohol hangover (AH) is the pathophysiological state after a binge-like drinking. We have previously demonstrated that AH induced bioenergetics impairments in a total fresh mitochondrial fraction in brain cortex and cerebellum. The aim of this work was to determine free radical production and antioxidant systems in non-synaptic mitochondria and synaptosomes in control and hangover animals. Superoxide production was not modified in non-synaptic mitochondria while a 17.5% increase was observed in synaptosomes. A similar response was observed for cardiolipin content as no changes were evidenced in non-synaptic mitochondria while a 55% decrease in cardiolipin content was found in synaptosomes. Hydrogen peroxide production was 3-fold increased in non-synaptic mitochondria and 4-fold increased in synaptosomes. In the presence of deprenyl, synaptosomal H2O2 production was 67% decreased in the AH condition. Hydrogen peroxide generation was not affected by deprenyl addition in non-synaptic mitochondria from AH mice. MAO activity was 57% increased in non-synaptic mitochondria and 3-fold increased in synaptosomes. Catalase activity was 40% and 50% decreased in non-synaptic mitochondria and synaptosomes, respectively. Superoxide dismutase was 60% decreased in non-synaptic mitochondria and 80% increased in synaptosomal fractions. On the other hand, GSH (glutathione) content was 43% and 17% decreased in synaptosomes and cytosol. GSH-related enzymes were mostly affected in synaptosomes fractions by AH condition. Acetylcholinesterase activity in synaptosomes was 11% increased due to AH. The present work reveals that AH provokes an imbalance in the cellular redox homeostasis mainly affecting mitochondria present in synaptic terminals.
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Affiliation(s)
- Analía G Karadayian
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisicoquímica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Gabriela Malanga
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisicoquímica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Analía Czerniczyniec
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisicoquímica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Paulina Lombardi
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisicoquímica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina
| | - Juanita Bustamante
- Universidad Abierta Interamericana, Centro de Altos Estudios en Ciencias de la Salud, Buenos Aires, Argentina
| | - Silvia Lores-Arnaiz
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisicoquímica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Buenos Aires, Argentina.
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