MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes.

Autor:	Vue Z; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Murphy A; Department of Biochemistry and Molecular Biology, The Huck Institute of the Life Sciences, Pennsylvania State University, State College, PA 16801., Le H; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Neikirk K; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Garza-Lopez E; Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA., Marshall AG; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Mungai M; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Jenkins B; Department of Biochemistry and Molecular Biology, The Huck Institute of the Life Sciences, Pennsylvania State University, State College, PA 16801., Vang L; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Beasley HK; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Ezedimma M; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Manus S; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Whiteside A; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Forni MF; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520., Harris C; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA.; Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208-3501, USA., Crabtree A; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Albritton CF; Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208-3501, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Jamison S; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Demirci M; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Prasad P; Department of Biochemistry and Molecular Biology, The Huck Institute of the Life Sciences, Pennsylvania State University, State College, PA 16801., Oliver A; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Actkins KV; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., Shao J; Central Microscopy Research Facility, University of Iowa, Iowa City, IA, 52242, USA., Zaganjor E; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Scudese E; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Rodriguez B; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Koh A; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Rabago I; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Moore JE; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Nguyen D; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA., Aftab M; Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA., Kirk B; Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA., Li Y; Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA., Wandira N; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Ahmad T; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.; Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Punjab,40100, Pakistan., Saleem M; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Kadam A; Department of Internal Medicine, Section of Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA., Katti P; National Heart, Lung and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.; Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, AP, 517619, India., Koh HJ; Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA., Evans C; Department of Cell Biology, Duke University School of Medicine, Durham, NC, 27708, USA., Koo YD; Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.; Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa, USA1., Wang E; Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA, 92697, USA., Smith Q; Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA, 92697, USA., Tomar D; Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Punjab,40100, Pakistan., Williams CR; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435 USA., Sweetwyne MT; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98195, USA., Quintana AM; Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, USA., Phillips MA; Department of Integrative Biology, Oregon State University, Corvallis, OR, 97331, USA., Hubert D; Department of Integrative Biology, Oregon State University, Corvallis, OR, 97331, USA., Kirabo A; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.; Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA.; Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, 37232, USA.; Vanderbilt Institute for Global Health, Nashville, TN, 37232, USA., Dash C; Department of Microbiology, Immunology and Physiology, Meharry Medical College, Nashville, TN, United States., Jadiya P; Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest University School of Medicine, Winston-Salem, NC., Kinder A; Artur Sá Earp Neto University Center - UNIFASE-FMP, Petrópolis Medical School, Brazil., Ajijola OA; UCLA Cardiac Arrhythmia Center, University of California, Los Angeles, CA, USA., Miller-Fleming TW; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States., McReynolds MR; Department of Biochemistry and Molecular Biology, The Huck Institute of the Life Sciences, Pennsylvania State University, State College, PA 16801., Hinton A Jr; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 03. Date of Electronic Publication: 2024 Jul 03.
DOI:	10.1101/2024.06.20.599846
Abstrakt:	The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques. Competing Interests: CONFLICT OF INTEREST The authors declare that they have no conflict of interest. All authors have no competing interests.
Databáze:	MEDLINE
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