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Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline

Anna A. Bakhtina, Gavin Pharaoh, Andrew D. Keller, Rudy Stuppard, David J. Marcinek, James E. Bruce
doi: https://doi.org/10.1101/2022.06.24.497539
Anna A. Bakhtina
1Department of Genome Sciences, University of Washington, Seattle, WA
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Gavin Pharaoh
2Department of Radiology, University of Washington, Seattle, WA
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Andrew D. Keller
1Department of Genome Sciences, University of Washington, Seattle, WA
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Rudy Stuppard
2Department of Radiology, University of Washington, Seattle, WA
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David J. Marcinek
2Department of Radiology, University of Washington, Seattle, WA
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  • For correspondence: jimbruce@uw.edu
James E. Bruce
1Department of Genome Sciences, University of Washington, Seattle, WA
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  • For correspondence: jimbruce@uw.edu
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Abstract

Genomic, transcriptomic, and proteomic approaches have been employed to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors in addition to abundance levels, such as modifications, localization, conformation, and protein-protein interactions. We have applied new robust quantitative chemical cross-linking technologies to uncover changes muscle mitochondrial interactome contributing to functional decline in aging. Statistically significant age-related changes in protein cross-link levels relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid beta-oxidation and TCA enzymes were observed. These changes showed remarkable correlation with measured CI based respiration differences within the same young-old animal pairs, indicating these cross-link levels offer new molecular insight on commonly observed age-related phenotypic differences. Overall, these system-wide quantitative mitochondrial interactome data provide the first molecular-level insight on ETS complex and substrate utilization enzyme remodeling that occur during age-related mitochondrial dysfunction. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies making this dataset a unique resource for many additional in-depth molecular studies that are needed to better understand complex molecular changes that occur with aging.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    ETS
    Electron Transport System
    TCA
    Tricarboxylic acid
    FAO
    Fatty Acid Oxidation
    LC-MS
    Liquid Chromatography – Mass Spectrometry
    ROS
    Reactive Oxygen Species
    ATP
    Adenosine Triphosphate
    qXL-MS
    quantitative crosslinking mass spectrometry
    iqPIR
    isobaric quantitative protein interaction reporter
    SCX
    Strong Cation Exchange
    SH
    Stump Heavy
    RH
    Reporter Heavy
    GO
    Gene Ontology
    KEGG
    Kyoto Encyclopedia of Genes and Genomes
    CS
    Citrate Synthase
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted June 26, 2022.
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    Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline
    Anna A. Bakhtina, Gavin Pharaoh, Andrew D. Keller, Rudy Stuppard, David J. Marcinek, James E. Bruce
    bioRxiv 2022.06.24.497539; doi: https://doi.org/10.1101/2022.06.24.497539
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    Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline
    Anna A. Bakhtina, Gavin Pharaoh, Andrew D. Keller, Rudy Stuppard, David J. Marcinek, James E. Bruce
    bioRxiv 2022.06.24.497539; doi: https://doi.org/10.1101/2022.06.24.497539

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