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

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.