# Structure-function changes in the mitochondrial interactome with age > **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2021 · $361,825 ## Abstract ABSTRACT Sarcopenia, the loss of skeletal muscle quantity and quality with age, is a significant and growing public health problem due to the associated loss of independence and frailty. Despite the high costs of sarcopenia in terms of both economic impact and the decline in quality of life in the elderly, there are few effective treatments to reverse the age-related loss of skeletal muscle function. Notably, the role of mitochondrial dysfunction in aging skeletal muscle remains controversial. We have consistently found decreased capacity for in vivo ATP production (ATPmax) in aged mouse and human skeletal muscle that can be reversed with an acute (hours) mitochondria targeted intervention (SS-31). However, data from permeabilized muscle fibers (PMF) shows little age-related decline in mitochondrial capacity in vitro. Application of a novel chemical cross-linking with mass spectrometry (XL-MS) approach points to specific disruption of protein interactions in ADP transport, ATP synthesis, and substrate supply to the electron transport system in aged muscle. Furthermore, XL-MS also indicates that SS- 31 directly interacts with specific mitochondrial proteins in these pathways and affects their interactome network. Altered ADP sensitivity and substrate supply are likely to be masked in PMF experiments performed under optimal conditions with saturating substrates. Thus, our central hypothesis is that the pathology of aging includes molecular defects in mitochondrial ADP sensitivity and substrate supply and that SS-31 interactions with proteins in these pathways provide in vivo performance benefits in aged mice. In support of this hypothesis our preliminary data indicate that acute treatment with SS-31 improves in vivo ADP sensitivity in aged mouse skeletal muscle and increases sensitivity to TCA cycle and fatty acid oxidation substrates in isolated mitochondria. The innovative application of quantitative XL-MS to assess the mitochondrial and SS-31 interactomes and our unique ability to measure ADP sensitivity in vivo and in vitro in both mouse and human skeletal muscle creates the ideal environment to test this hypothesis. We propose the following specific aims. Aim 1 – tests whether aging affects SS-31 binding to mitochondrial proteins and the functional consequences of this direct interaction; Aim 2 – tests whether SS-31 treatment reverses age-related changes in the mitochondrial interactome underlying functional changes in ADP and substrate sensitivity. Aims 1 and 2 use in vivo and in vitro assays of mitochondrial function, metabolomics, and XL-MS to test whether aging impairs and SS-31 treatment improves ADP sensitivity and substrate supply in aged mice. Aim 3 – capitalizes on our unique ability to measure in vivo and in vitro mitochondrial function in human subjects to test whether the effects of age and SS-31 on the mitochondrial interactome, ADP sensitivity, and reduced substrate supply differ between aged subjects with low and high mitochondr... ## Key facts - **NIH application ID:** 10490488 - **Project number:** 1R56AG070096-01A1 - **Recipient organization:** UNIVERSITY OF WASHINGTON - **Principal Investigator:** James Edward Bruce - **Activity code:** R56 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $361,825 - **Award type:** 1 - **Project period:** 2021-09-30 → 2023-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10490488 ## Citation > US National Institutes of Health, RePORTER application 10490488, Structure-function changes in the mitochondrial interactome with age (1R56AG070096-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10490488. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*