# Aging Mitochondrial Interactome

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2022 · $361,402

## Abstract

Changes in mitochondrial function play a central role in age-related pathologies, loss of resilience, and the
decline in quality of life in older adults. As we age there is a shift in our mitochondria toward a reduced ability to
generate ATP and increased oxidant production. These changes lead to disruption of redox and energy
homeostasis, altered metabolite levels, and increased sensitivity to permeability transition, all of which contribute
to tissue dysfunction. Mitochondria are dynamic organelles that continuously adapt to changing cellular demands
by altering protein assembly and interactions to modify their function. Despite the obvious importance, little is
known about how age-related changes in mitochondrial protein interactions (interactome) underlie changes in
function with age. To address this fundamental question, we propose to apply a state of the art quantitative
chemical cross-linking with mass spectrometry (qXL-MS) strategy to quantify changes in the mitochondrial
interactome with age. By combining this innovative qXL-MS approach with detailed assays of mitochondrial
metabolism and interventions we have developed over the last several years to manipulate mitochondria in vivo
and in vitro, we are uniquely positioned to identify the molecular level changes in mitochondrial interactome that
underlie age-related mitochondrial dysfunction. Our preliminary data indicate disruption of multiple protein
interaction networks involved in ADP transport, ATP synthesis, and substrate supply to the electron transport
system in aged heart and skeletal muscle. These changes are associated with previously demonstrated
decreases in ATP production and lower sensitivity to ADP. Furthermore, we have shown that a mitochondrial
targeted intervention (SS-31) that reverses mitochondrial dysfunction in heart and skeletal muscle, specifically
interacts with many of the same protein complexes that our interactome studies reveal are disrupted in aging,
including the ANT and complexes IV and V of the electron transport system. Our overall hypothesis tested in this
proposal is that changes in the mitochondrial interactome with age underlie decreased ATP production and
increased oxidant production in mitochondria from aged heart and skeletal muscle. Aim 1 applies XL-MS and
protein and site-specific mitochondrial assays to quantify changes in the mitochondrial interactome with age and
those induced by pro-oxidant treatment in vivo and in vitro in mouse heart and skeletal muscle. Aim 2 quantifies
the effect on the mitochondrial interactome of two well established mitochondrial targeted interventions, SS-31
and mitochondrial targeted catalase, to identify the most important age-related changes in the protein interaction
networks. Aim 3 tests whether changes in the mitochondrial interactome identified in aims 1 and 2 translate into
aged human skeletal muscle. The mitochondrial interactome, function, and effects of SS-31 from older adults
separated into low and high p...

## Key facts

- **NIH application ID:** 10688325
- **Project number:** 1R56AG078279-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** James Edward Bruce
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,402
- **Award type:** 1
- **Project period:** 2022-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10688325

## Citation

> US National Institutes of Health, RePORTER application 10688325, Aging Mitochondrial Interactome (1R56AG078279-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10688325. Licensed CC0.

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