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Aging Mitochondrial Interactome

衰老线粒体相互作用组

基本信息

批准号：
10658412
负责人：
James Edward Bruce
金额：
$ 54.51万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658412
关键词：
ATP Synthesis Pathway Activity Cycles Acute Address Adult Age Aging Biological Assay Biopsy Calcium Cardiovascular system Chemicals Citric Acid Cycle Complex Data Elderly Electron Transport Functional disorder Genes Glutamate Dehydrogenase Glutamate Metabolism Pathway Glutamates Heart Homeostasis Human Impairment In Vitro Intervention Lead Link Maps Mass Spectrum Analysis Measures Mediating Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Mus Muscle Muscle Mitochondria Myocardium Nature Nucleic Acid Regulatory Sequences Organ Organelles Oxidation-Reduction Pathology Peptides Permeability Phosphorylation Play Positioning Attribute Production Protein Conformation Proteins Quality of life Regulation Research Respiration Role SOD2 gene Site Skeletal Muscle Stress System Testing Tissues Translating Uncertainty age related aged alpha ketoglutarate catalase crosslink experimental study functional decline human subject improved in vivo induced pluripotent stem cell derived cardiomyocytes innovation insight knock-down mitochondrial dysfunction mitochondrial metabolism mouse model neuromuscular novel protein complex resilience tool young adult

项目摘要

Mitochondria play a central role in age-related pathologies, loss of resilience, and the decline in quality of life in older adults. As we age changes in mitochondrial function lead to disruption of redox and energy homeostasis, altered metabolite levels, impaired calcium regulation, 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 underlie changes in function. To address this fundamental question we propose to apply a state of the art novel quantitative chemical cross-linking with mass spectrometry approach (XL-MS) to quantify the changes in the mitochondrial interactome in heart and skeletal muscles with age. By combining this innovative XL-MS approach with targeted functional assays and interventions developed over the last several years to manipulate mitochondria in vivo and in vitro we are uniquely positioned to identify the changes in mitochondrial protein interactions that underlie age- related mitochondrial dysfunction. Our preliminary data indicate specific disruption of multiple protein interaction networks involved in ADP transport, ATP synthesis, glutamate metabolism, and complexes of the electron transport system with age. Many of these protein complexes that XL-MS indicates are disrupted in aging directly interact with the mitochondrial targeted peptide SS-31 that we have shown reverses mitochondrial dysfunction in heart and skeletal muscle. Our overall hypothesis is that changes in the mitochondrial interactome driven by elevated mitochondrial redox stress underlie decreased ATP production and altered metabolite levels in mitochondria from aged heart and skeletal muscle. In aim 1 we will apply XL-MS and site-specific assays to measure the link between the interactome and function in mitochondria from aged mouse heart and skeletal muscle. As a specific test of new mechanistic insights available from this approach we will use gene-edited iPSC derived cardiomyocytes to test the causal relationship between altered interactions in the glutamate dehydrogenase regulatory region, the largest change identified in the aged mitochondrial interactome, and impaired glutamate and α-ketoglutarate metabolism. In aim 2 we will use mitochondrial targeted interventions to reverse mitochondrial dysfunction, SS-31 and AAV-mitochondrial targeted catalase, and induce mitochondrial redox stress to identify the most functionally important changes in the mitochondrial interactome from aim 1. In aim 3 we use human muscle biopsies to test whether changes in the mitochondrial interactome identified in aims 1 and 2 translate into aged human skeletal muscle. We will separate older adults into low and high performing groups to compare the mitochondrial interactomes and function with those of young adults. Results from these experiments will have a transformative impact on the field by providing the first window into the links between the mitochondrial protein interaction network and age-related mitochondrial dysfunction. 1

线粒体在老年人的年龄相关病理、恢复能力丧失和生活质量下降中起着核心作用