Aging Mitochondrial Interactome

衰老线粒体相互作用组

基本信息

  • 批准号:
    10658412
  • 负责人:
  • 金额:
    $ 54.51万
  • 依托单位:
  • 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

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
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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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James Edward Bruce其他文献

James Edward Bruce的其他文献

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{{ truncateString('James Edward Bruce', 18)}}的其他基金

Aging Mitochondrial Interactome
衰老线粒体相互作用组
  • 批准号:
    10688325
  • 财政年份:
    2022
  • 资助金额:
    $ 54.51万
  • 项目类别:
Dynamics of the cellular interactome
细胞相互作用组的动力学
  • 批准号:
    10398009
  • 财政年份:
    2020
  • 资助金额:
    $ 54.51万
  • 项目类别:
Dynamics of the cellular interactome
细胞相互作用组的动力学
  • 批准号:
    10613517
  • 财政年份:
    2020
  • 资助金额:
    $ 54.51万
  • 项目类别:
The heart failure interactome
心力衰竭相互作用组
  • 批准号:
    10447592
  • 财政年份:
    2019
  • 资助金额:
    $ 54.51万
  • 项目类别:
The heart failure interactome
心力衰竭相互作用组
  • 批准号:
    9816197
  • 财政年份:
    2019
  • 资助金额:
    $ 54.51万
  • 项目类别:
The heart failure interactome
心力衰竭相互作用组
  • 批准号:
    10218262
  • 财政年份:
    2019
  • 资助金额:
    $ 54.51万
  • 项目类别:
Investigating treatment resistance mechanisms in chronic bacterial infections
研究慢性细菌感染的治疗耐药机制
  • 批准号:
    8341304
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Investigating treatment resistance mechanisms in chronic bacterial infections
研究慢性细菌感染的治疗耐药机制
  • 批准号:
    8470546
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Investigating treatment resistance mechanisms in chronic bacterial infections
研究慢性细菌感染的治疗耐药机制
  • 批准号:
    9081460
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Investigating treatment resistance mechanisms in chronic bacterial infections
研究慢性细菌感染的治疗耐药机制
  • 批准号:
    8685119
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:

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