The Role of GCN5L1 Mediated Mitochondria to Nucleus Retrograde Cardiac Metabolism Reprogramming in Exercise and Heart Failure

GCN5L1 介导的线粒体对运动和心力衰竭中细胞核逆行心脏代谢重编程的作用

基本信息

  • 批准号:
    10600019
  • 负责人:
  • 金额:
    $ 16.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT ABSTRACT Heart failure is a major public health challenge. Impaired cardiac metabolism is one of the fundamental mechanisms underlying heart failure progression. Expression profiling of cardiac tissues reveals repressed transcription factor network activation in heart failure, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), the master regulator of mitochondrial biogenesis and oxidative phosphorylation, resulting in many metabolic genes downregulation. In contrast to heart failure, endurance exercise enhances cardiac energetics through the upregulation of the PGC-1α expression, placing this molecule at the center of the exercise-induced adaptive response. The molecular mechanisms governing the expression of PGC-1α in response to exercise or pathological stress leading to heart failure are poorly understood. Mitochondrial function is also regulated by post-translational modifications of mitochondrial proteins. Our group identified General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) as the first acetyltransferase protein responsible for dynamic mitochondrial acetylation regulating fatty acid oxidation. The role of GCN5L1 in cardiac energetics regulation and heart failure are largely unknown. In our new preliminary data, we found that GCN5L1 expression was decreased in human and murine failing hearts and cardiac GCN5L1 knockout mice (cGCN5L1 KO) displayed exacerbated heart failure progression following transaortic constriction (TAC), highlighting that GCN5L1 plays an important role in heart failure. Beyond nuclear-mitochondria one-way communication, emerging evidence show that mitochondria can also engage in retrograde signaling to the nucleus via metabolic intermediates, reactive oxidative species or peptides to reprogram metabolic gene transcription. GCN5L1 is predominantly located in mitochondria and is absent in the nucleus. In our preliminary data, the exercise induced PGC-1α upregulation was blunted in cGCN5L1 KO mice relative to WT controls, and PGC-1α expression was also decreased in TAC cGCN5L1 KO mice hearts compared to TAC WT mice. These findings suggest that GCN5L1 plays an important role in controlling PGC-1α expression. In this proposal, leveraging our novel genetic mouse model, we will test the hypothesis that GCN5L1 plays a critical role in enhancing cardiac bioenergetics through retrograde activation of PGC-1α signaling during exercise or heart failure development. Three specific aims are proposed: 1) To test the hypothesis that GCN5L1 induces PGC-1α expression in response to pressure overload through retrograde activation of p38 MAPK, 2) To test the hypothesis that GCN5L1 induces PGC-1α expression in response to pressure overload through retrograde histone acetylation at H3K27, 3) To test the hypothesis that GCN5L1 governs adaptive response to endurance exercise through retrograde activation of PGC-1α signaling.
项目摘要

项目成果

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Manling Zhang其他文献

Manling Zhang的其他文献

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{{ truncateString('Manling Zhang', 18)}}的其他基金

The Role of GCN5L1 Mediated Mitochondria to Nucleus Retrograde Cardiac Metabolism Reprogramming in Exercise and Heart Failure
GCN5L1 介导的线粒体对运动和心力衰竭中细胞核逆行心脏代谢重编程的作用
  • 批准号:
    10189058
  • 财政年份:
    2021
  • 资助金额:
    $ 16.05万
  • 项目类别:
The Role of GCN5L1 Mediated Mitochondria to Nucleus Retrograde Cardiac Metabolism Reprogramming in Exercise and Heart Failure
GCN5L1 介导的线粒体对运动和心力衰竭中细胞核逆行心脏代谢重编程的作用
  • 批准号:
    10372167
  • 财政年份:
    2021
  • 资助金额:
    $ 16.05万
  • 项目类别:

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