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心脏病中的线粒体动态/健康/生物发生相互作用组 多恩 GW II 摘要 心肌细胞线粒体是 ATP 的重要提供者,为收缩和正常活动提供能量 或修复性心肌细胞生长。据观察,心肌细胞对代谢底物的利用 在心脏发育过程中,从胎儿对碳水化合物的偏好发展到正常成人 对脂肪酸的偏好。在成人心脏中,线粒体利用的病理逆转 据推测,碳水化合物会导致心脏肥大、心力衰竭和心肌梗塞 梗塞。然而,我们对直接心脏底物利用的具体机制的掌握是 心肌细胞线粒体的不完整和强制遗传产生尚未被证明具有治疗作用 在心脏病的实验模型中。 我们概念上的突破是心脏代谢不是由“大师”决定的 调节器”,而是由线粒体活力、适应性和生物发生之间的相互作用来指导。 我们认为心肌代谢重塑需要线粒体自噬的协调调节 线粒体去除、生物线粒体替代和融合/裂变介导的线粒体 重新分配。通过单独破坏这些途径并定义其后果 线粒体、细胞和器官功能我们确定了这三个过程如何共同调节 并且在功能上相互依赖,其中定义了 Mfn2 作为协调者的核心角色 线粒体命运(即保留与去除)。通过设计人工 Mfn2 突变并研究 通过对心肌病队列进行 DNA 测序,我们发现了具有破坏性的人类 Mfn2 突变 正在了解相互作用组中的每个主要过程如何通过调制进行内部微调 功能相反的对。具体来说,Mfn 介导的线粒体融合受到 Drp1- 的反对 介导线粒体裂变; PGC1 介导的脂肪酸分解代谢线粒体的生物发生是 与 PRC 介导的碳水化合物分解代谢线粒体的生物合成相反;和线粒体 复制受到 Parkin 介导的线粒体消除的阻碍。基于这些见解, 代表了 HL59888(线粒体融合)和 HL128441(线粒体自噬)研究目标的融合, 我们开发了新的遗传和生化工具,即功能分离突变体 Mfn2 蛋白质和细胞渗透肽,专门操纵线粒体活力或线粒体自噬 体外和体内。我们将利用这些新概念和试剂来剖析分子 驱动正常和患病心脏代谢重塑的机制,并发展 通过“拨号-”将心脏代谢与病理生理状态最佳匹配的可翻译方法 通过相互作用组内的精确操作来控制线粒体的质量和数量。
英文摘要
The mitochondrial dynamism/fitness/biogenesis interactome in cardiac disease Dorn GW II Abstract Cardiomyocyte mitochondria are essential providers of ATP that fuels contraction and normal or reparative cardiomyocyte growth. Observationally, cardiomyocyte utilization of metabolic substrates evolves during cardiac development from a fetal preference for carbohydrates to the normal adult preference for fatty acids. In adult hearts, pathological reversion toward mitochondrial utilization of carbohydrates is postulated to contribute to cardiac hypertrophy, heart failure and myocardial infarction. However, our grasp of specific mechanisms that direct cardiac substrate utilization is incomplete, and forced genetic production of cardiomyocyte mitochondria has not proven therapeutic in experimental models of heart disease. Our conceptual breakthrough was that cardiac metabolism is not determined by a “master regulator”, but is directed by the interplay between mitochondrial dynamism, fitness and biogenesis. We posit that myocardial metabolic remodeling requires coordinated modulation of mitophagic mitochondrial removal, biogenic mitochondrial replacement and fusion/fission-mediated mitochondrial redistribution. By individually disrupting these pathways and defining the consequences on mitochondrial, cell and organ functioning we determined how these three processes are co-regulated and functionally-interdependent, therein defining a central role for Mfn2 as orchestrator of mitochondrial fate (i.e. retention vs removal). By engineering artificial Mfn2 mutations and studying damaging human Mfn2 mutations identified through DNA sequencing of cardiomyopathy cohorts we are learning how each major process within the interactome is internally fine-tuned through modulation of functionally opposing pairs. Specifically, Mfn-mediated mitochondrial fusion is opposed by Drp1- mediated mitochondrial fission; PGC1-mediated biogenesis of fatty acid-catabolizing mitochondria is opposed by PRC-mediated biogenesis of carbohydrate-catabolizing mitochondria; and mitochondrial replication is opposed by Parkin-mediated mitochondrial elimination. Based on these insights, which represent a convergence of the research aims of HL59888 (mito fusion) and HL128441 (mitophagy), we developed novel genetic and biochemical tools, namely Separation-of-Function mutant Mfn2 proteins and cell-permeant peptides, to specifically manipulate mitochondrial dynamism or mitophagy in vitro and in vivo. We will employ these new concepts and reagents to dissect the molecular mechanisms that drive metabolic remodeling in normal and diseased hearts, and to develop translatable means of optimally matching cardiac metabolism to pathophysiological status by “dialing- in” mitochondrial quality and quantity via precision manipulations within the interactome.
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Mitofusin Agonists to Treat Neurodegenerative Disease
  • 批准号:
    10383118
  • 项目类别:
  • 资助金额:
    $96.87万
  • 财政年份:
    2022
  • 负责人:
    Gerald W. Dorn
  • 依托单位:
Mitofusin Agonists to Treat Neurodegenerative Disease
  • 批准号:
    10618385
  • 项目类别:
  • 资助金额:
    $98.62万
  • 财政年份:
    2022
  • 负责人:
    Gerald W. Dorn
  • 依托单位:
MITOFUSIN AGONISTS TO TREAT NEURODEGENERATIVE DISEASE
  • 批准号:
    10290982
  • 项目类别:
  • 资助金额:
    $7.85万
  • 财政年份:
    2021
  • 负责人:
    Gerald W. Dorn
  • 依托单位:
MITOFUSIN AGONISTS TO TREAT NEURODEGENERATIVE DISEASE
  • 批准号:
    10020801
  • 项目类别:
  • 资助金额:
    $22.47万
  • 财政年份:
    2019
  • 负责人:
    Gerald W. Dorn
  • 依托单位:
国内基金
海外基金
UMSC-Exo通过调控Ribosome biogenesis诱导心肌再生的策略及机制研究
  • 批准号:
    82370264
  • 项目类别:
    面上项目
  • 资助金额:
    49万元
  • 批准年份:
    2023
  • 负责人:
    李杨欣
  • 依托单位:
活体动物线粒体biogenesis、fission及fusion对肝脏再生中能量供应影响机制的研究
  • 批准号:
    81470878
  • 项目类别:
    面上项目
  • 资助金额:
    73.0万元
  • 批准年份:
    2014
  • 负责人:
    柳勤龙
  • 依托单位: