THE MITOCHONDRIAL DYNAMISM/FITNESS/BIOGENESIS INTERACTOME IN CARDIAC DISEASE

心脏疾病中线粒体动力学/适应性/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，ATP为收缩和正常 或修复性心肌细胞生长。从观察上看，心肌细胞利用代谢底物 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， 碳水化合物被认为有助于心脏肥大、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特定机制的掌握是 心肌细胞线粒体的不完全和强制遗传产生尚未被证明具有治疗作用 心脏病的实验模型。 我们在概念上的突破是，心脏代谢不是由一个“主”决定的， 调节器”，但由线粒体动力学，健身和生物发生之间的相互作用指导。 我们认为心肌代谢重构需要线粒体吞噬细胞的协调调节， 线粒体去除、生物源性线粒体替代和融合/分裂介导的线粒体 再分配通过单独破坏这些途径并确定其后果， 线粒体，细胞和器官功能，我们确定了这三个过程是如何共同调节的 并且在功能上相互依赖，其中定义了Mfn 2作为 线粒体命运（即保留与去除）。通过设计人工Mfn 2突变并研究 通过心肌病队列的DNA测序鉴定的破坏性人类Mfn 2突变， 正在学习相互作用组中的每个主要过程是如何通过调制进行内部微调的 功能相反的一对。具体地说，Mfn介导的线粒体融合被Drp 1- 介导的线粒体分裂; PGC 1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; 复制受到帕金森介导的线粒体消除的阻碍。基于这些见解， 代表了HL 59888（线粒体融合）和HL 128441（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Mfn 2 蛋白质和细胞渗透肽，以特异性地操纵线粒体动力学或线粒体自噬 在体外和体内。我们将利用这些新概念和试剂来剖析分子 在正常和患病的心脏中驱动代谢重塑的机制， 最佳匹配心脏代谢的病理生理状态的可翻译的手段，通过“拨号- 在”线粒体的质量和数量，通过精确的操纵内的相互作用组。

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.