THE MITOCHONDRIAL DYNAMISM/FITNESS/BIOGENESIS INTERACTOME IN CARDIAC DISEASE

心脏病中的线粒体活力/健康/生物发生相互作用

• 批准号: 10530619
• 负责人: Gerald W. Dorn
• 金额: $ 91.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530619
• 关键词: Adult; Biogenesis; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; DNA sequencing; Engineering; Excision; Exhibits; Experimental Models; Fatty Acids; Fatty acid glycerol esters; Foundations; Gene Mutation; Genetic; Genetic Programming; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart Mitochondria; Heart failure; Human; Hypertrophy; Impairment; In Vitro; Individual; Learning; Mediating; Metabolic; Mitochondria; Mitochondrial Diseases; Molecular; Mutation; Myocardial; Myocardial Infarction; Organ; Parkin; Pathologic; Pathway interactions; Patients; Peptides; Process; Production; Proteins; Provider; Reagent; Research; Role; Therapeutic; Weight; biochemical tools; cardiac repair; cardiogenesis; cohort; exome sequencing; fetal; fitness; genome sequencing; grasp; heart damage; heart metabolism; in vivo; insight; mitochondrial dysfunction; mitochondrial metabolism; mutant; novel; novel strategies; pharmacologic; preference; repaired; sugar; whole genome

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.

线粒体动力性/适应性/生物发生相互作用组在心脏病中的作用 多恩GW II 摘要 心肌细胞线粒体是三磷酸腺苷的重要供应者，三磷酸腺苷为收缩和正常提供能量 或修复性的心肌细胞生长。观察到，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进化到正常的成年人 偏爱脂肪酸。在成人心脏中，线粒体利用的病理逆转 碳水化合物被认为是导致心肌肥大、心力衰竭和心肌梗死的原因。 脑梗塞。然而，我们对直接利用心脏底物的具体机制的理解是 不完全的和强迫的心肌细胞线粒体的遗传生产尚未被证明是有效的 在心脏病的实验模型中。 我们在概念上的突破是心脏新陈代谢不是由“大师”决定的 调节“，但由线粒体动力性、适合性和生物发生之间的相互作用指导。 我们认为心肌代谢重塑需要有丝分裂的协同调节。 线粒体去除、生物线粒体置换和融合/裂变介导的线粒体 重新分配。通过单独扰乱这些途径并定义对 线粒体、细胞和器官的功能我们确定了这三个过程是如何共同调节的 并在功能上相互依赖，其中定义了MFN2作为 线粒体的命运(即保留与移除)。通过对人工Mfn2突变进行工程设计和研究 通过对心肌病队列进行DNA测序发现人类Mfn2基因突变具有损伤性 正在学习如何通过调制在内部微调相互作用组中的每个主要过程 在功能上相反的配对。具体地说，MFN介导的线粒体融合受到Drp1的反对。 介导线粒体分裂；PGC1介导的脂肪酸分解代谢线粒体的生物发生 反对PRC介导的碳水化合物分解代谢线粒体的生物发生；以及线粒体 复制与Parkin介导的线粒体消除相反。基于这些洞察力， 代表了HL59888(有丝分裂融合)和HL128441(有丝分裂)的研究目标的趋同， 我们开发了新的遗传和生化工具，即功能分离突变体Mfn2 蛋白质和细胞特指的多肽，以特定地操纵线粒体的动力或有丝分裂 在体外和体内。我们将使用这些新的概念和试剂来剖析分子 推动正常和疾病心脏代谢重塑和发展的机制 将心脏代谢与病理生理状态最佳匹配的可翻译方法，通过“拨号- 在“线粒体的质量和数量通过相互作用组内的精确操作。

项目成果

Assessing the effects of mitofusin 2 deficiency in the adult heart using 3D electron tomography.

• DOI: 10.14814/phy2.13437
• 发表时间: 2017-09
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Beikoghli Kalkhoran S;Hall AR;White IJ;Cooper J;Fan Q;Ong SB;Hernández-Reséndiz S;Cabrera-Fuentes H;Chinda K;Chakraborty B;Dorn GW 2nd;Yellon DM;Hausenloy DJ
• 通讯作者: Hausenloy DJ

Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy.

• DOI: 10.1038/s41419-022-04741-9
• 发表时间: 2022-04-22
• 期刊: CELL DEATH & DISEASE
• 影响因子: 9
• 作者: Vianello, Caterina;Cocetta, Veronica;Catanzaro, Daniela;Dorn, Gerald W. I. I. I. I.;De Milito, Angelo;Rizzolio, Flavio;Canzonieri, Vincenzo;Cecchin, Erika;Roncato, Rossana;Toffoli, Giuseppe;Quagliariello, Vincenzo;Di Mauro, Annabella;Losito, Simona;Maurea, Nicola;Cono, Scaffa;Sales, Gabriele;Scorrano, Luca;Giacomello, Marta;Montopoli, Monica
• 通讯作者: Montopoli, Monica

Mitofusin activation enhances mitochondrial motility and promotes neuroregeneration in CMT2A.

• DOI: 10.4103/1673-5374.310684
• 发表时间: 2021-11
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Dorn GW

Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.

• DOI: 10.1124/jpet.122.001332
• 发表时间: 2022-11
• 期刊: The Journal of pharmacology and experimental therapeutics

Context-dependent mitochondrial modulation of diastolic sarcoplasmic reticular calcium release.

舒张期肌浆网状钙释放的上下文依赖性线粒体调节。

• DOI: 10.1093/cvr/cvac150
• 发表时间: 2022
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Dorn,GeraldW