Regulation of Mitochondrial Fission and Fusion

线粒体裂变和融合的调节

• 批准号: 8940074
• 负责人: Craig Blackstone
• 金额: $ 11.8万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8940074
• 关键词: American; Apoptosis; Area; Autosomal Dominant Optic Atrophy; Brain; Cell physiology; Cells; Cellular biology; Charcot-Marie-Tooth Disease; Development; Disease; Dynamin; Dystonia; Equilibrium; Event; Functional disorder; Genes; Guanosine Triphosphate Phosphohydrolases; Hereditary Spastic Paraplegia; Inherited; Integral Membrane Protein; Investigation; Laboratories; Mammals; Mitochondria; Mitochondrial Diseases; Molecular; Molecular Biology; Morphology; Mutate; Mutation; Neurodegenerative Disorders; Neurology; Optic Atrophy; Organelles; Patients; Process; Proteins; Publishing; Regulation; Research; Structure; Syndrome; clinically relevant; human OPA1 protein; insight; lactic acidemia; nervous system disorder; new therapeutic target; novel

Research in the Cellular Neurology Unit focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, dystonia, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for many of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. In this project, we are emphasizing investigations into the regulation of mitochondrial morphology within cells. Indeed, fusion and fission events that regulate mitochondrial morphology are essential for proper mitochondrial function, and their regulation is increasingly recognized in diverse cellular functions. Mitochondrial fission events in mammals are orchestrated by at least two proteins; the dynamin-related protein Drp1 and the integral membrane protein Fis1. The reciprocal process of mitochondrial fusion also requires large GTPases of the dynamin superfamily: OPA1 and the mitofusins Mfn1 and Mfn2. Since mutations in Drp1, Mfn2, and OPA1 have been identified in patients with inherited neurological disorders, and there is prominent fragmentation of mitochondria during programmed cell death, insights into the regulation of these processes is highly relevant clinically. We have recently published a study of the Drp1 A395D mutation that caused a neonatally fatal mitochondrial disorder due to markedly diminished mitochondrial fission. In this study, we were able to show that this mutation resulted in loss of higher-order multimeric interactions of the Drp1 protein. In complementary studies, we have now identified mutation in Drp1 that dramatically stabilizes higher-order Drp1 structures. Lastly, in ongoing studies we have identified a number of Drp1-interacting proteins that may be involved in the proper distribution of mitochondria within cells as well as novel proteins that regulate the mitochondrial fission/fusion balance thorugh unknown mechanisms. Together, these studies are continuing to provide critical insights into the regulation of mitochondrial morphology within a cell, an area of increasing clinical relevance and importance.

细胞神经病学部门的研究重点是许多神经退行性疾病的分子机制，包括线粒体疾病，肌张力障碍和遗传性痉挛性跨性疾病（HSPS）。 这些疾病共同遭受了数百万美国人的困扰，在多年中，阴险的恶化，其中许多疾病受到限制。 我们的实验室正在使用分子和细胞生物学方法研究这些疾病的遗传形式，以研究疾病基因中的突变如何最终导致细胞功能障碍。 在这个项目中，我们正在强调调查细胞内线粒体形态的调节。实际上，调节线粒体形态的融合和裂变事件对于适当的线粒体功能至关重要，并且它们的调节在多种细胞功能中被越来越多地认识到。 哺乳动物中的线粒体裂变事件至少由两种蛋白质精心策划。动力蛋白相关的蛋白DRP1和整体膜蛋白FIS1。 线粒体融合的倒数过程还需要Dynamin超家族的大量GTPase：OPA1和Mitofusins MFN1和MFN2。 由于在遗传神经系统疾病的患者中已经鉴定出DRP1，MFN2和OPA1的突变，并且在程序性细胞死亡期间线粒体存在明显的碎片，因此对这些过程的调节的见解在临床上是高度相关的。 我们最近发表了一项关于DRP1 A395D突变的研究，该突变引起了新生儿致命的线粒体疾病，这是由于线粒体裂变明显减少。 在这项研究中，我们能够证明该突变导致DRP1蛋白的高阶多聚体相互作用的丧失。在互补研究中，我们现在已经确定了DRP1中的突变，该突变大大稳定了高阶DRP1结构。最后，在正在进行的研究中，我们已经确定了许多DRP1相互作用的蛋白质，这些蛋白可能参与细胞内线粒体的适当分布以及调节线粒体裂变/融合平衡Thorugh未知机制的新型蛋白质。 总之，这些研究继续为细胞内线粒体形态的调节提供关键见解，这是临床相关性和重要性增加的领域。