Regulation of Mitochondrial Fission and Fusion

细胞神经病学单位的研究重点是一些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截瘫（HSPs）。这些疾病折磨着数以百万计的美国人，随着时间的推移，病情逐渐恶化，其中许多人的治疗选择有限。我们的实验室正在研究这些疾病的遗传形式，使用分子和细胞生物学方法研究疾病基因的突变如何最终导致细胞功能障碍。

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.