Hypertonia-linked protein Trakl functions with mitofusins to promote mitochondrial tethering and fusion

作     者：Crystal A. Lee Lih-Shen Chin Lian Li 

作者机构：Department of Pharmacology Emory University School of Medicine Atlanta GA 30322 USA Cell Biology Section Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD 20892 USA 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2018年第9卷第8期

页      面：693-716页

核心收录：

学科分类：0710[理学-生物学] 080706[工学-化工过程机械] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 0807[工学-动力工程及工程热物理] 

基　　金：funded by HHS | National Institutes of Health (NIH) pilot grant awards from NIH-funded Emory Udall Parkinson's Disease Center Emory University Research Committee supported by NIH Training 

主　　题：mitochondria mitochondrial fusion mitochondrial tethering mitofusin hypertonia 

摘      要：Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trakl that causes hypertonia in mice. Moreover, elevated Trakl protein expression is associated with several types of cancers and variants in Trakl are linked to childhood absence epilepsy in humans. Despite the importance of Trakl in health and disease, the mechanisms of Trakl action remain unclear and the pathogenic effects of Trakl mutation are unknown. Here we report that Trakl has a crucial function in regulation of mitochondrial fusion. Depletion of Trakl inhibits mitochondrial fusion, result- ing in mitochondrial fragmentation, whereas overex- pression of Trakl elongates and enlarges mitochondria. Our analyses revealed that Trakl interacts and colocal- izes with mitofusins on the outer mitochondrial mem- brane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trakl is required for stress-induced mitochondrial hyperfu- sion and pro-survival response. We found that hyper- tonia-associated mutation impairs Trakl mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trakl as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochon- drial dynamics to hypertonia pathogenesis.