RESEARCH ARTICLE

Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion

  • Crystal A. Lee 1,2 ,
  • Lih-Shen Chin 1 ,
  • Lian Li , 1
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  • 1. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA
  • 2. Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA

Received date: 15 Jun 2017

Accepted date: 21 Aug 2017

Published date: 14 Aug 2018

Copyright

2017 The Author(s) 2017. This article is an open access publication

Abstract

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 Trak1 that causes hypertonia in mice. Moreover, elevated Trak1 protein expression is associated with several types of cancersand variants in Trak1 are linked to childhood absence epilepsy in humans. Despite the importance of Trak1 in health and disease, the mechanisms of Trak1 action remain unclear and the pathogenic effects of Trak1 mutation are unknown. Here we report that Trak1 has a crucial function in regulation of mitochondrial fusion. Depletion of Trak1 inhibits mitochondrial fusion, resulting in mitochondrial fragmentation, whereas overexpression of Trak1 elongates and enlarges mitochondria. Our analyses revealed that Trak1 interacts and colocalizes with mitofusins on the outer mitochondrial membrane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trak1 is required for stress-induced mitochondrial hyperfusion and pro-survival response. We found that hypertonia-associated mutation impairs Trak1 mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trak1 as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochondrial dynamics to hypertonia pathogenesis.

Cite this article

Crystal A. Lee , Lih-Shen Chin , Lian Li . Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion[J]. Protein & Cell, 2018 , 9(8) : 693 -716 . DOI: 10.1007/s13238-017-0469-4

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