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

• Type of Material: Article
• Authors: Crystal A. Lee, Emory University; Lih-Shen Chin, Emory University; Lian Li, Emory University
• Language: English
• Date: 2018-08-01
• Publisher: SpringerOpen (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2017, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s13238-017-0469-4
• Title of Journal or Parent Work: Protein and Cell
• ISSN: 1674-800X
• Volume: 9
• Issue: 8
• Start Page: 693
• End Page: 716
• Grant/Funding Information: National Institutes of Health (NIH) (GM103613, NS092343, and NS093550); and pilot grant awards from NIH-funded Emory Udall Parkinson’s Disease Center (P50 NS071669) and Emory University Research Committee (SK46673).; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.; This work, including the efforts of Lih-Shen Chin, Lian Li, and Crystal Lee, was funded by HHS; C.A.L. was a trainee supported by NIH Training Grant T32 GM008367.
• Keywords: MAMMALIAN HOMOLOGS; mitofusin; DYNAMIN-RELATED PROTEIN; mitochondria; Cell Biology; DISEASE; MEMBRANE-FUSION; AXONAL-TRANSPORT; Life Sciences & Biomedicine; TRAFFICKING; KINESIN; DOMINANT OPTIC ATROPHY; mitochondrial tethering; FISSION; DEGRADATION; Science & Technology; mitochondrial fusion; hypertonia
• Research Categories: Biology, Cell; Health Sciences, Pharmacology

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 cancers and 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.