Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion
Received date: 15 Jun 2017
Accepted date: 21 Aug 2017
Published date: 14 Aug 2018
Copyright
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.
Key words: mitochondria; mitochondrial fusion; mitochondrial tethering; mitofusin; hypertonia
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
1 |
Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A
|
2 |
An Y, Zhou Y, Ren G, Tian Q, Lu Y, Li H
|
3 |
Barel O, Christine VMM, Ben-Zeev B, Kandel J, Pri-Chen H, Stephen J
|
4 |
Bar-On L, Molenaers G, Aertbelien E, Van Campenhout A, Feys H, Nuttin B
|
5 |
Brickley K, Stephenson FA (2011) Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons. J Biol Chem 286(20):18079–18092.
|
6 |
Brickley K, Smith MJ, Beck M, Stephenson FA (2005) GRIF-1 and OIP106, members of a novel gene family of coiled-coil domain proteins: association in vivo and in vitro with kinesin. J Biol Chem 280(15):14723–14732.
|
7 |
Brocker C, Engelbrecht-Vandre S, Ungermann C (2010) Multisubunit tethering complexes and their role in membrane fusion. Curr Biol 20(21):R943–R952.
|
8 |
Cagalinec M, Safiulina D, Liiv M, Liiv J, Choubey V, Wareski P
|
9 |
Chan DC (2012) Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet 46:265–287.
|
10 |
Chen H, Chan DC (2009) Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases. Hum Mol Genet 18(R2):R169–R176.
|
11 |
Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160(2):189–200.
|
12 |
Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280 (28):26185–26192.
|
13 |
Chen J, Li L, Chin LS (2010) Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum Mol Genet 19(12):2395–2408.
|
14 |
Chin LS, Raynor MC, Wei X, Chen HQ, Li L (2001) Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor. J Biol Chem 276(10):7069–7078.
|
15 |
Chioza BA, Aicardi J, Aschauer H, Brouwer O, Callenbach P, Covanis A
|
16 |
Cipolat S, de Brito OM, Zilio BD, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101(45):15927–15932.
|
17 |
Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P
|
18 |
Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8(11):870–879.
|
19 |
Eura Y, Ishihara N, Yokota S, Mihara K (2003) Two mitofusin proteins, mammalian homologues of FZO, with distinct functions are both required for mitochondrial fusion. J Biochem 134 (3):333–344
|
20 |
Eura Y, Ishihara N, Oka T, Mihara K (2006) Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function. J Cell Sci 119(Pt 23):4913–4925.
|
21 |
Fallaize D, Chin LS, Li L (2015) Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways. Cell Signal 27(12):2543–2554.
|
22 |
Gilbert SL, Zhang L, Forster ML, Anderson JR, Iwase T, Soliven B
|
23 |
Giles LM, Li L, Chin LS (2009) Printor, a novel torsinA-interacting protein implicated in dystonia pathogenesis. J Biol Chem 284 (32):21765–21775.
|
24 |
Glater EE, Megeath LJ, Stowers RS, Schwarz TL (2006) Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J Cell Biol 173(4):545–557.
|
25 |
Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598.
|
26 |
Huang B, Bates M, Zhuang X (2009) Super-resolution fluorescence microscopy. Annu Rev Biochem 78:993–1016.
|
27 |
Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ (2006) Role of Bax and Bak in mitochondrial morphogenesis. Nature 443 (7112):658–662.
|
28 |
Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305(5685):858–862.
|
29 |
Koutsopoulos OS, Laine D, Osellame L, Chudakov DM, Parton RG, Frazier AE
|
30 |
Lazarou M, Jin SM, Kane LA, Youle RJ (2012) Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell 22(2):320–333.
|
31 |
Lee SM, Olzmann JA, Chin LS, Li L (2011) Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresomeautophagy pathways. J Cell Sci 124(Pt 19):3319–3331.
|
32 |
Lee SM, Chin LS, Li L (2012) Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. J Cell Biol 199(5):799–816.
|
33 |
Legros F, Lombes A, Frachon P, Rojo M (2002) Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell 13(12):4343–4354.
|
34 |
Li L, Chin LS (2003) The molecular machinery of synaptic vesicle exocytosis. Cell Mol Life Sci 60(5):942–960.
|
35 |
Macaskill AF, Rinholm JE, Twelvetrees AE, Arancibia-Carcamo IL, Muir J, Fransson A
|
36 |
Magrane J, Sahawneh MA, Przedborski S, Estevez AG, Manfredi G (2012) Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci 32(1):229–242.
|
37 |
Mishra P, Carelli V, Manfredi G, Chan DC (2014) Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab 19(4):630–641.
|
38 |
Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H (2005) Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 280(26):25060–25070.
|
39 |
Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148(6):1145–1159.
|
40 |
Parsons MJ, Green DR (2010) Mitochondria in cell death. Essays Biochem 47:99–114.
|
41 |
Pernas L, Scorrano L (2016) Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu Rev Physiol 78:505–531.
|
42 |
Pfeffer SR (1999) Transport-vesicle targeting: tethers before SNAREs. Nat Cell Biol 1(1):E17–E22.
|
43 |
Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J(2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 108(25):10190–10195.
|
44 |
Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z
|
45 |
Rojo M, Legros F, Chateau D, Lombes A (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 115(Pt 8):1663–1674
|
46 |
Sanger TD, Delgado MR, Gaebler-Spira D, Hallett M, Mink JW (2003) Task Force on Childhood Motor D. Classification and definition of disorders causing hypertonia in childhood. Pediatrics 111(1):e89–e97
|
47 |
Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114(Pt 5):867–874
|
48 |
Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P
|
49 |
Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (1998) A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 143(2):351–358
|
50 |
Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12(8):2245–2256
|
51 |
Stowers RS, Megeath LJ, Gorska-Andrzejak J, Meinertzhagen IA, Schwarz TL (2002) Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36 (6):1063–1077
|
52 |
Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S
|
53 |
Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G
|
54 |
van Spronsen M, Mikhaylova M, Lipka J, Schlager MA, van den Heuvel DJ, Kuijpers M
|
55 |
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA
|
56 |
Wang S, Xiao W, Shan S, Jiang C, Chen M, Zhang Y
|
57 |
Webber E, Li L, Chin LS (2008) Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking. J Mol Biol 382(3):638–651.
|
58 |
Winklhofer KF, Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta 1802(1):29–44.
|
59 |
Yu IM, Hughson FM (2010) Tethering factors as organizers of intracellular vesicular traffic. Annu Rev Cell Dev Biol 26:137–156.
|
60 |
Zhang F, Ren G, Lu Y, Jin B, Wang J, Chen X
|
61 |
Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW
|
62 |
Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL
|
/
〈 |
|
〉 |