New Splicing Variants of Mitochondrial Rho GTPase-1 (Miro1) Transport Peroxisomes

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2017 Dec 10

PMID 29222186

Citations 34

Authors

Kanji Okumoto

Tatsuaki Ono

Ryusuke Toyama

Ayako Shimomura

Aiko Nagata

Yukio Fujiki

Affiliations

Soon will be listed here.

Abstract

Microtubule-dependent long-distance movement of peroxisomes occurs in mammalian cells. However, its molecular mechanisms remain undefined. In this study, we identified three distinct splicing variants of human mitochondrial Rho GTPase-1 (Miro1), each containing amino acid sequence insertions 1 (named Miro1-var2), 2 (Miro1-var3), and both 1 and 2 (Miro1-var4), respectively, at upstream of the transmembrane domain. Miro1-var4 and Miro1-var2 are localized to peroxisomes in a manner dependent on the insertion 1 that is recognized by the cytosolic receptor Pex19p. Exogenous expression of Miro1-var4 induces accumulation of peroxisomes at the cell periphery and augments long-range movement of peroxisomes along microtubules. Depletion of all Miro1 variants by knocking down suppresses the long-distance movement of peroxisomes. Such abrogated movement is restored by reexpression of peroxisomal Miro1 variants. Collectively, our findings identify for the first time peroxisome-localized Miro1 variants as adapter proteins that link peroxisomes to the microtubule-dependent transport complexes including TRAK2 in the intracellular translocation of peroxisomes in mammalian cells.

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References

Kemper C, Habib S, Engl G, Heckmeyer P, Dimmer K, Rapaport D . Integration of tail-anchored proteins into the mitochondrial outer membrane does not require any known import components. J Cell Sci. 2008; 121(Pt 12):1990-8. DOI: 10.1242/jcs.024034. View

Hua R, Cheng D, Coyaud E, Freeman S, Di Pietro E, Wang Y . VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis. J Cell Biol. 2017; 216(2):367-377. PMC: 5294787. DOI: 10.1083/jcb.201608128. View

Borgese N, Fasana E . Targeting pathways of C-tail-anchored proteins. Biochim Biophys Acta. 2010; 1808(3):937-46. DOI: 10.1016/j.bbamem.2010.07.010. View

Wali G, Sutharsan R, Fan Y, Stewart R, Tello Velasquez J, Sue C . Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia. Sci Rep. 2016; 6:27004. PMC: 4882512. DOI: 10.1038/srep27004. View

Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P . Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci U S A. 2008; 105(52):20728-33. PMC: 2634948. DOI: 10.1073/pnas.0808953105. View

Okumoto K, Noda H, Fujiki Y . Distinct modes of ubiquitination of peroxisome-targeting signal type 1 (PTS1) receptor Pex5p regulate PTS1 protein import. J Biol Chem. 2014; 289(20):14089-108. PMC: 4022878. DOI: 10.1074/jbc.M113.527937. View

Abrahamsen G, Fan Y, Matigian N, Wali G, Bellette B, Sutharsan R . A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations. Dis Model Mech. 2012; 6(2):489-502. PMC: 3597030. DOI: 10.1242/dmm.010884. View

Halbach A, Landgraf C, Lorenzen S, Rosenkranz K, Volkmer-Engert R, Erdmann R . Targeting of the tail-anchored peroxisomal membrane proteins PEX26 and PEX15 occurs through C-terminal PEX19-binding sites. J Cell Sci. 2006; 119(Pt 12):2508-17. DOI: 10.1242/jcs.02979. View

Shimozawa N, Tsukamoto T, Nagase T, Takemoto Y, Koyama N, Suzuki Y . Identification of a new complementation group of the peroxisome biogenesis disorders and PEX14 as the mutated gene. Hum Mutat. 2004; 23(6):552-8. DOI: 10.1002/humu.20032. View

10.

Berger J, Dorninger F, Forss-Petter S, Kunze M . Peroxisomes in brain development and function. Biochim Biophys Acta. 2015; 1863(5):934-55. PMC: 4880039. DOI: 10.1016/j.bbamcr.2015.12.005. View

11.

Nishimura Y, Higaki M, Kato K . Identification of a precursor form of cathepsin D in microsomal lumen: characterization of enzymatic activation and proteolytic. Biochem Biophys Res Commun. 1987; 148(1):335-43. DOI: 10.1016/0006-291x(87)91115-6. View

12.

Fransson S, Ruusala A, Aspenstrom P . The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem Biophys Res Commun. 2006; 344(2):500-10. DOI: 10.1016/j.bbrc.2006.03.163. View

13.

Yagita Y, Hiromasa T, Fujiki Y . Tail-anchored PEX26 targets peroxisomes via a PEX19-dependent and TRC40-independent class I pathway. J Cell Biol. 2013; 200(5):651-66. PMC: 3587837. DOI: 10.1083/jcb.201211077. View

14.

Liu Y, Yagita Y, Fujiki Y . Assembly of Peroxisomal Membrane Proteins via the Direct Pex19p-Pex3p Pathway. Traffic. 2016; 17(4):433-55. DOI: 10.1111/tra.12376. View

15.

Babic M, Russo G, Wellington A, Sangston R, Gonzalez M, Zinsmaier K . Miro's N-terminal GTPase domain is required for transport of mitochondria into axons and dendrites. J Neurosci. 2015; 35(14):5754-71. PMC: 4388930. DOI: 10.1523/JNEUROSCI.1035-14.2015. View

16.

Kural C, Kim H, Syed S, Goshima G, Gelfand V, Selvin P . Kinesin and dynein move a peroxisome in vivo: a tug-of-war or coordinated movement?. Science. 2005; 308(5727):1469-72. DOI: 10.1126/science.1108408. View

17.

Wanders R . Metabolic functions of peroxisomes in health and disease. Biochimie. 2013; 98:36-44. DOI: 10.1016/j.biochi.2013.08.022. View

18.

Fujiki Y, Hubbard A, Fowler S, Lazarow P . Isolation of intracellular membranes by means of sodium carbonate treatment: application to endoplasmic reticulum. J Cell Biol. 1982; 93(1):97-102. PMC: 2112113. DOI: 10.1083/jcb.93.1.97. View

19.

Chen Y, Sheng Z . Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J Cell Biol. 2013; 202(2):351-64. PMC: 3718985. DOI: 10.1083/jcb.201302040. View

20.

Fagarasanu A, Fagarasanu M, Eitzen G, Aitchison J, Rachubinski R . The peroxisomal membrane protein Inp2p is the peroxisome-specific receptor for the myosin V motor Myo2p of Saccharomyces cerevisiae. Dev Cell. 2006; 10(5):587-600. DOI: 10.1016/j.devcel.2006.04.012. View