title: Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation.
abstract: The optic atrophy 3 (OPA3) gene, which has no known homolog or biological function, is mutated in patients with hereditary optic neuropathies. Here, we identified OPA3 as an integral protein of the mitochondrial outer membrane (MOM), with a C-terminus exposed to the cytosol and an N-terminal mitochondrial targeting domain. By quantitative analysis, we demonstrated that overexpression of OPA3 significantly induced mitochondrial fragmentation, whereas OPA3 knockdown resulted in highly elongated mitochondria. Cells with mitochondria fragmented by OPA3 did not undergo spontaneous apoptotic cell death, but were significantly sensitized to staurosporine- and TRAIL-induced apoptosis. In contrast, overexpression of a familial OPA3 mutant (G93S) induced mitochondrial fragmentation and spontaneous apoptosis, suggesting that OPA3 mutations may cause optic atrophy via a gain-of-function mechanism. Together, these results indicate that OPA3, as an integral MOM protein, has a crucial role in mitochondrial fission, and provides a direct link between mitochondrial morphology and optic atrophy.
authors.affiliation: Cell Signaling and Bioimaging Laboratory, Department of Bio and Brain Engineering, KAIST, Yuseong-gu, Daejeon 305-701, Korea. ryus@kaist.ac.kr
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Ryu
authors.forename: Hyeon Joo
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Myunghwan
authors.initials: M
authors.lastname: Choi
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D017931:DNA Primers; D034281:Dynamins; D019286:Endopeptidase K / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D009901:Optic Nerve Diseases / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D017931:DNA Primers; C476525:FIS1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C443108:OPA3 protein, human; D011506:Proteins; D034741:RNA, Small Interfering; D012313:RNA; D019286:Endopeptidase K; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D019311:Staurosporine