Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation |
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Authors: | Seung-Wook Ryu Hyeon Joo Jeong Myunghwan Choi Mariusz Karbowski Chulhee Choi |
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Institution: | (1) Cell Signaling and Bioimaging Laboratory, Department of Bio and Brain Engineering, KAIST, 335 Gwahangno, Yuseong-gu, Daejeon, 305-701, Korea;(2) KI for Biocentury, KAIST, Daejeon, 305-701, Korea;(3) Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA |
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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. |
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