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Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion
Open accessAbstract
Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases--OPA1 and the mitofusins Mfn1 and Mfn2--are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast.
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“Depletion of any of one these proteins results in severe dysfunction in respiratory capacity and fragmentation of mitochondria (Chen et al., 2005; Chen et al., 2010; Song et al., 2009)”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Song et al., 2009
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Metadata
- Authors
- Song, Z., Ghochani, M., McCaffery, J. M., Frey, T. G., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- Departments of ‡Physics and
- Johns Hopkins University (US)
- San Diego State University (US)
- Venue
- Molecular Biology of the Cell
- Published
- 2009-08
- Volume
- 20
- Issue
- 15
- Pages
- 3525-3532
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2719570
- OpenAlex
- W2164886443
- Cited by
- 623
- References
- 38
- Citations by year
- 2026: 32 · 2025: 45 · 2024: 46 · 2023: 39 · 2022: 62 · 2021: 41 · 2020: 41 · 2019: 35 · 2018: 36 · 2017: 36 · 2016: 31 · 2015: 33 · 2014: 33 · 2013: 38 · 2012: 31
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- California Institute of Technology
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM062967, GM062967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitochondrial fusion, mitofusins, Mfn1, mitofusin 2, OPA1, prohibitin, autosomal dominant optic atrophy, GTPase
- MeSH terms
- Animals, Cell Fusion, Cells, Cultured, Fibroblasts, Hybrid Cells, Membrane Fusion, Membrane Proteins, Microscopy, Electron, Polyethylene Glycols, Mice, Knockout, Microscopy, Confocal, GTP Phosphohydrolases, Mitochondrial Proteins, Adaptor Proteins, Signal Transducing, Green Fluorescent Proteins, Mitochondrial Membranes, Mice
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