Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion.

By Zhiyin Song, Mariam Ghochani, J. McCaffery, T. Frey, D. C. Chan. Molecular Biology of the Cell, 2009

607 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/932babd1fbc350bd7a8dc2852be34c37d4a10f25

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Citations in the corpus

Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations (2010, positive): “Moreover, we found that OPA1 null cells, which are deficient for fusion of the inner mitochondrial membrane, but proficient for outer membrane fusion (Song et al., 2009), also display mtDNA depletion (Figure 3C), suggesting that lack of mixing of the matrix compartment is ultimately responsible for ”
Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases (2009, background): “Potential answers include differential expression patterns between Mfn2 versus OPA1, functional differences between OPA1 (11) and Mfn2 (12), differences in an outer membrane fusion defect versus an inner membrane fusion defect (4) and redundancy between Mfn1 and Mfn2 (6,13).”