OPA1 Requires Mitofusin 1 to Promote Mitochondrial Fusion

OPA1 Requires Mitofusin 1 to Promote Mitochondrial Fusion

The regulated equilibrium between mitochondrial fusion and fission is essential to maintain integrity of the organelle. Mechanisms of mitochondrial fusion are largely uncharacterized in mammalian cells. It is unclear whether OPA1, a dynamin-related protein of the inner membrane mutated in autosomal...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 45; pp. 15927 - 15932
Main Authors: Cipolat, Sara, de Brito, Olga Martins, Zilio, Barbara Dal, Scorrano, Luca, Korsmeyer, Stanley J.
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 09-11-2004
National Acad Sciences
Subjects:
Animals
Beta cells
Biological Sciences
Cells, Cultured
Cellular biology
Daughter cells
Fluorescence
Fusion
Gene Targeting
GTP Phosphohydrolases - antagonists & inhibitors
GTP Phosphohydrolases - deficiency
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - physiology
HeLa cells
Imaging
In Vitro Techniques
Membrane Fusion
Mice
Mice, Knockout
Mitochondria
Mitochondria - physiology
Mitochondria - ultrastructure
Mitochondrial DNA
Optic atrophy
Organelles
Proteins
RNA Interference
Transfection
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Summary:The regulated equilibrium between mitochondrial fusion and fission is essential to maintain integrity of the organelle. Mechanisms of mitochondrial fusion are largely uncharacterized in mammalian cells. It is unclear whether OPA1, a dynamin-related protein of the inner membrane mutated in autosomal dominant optic atrophy, participates in fusion or fission. OPA1 promoted the formation of a branched network of elongated mitochondria, requiring the integrity of both its GTPase and C-terminal coiled-coil domain. Stable reduction of OPA1 levels by RNA interference resulted in small, fragmented, and scattered mitochondria. Levels of OPA1 did not affect mitochondrial docking, but they correlated with the extent of fusion as measured by polyethylene glycol mitochondrial fusion assays. A genetic analysis proved that OPA1 was unable to tubulate and fuse mitochondria lacking the outer membrane mitofusin 1 but not mitofusin 2. Our data show that OPA1 functionally requires mitofusin 1 to regulate mitochondrial fusion and reveal a specific functional difference between mitofusin 1 and 2.
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Communicated by Stanley J. Korsmeyer, Dana–Farber Cancer Institute, Boston, MA, September 23, 2004
To whom correspondence should be addressed. E-mail: luca.scorrano@unipd.it.
Abbreviations: DRP1, dynamin-related protein 1; MEF, mouse embryonic fibroblast; mtCFP, mitochondrially targeted cyan fluorescent protein; mtYFP, mitochondrially targeted yellow fluorescent protein; mtRFP, mitochondrially targeted dsRED; MFN, mitofusin; PEG, polyethylene glycol; RNAi, RNA interference.
Author contributions: L.S. designed research; S.C., O.M.d.B., and B.D.Z. performed research; S.C. analyzed data; O.M.d.B. contributed new reagents/analytic tools; and L.S. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407043101