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First published online 28 June 2005
doi: 10.1242/jcs.02449

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Mutational analysis of action of mitochondrial fusion factor mitofusin-2

Department of Biological Sciences, Tokyo Institute of Technology, 4259-B-19 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

^* Author for correspondence (email: shirose{at}bio.titech.ac.jp)

Accepted 21 April 2005

Mitofusin-2 (Mfn2) is an essential component of mitochondrial fusion machinery, but its molecular mechanism of action is not clear. We found that a Mfn2 deletion mutant lacking two transmembrane spans (Mfn^TM) acts as a dominant-negative mutant and blocks mitochondrial fusion. Furthermore, detailed analysis of various mutants of Mfn^TM revealed that GTPase activity and four regions highly conserved from nematodes to mammals are necessary for the dominant-negative effect. Immunoprecipitation studies of the N- and C-terminal cytosolic tails of Mfn2 showed that in addition to the coiled-coil domains previously identified, a highly conserved domain in the most N-terminal region and GTPase activity are necessary for the interaction between the N- and C-terminal tails, which is in turn required for the dominant-negative effect. In addition, we found unexpectedly that overexpression of the deletion mutant composed of one short region each in the N- and C-terminal tails of Mfn2 resulted in loss of mitochondrial membrane potential, suggesting that Mfn2 might also be connected to maintenance of mitochondrial membrane potential.

Key words: mitochondria, mitofusin, mitochondrial morphology, mitochondrial membrane potential

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