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J. Biol. Chem., Vol. 280, Issue 28, 26185-26192, July 15, 2005
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From the Division of Biology, California Institute of Technology, Pasadena, California 91125
Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and Mfn2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzo
yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.
Received for publication, March 21, 2005
* This research was supported in part by the National Institutes of Health (NIH) Grant 1 RO1 GM62967–01 and the Muscular Dystrophy Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.
Supported by NIH Grant GM11726.
Supported by a United Mitochondrial Disease Foundation grant. A Bren scholar and Beckman Young investigator. To whom correspondence should be addressed: Division of Biology, California Institute of Technology, 1200 E. California Blvd., MC114-96, Pasadena, CA 91125. Tel.: 626-395-2670; Fax: 626-395-8826; E-mail: dchan{at}caltech.edu.
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