Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development

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  • Hsiuchen Chen
    1Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125
  • Scott A. Detmer
    1Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125
  • Andrew J. Ewald
    1Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125
  • Erik E. Griffin
    1Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125
  • Scott E. Fraser
    1Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125
  • David C. Chan
    1Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125

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<jats:p>Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.</jats:p>

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