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

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.

Pubmed ID: 12527753

Authors

  • Chen H
  • Detmer SA
  • Ewald AJ
  • Griffin EE
  • Fraser SE
  • Chan DC

Journal

The Journal of cell biology

Publication Data

January 20, 2003

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 1 R01 GM62967-01
  • Agency: NIGMS NIH HHS, Id: GM07616

Mesh Terms

  • Animals
  • Cell Movement
  • Cells, Cultured
  • Cytoskeletal Proteins
  • Embryo Loss
  • Embryo, Mammalian
  • Embryonic and Fetal Development
  • Female
  • Fetus
  • GTP Phosphohydrolases
  • Gene Expression Regulation, Developmental
  • Genes, Lethal
  • Intracellular Membranes
  • Macromolecular Substances
  • Male
  • Membrane Potentials
  • Membrane Proteins
  • Membrane Transport Proteins
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Placenta
  • Trophoblasts
  • Utrophin