Chen, Hsiuchen and Detmer, Scott A. and Ewald, Andrew J. and Griffin, Erik E. and Fraser, Scott E. and Chan, David C. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. Journal of Cell Biology, 160 (2). pp. 189-200. ISSN 0021-9525. http://resolver.caltech.edu/CaltechAUTHORS:20111025-153633703
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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.
|Additional Information:||© 2003 Rockefeller University Press. The online version of this article contains supplemental material. Submitted: 12 November 2002. Accepted: 12 December 2002. Revision received 12 December 2002. We thank Dr. Philip Leder for his support in the early stages of this work. We are grateful to M. Michelman for embryonic stem cell culture assistance and A. Harrington for blastocyst injections. We thank Drs. M. Rojo and A. Lombes for stimulating discussions about the PEG fusion assay. H. Chen is supported by an Alcott Postdoctoral fellowship. S.A. Detmer and E.E. Griffin are supported by a National Institutes of Health training grant NIHGM07616 and E.E. Griffin is funded by a Ferguson fellowship. A.J. Ewald is a participant in the Initiative in Computational Molecular Biology funded by the Burroughs Wellcome Fund Interfaces program. D.C. Chan is a Bren scholar, Rita Allen scholar, Beckman Young investigator, and recipient of a Burroughs Wellcome Fund Career Development award in Biomedical Sciences. This research was supported by the National Institutes of Health (grant 1 RO1 GM62967-01).|
|Official Citation:||Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development Hsiuchen Chen, Scott A. Detmer, Andrew J. Ewald, Erik E. Griffin, Scott E. Fraser, and David C. Chan J Cell Biol 2003 160:189-200. Published January 13, 2003, doi:10.1083/jcb.200211046|
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|Deposited By:||Ruth Sustaita|
|Deposited On:||25 Oct 2011 23:05|
|Last Modified:||26 Dec 2012 14:19|
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