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

Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC - J. Cell Biol. (2003)

Bottom Line: 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.Strikingly, a subset of mitochondria in mutant cells lose membrane potential.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.

ABSTRACT
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.

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Morphological defects in mitochondria of mutant cells. (A–F) Mitochondrial morphology in wild-type (A and B), Mfn1 mutant (C and D), and Mfn2 mutant (E and F) MEF cells. MEFs expressing mitochondrial EYFP (green) were counterstained with rhodamine-phalloidin (red). (B, D, and F) Higher magnification images of the boxed areas in A, C, and E, respectively. Arrow indicates a tubule >10 μm in length. (G and H) Mitochondrial morphology in live wild-type (G) and mutant (H) TS cells. The mitochondria were stained with MitoTracker Red, and the nuclei were stained with Syto16 (green). Several cells are tightly clustered.
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fig3: Morphological defects in mitochondria of mutant cells. (A–F) Mitochondrial morphology in wild-type (A and B), Mfn1 mutant (C and D), and Mfn2 mutant (E and F) MEF cells. MEFs expressing mitochondrial EYFP (green) were counterstained with rhodamine-phalloidin (red). (B, D, and F) Higher magnification images of the boxed areas in A, C, and E, respectively. Arrow indicates a tubule >10 μm in length. (G and H) Mitochondrial morphology in live wild-type (G) and mutant (H) TS cells. The mitochondria were stained with MitoTracker Red, and the nuclei were stained with Syto16 (green). Several cells are tightly clustered.

Mentions: To examine mitochondrial morphology in Mfn-deficient cells, we derived mouse embryonic fibroblasts (MEFs) from e10.5 embryos. The MEF cultures were infected with a retrovirus expressing mitochondrially targeted enhanced yellow fluorescent protein (EYFP). Wild-type MEFs showed a range of mitochondrial morphologies. The major morphological class, which encompassed >90% of wild-type cells, was characterized by a network of extended wavy tubules distributed in a roughly radial manner throughout the cytoplasm. Such cells had no or only a few spherical mitochondria. The length of these mitochondrial tubules ranged from several microns to >10 μm (Fig. 3, A and B, arrow). A much smaller morphological class, which encompassed only ∼6% of wild-type cells, had mitochondria that were mostly spherical and were termed as “fragmented.”


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

Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC - J. Cell Biol. (2003)

Morphological defects in mitochondria of mutant cells. (A–F) Mitochondrial morphology in wild-type (A and B), Mfn1 mutant (C and D), and Mfn2 mutant (E and F) MEF cells. MEFs expressing mitochondrial EYFP (green) were counterstained with rhodamine-phalloidin (red). (B, D, and F) Higher magnification images of the boxed areas in A, C, and E, respectively. Arrow indicates a tubule >10 μm in length. (G and H) Mitochondrial morphology in live wild-type (G) and mutant (H) TS cells. The mitochondria were stained with MitoTracker Red, and the nuclei were stained with Syto16 (green). Several cells are tightly clustered.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172648&req=5

fig3: Morphological defects in mitochondria of mutant cells. (A–F) Mitochondrial morphology in wild-type (A and B), Mfn1 mutant (C and D), and Mfn2 mutant (E and F) MEF cells. MEFs expressing mitochondrial EYFP (green) were counterstained with rhodamine-phalloidin (red). (B, D, and F) Higher magnification images of the boxed areas in A, C, and E, respectively. Arrow indicates a tubule >10 μm in length. (G and H) Mitochondrial morphology in live wild-type (G) and mutant (H) TS cells. The mitochondria were stained with MitoTracker Red, and the nuclei were stained with Syto16 (green). Several cells are tightly clustered.
Mentions: To examine mitochondrial morphology in Mfn-deficient cells, we derived mouse embryonic fibroblasts (MEFs) from e10.5 embryos. The MEF cultures were infected with a retrovirus expressing mitochondrially targeted enhanced yellow fluorescent protein (EYFP). Wild-type MEFs showed a range of mitochondrial morphologies. The major morphological class, which encompassed >90% of wild-type cells, was characterized by a network of extended wavy tubules distributed in a roughly radial manner throughout the cytoplasm. Such cells had no or only a few spherical mitochondria. The length of these mitochondrial tubules ranged from several microns to >10 μm (Fig. 3, A and B, arrow). A much smaller morphological class, which encompassed only ∼6% of wild-type cells, had mitochondria that were mostly spherical and were termed as “fragmented.”

Bottom Line: 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.Strikingly, a subset of mitochondria in mutant cells lose membrane potential.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.

ABSTRACT
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.

Show MeSH