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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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Dynamics of mitochondria in wild-type and mutant cells. Still frames from time-lapse confocal microscopy. (A) In a wild-type cell, two pairs of mitochondria can be seen moving toward each other. These pairs contact end-to-end and fuse immediately. Note that mitochondria move along their long axes. (B) In a Mfn1 mutant cell, the mitochondria move in an undirected manner. (C) In a Mfn2 mutant cell, two ovoid mitochondria contact each other but do not fuse until much later. Note also the lack of directed movement in most mitochondria. (D) One spherical Mfn2-deficient mitochondrion protrudes a tubular extension that separates and then migrates away along its long axis. Images were processed in Adobe Photoshop® with the emboss filter, and selected mitochondria were manually highlighted in blue. See also videos 1–3 available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1.
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fig4: Dynamics of mitochondria in wild-type and mutant cells. Still frames from time-lapse confocal microscopy. (A) In a wild-type cell, two pairs of mitochondria can be seen moving toward each other. These pairs contact end-to-end and fuse immediately. Note that mitochondria move along their long axes. (B) In a Mfn1 mutant cell, the mitochondria move in an undirected manner. (C) In a Mfn2 mutant cell, two ovoid mitochondria contact each other but do not fuse until much later. Note also the lack of directed movement in most mitochondria. (D) One spherical Mfn2-deficient mitochondrion protrudes a tubular extension that separates and then migrates away along its long axis. Images were processed in Adobe Photoshop® with the emboss filter, and selected mitochondria were manually highlighted in blue. See also videos 1–3 available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1.

Mentions: Because mitochondria are such dynamic organelles, we used time-lapse confocal microscopy to determine whether mutant MEFs display aberrations in mitochondrial dynamics. In wild-type cells, the mitochondria are highly motile, and at least one apparent fusion or fission event was observed for most mitochondria during 20-min recordings (Fig. 4 A; video 1, available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1). However, in both Mfn1 and Mfn2 mutant cells the ovoid or spherical mitochondria undergo fusion events much less frequently (videos 2 and 3, available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1), although a few such events can be found (Fig. 4 C).


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)

Dynamics of mitochondria in wild-type and mutant cells. Still frames from time-lapse confocal microscopy. (A) In a wild-type cell, two pairs of mitochondria can be seen moving toward each other. These pairs contact end-to-end and fuse immediately. Note that mitochondria move along their long axes. (B) In a Mfn1 mutant cell, the mitochondria move in an undirected manner. (C) In a Mfn2 mutant cell, two ovoid mitochondria contact each other but do not fuse until much later. Note also the lack of directed movement in most mitochondria. (D) One spherical Mfn2-deficient mitochondrion protrudes a tubular extension that separates and then migrates away along its long axis. Images were processed in Adobe Photoshop® with the emboss filter, and selected mitochondria were manually highlighted in blue. See also videos 1–3 available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1.
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Related In: Results  -  Collection

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fig4: Dynamics of mitochondria in wild-type and mutant cells. Still frames from time-lapse confocal microscopy. (A) In a wild-type cell, two pairs of mitochondria can be seen moving toward each other. These pairs contact end-to-end and fuse immediately. Note that mitochondria move along their long axes. (B) In a Mfn1 mutant cell, the mitochondria move in an undirected manner. (C) In a Mfn2 mutant cell, two ovoid mitochondria contact each other but do not fuse until much later. Note also the lack of directed movement in most mitochondria. (D) One spherical Mfn2-deficient mitochondrion protrudes a tubular extension that separates and then migrates away along its long axis. Images were processed in Adobe Photoshop® with the emboss filter, and selected mitochondria were manually highlighted in blue. See also videos 1–3 available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1.
Mentions: Because mitochondria are such dynamic organelles, we used time-lapse confocal microscopy to determine whether mutant MEFs display aberrations in mitochondrial dynamics. In wild-type cells, the mitochondria are highly motile, and at least one apparent fusion or fission event was observed for most mitochondria during 20-min recordings (Fig. 4 A; video 1, available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1). However, in both Mfn1 and Mfn2 mutant cells the ovoid or spherical mitochondria undergo fusion events much less frequently (videos 2 and 3, available at http://www.jcb.org/cgi/content/full/jcb.200211046/DC1), although a few such events can be found (Fig. 4 C).

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
Related in: MedlinePlus