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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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Models. (A) The protective role of mitochondrial fusion. At a low rate, individual mitochondria stochastically lose function. In wild-type cells, a defective mitochondrion (shaded) undergoes fusion with functional mitochondria and regains activity. In Mfn- deficient cells, such rescue occurs at a much reduced rate. (B) Three modes of mitofusin action. Mitofusins form homotypic and heterotypic complexes that lead to three activities (I, II, III) involving fusion. See Discussion for details. Mfn1 mutant cells contain only activity III; Mfn2 mutant cells contain only activity I. Since disruption of either Mfn1 or Mfn2 fragments mitochondria and results in distinct phenotypes, MEFs appear to use all three activities (indicated by asterisks). In contrast, trophoblast giant cells predominantly use activity III because they are affected in Mfn2 mutants and not Mfn1 mutants.
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fig10: Models. (A) The protective role of mitochondrial fusion. At a low rate, individual mitochondria stochastically lose function. In wild-type cells, a defective mitochondrion (shaded) undergoes fusion with functional mitochondria and regains activity. In Mfn- deficient cells, such rescue occurs at a much reduced rate. (B) Three modes of mitofusin action. Mitofusins form homotypic and heterotypic complexes that lead to three activities (I, II, III) involving fusion. See Discussion for details. Mfn1 mutant cells contain only activity III; Mfn2 mutant cells contain only activity I. Since disruption of either Mfn1 or Mfn2 fragments mitochondria and results in distinct phenotypes, MEFs appear to use all three activities (indicated by asterisks). In contrast, trophoblast giant cells predominantly use activity III because they are affected in Mfn2 mutants and not Mfn1 mutants.

Mentions: Our analysis of Mfn-deficient cells suggests an answer to this question. Although bulk cultures of Mfn-deficient fibroblasts show normal levels of endogenous and coupled respiration by oxygen electrode measurements, when individual mitochondria are examined we find that many cells contain a percentage of nonfunctional mitochondria as evidenced by loss of membrane potential. In other cell culture systems, the use of dyes sensitive to mitochondrial membrane potential has revealed occasional and transient losses of membrane potential within small regions of a single mitochondrial tubule (Loew, 1999). We suggest that the dynamic nature of mitochondria protects these organelles by ensuring that regional losses of membrane potential, caused perhaps by local depletion of metabolic substrates or mtDNA, are always transient (Fig. 10 A). Mitochondrial fusion enables intermitochondrial cooperation by allowing exchange of both membrane and matrix contents and therefore may help to restore local depletions and maintain mitochondrial function (Nakada et al., 2001a). Although there is no gross loss of mtDNA in mutant cells, we currently do not know if the individual, defective mitochondria have lost mtDNA.


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)

Models. (A) The protective role of mitochondrial fusion. At a low rate, individual mitochondria stochastically lose function. In wild-type cells, a defective mitochondrion (shaded) undergoes fusion with functional mitochondria and regains activity. In Mfn- deficient cells, such rescue occurs at a much reduced rate. (B) Three modes of mitofusin action. Mitofusins form homotypic and heterotypic complexes that lead to three activities (I, II, III) involving fusion. See Discussion for details. Mfn1 mutant cells contain only activity III; Mfn2 mutant cells contain only activity I. Since disruption of either Mfn1 or Mfn2 fragments mitochondria and results in distinct phenotypes, MEFs appear to use all three activities (indicated by asterisks). In contrast, trophoblast giant cells predominantly use activity III because they are affected in Mfn2 mutants and not Mfn1 mutants.
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Related In: Results  -  Collection

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fig10: Models. (A) The protective role of mitochondrial fusion. At a low rate, individual mitochondria stochastically lose function. In wild-type cells, a defective mitochondrion (shaded) undergoes fusion with functional mitochondria and regains activity. In Mfn- deficient cells, such rescue occurs at a much reduced rate. (B) Three modes of mitofusin action. Mitofusins form homotypic and heterotypic complexes that lead to three activities (I, II, III) involving fusion. See Discussion for details. Mfn1 mutant cells contain only activity III; Mfn2 mutant cells contain only activity I. Since disruption of either Mfn1 or Mfn2 fragments mitochondria and results in distinct phenotypes, MEFs appear to use all three activities (indicated by asterisks). In contrast, trophoblast giant cells predominantly use activity III because they are affected in Mfn2 mutants and not Mfn1 mutants.
Mentions: Our analysis of Mfn-deficient cells suggests an answer to this question. Although bulk cultures of Mfn-deficient fibroblasts show normal levels of endogenous and coupled respiration by oxygen electrode measurements, when individual mitochondria are examined we find that many cells contain a percentage of nonfunctional mitochondria as evidenced by loss of membrane potential. In other cell culture systems, the use of dyes sensitive to mitochondrial membrane potential has revealed occasional and transient losses of membrane potential within small regions of a single mitochondrial tubule (Loew, 1999). We suggest that the dynamic nature of mitochondria protects these organelles by ensuring that regional losses of membrane potential, caused perhaps by local depletion of metabolic substrates or mtDNA, are always transient (Fig. 10 A). Mitochondrial fusion enables intermitochondrial cooperation by allowing exchange of both membrane and matrix contents and therefore may help to restore local depletions and maintain mitochondrial function (Nakada et al., 2001a). Although there is no gross loss of mtDNA in mutant cells, we currently do not know if the individual, defective mitochondria have lost mtDNA.

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