Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development.
Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development.
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DOI：
10.1083/jcb.200211046
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发表时间：
2003-01-20
期刊：
影响因子：
--
通讯作者：
Chan DC
中科院分区：
文献类型：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
线粒体形态是由细胞器融合和分裂之间的动态平衡决定的，但这些过程在脊椎动物中的意义尚不清楚。已经显示，当过表达时，丝裂融合蛋白Mfn1和Mfn2影响线粒体形态。我们发现Mfn 1或Mfn 2缺陷的小鼠在妊娠中期死亡。然而，尽管Mfn2突变胚胎具有胎盘滋养层巨细胞层的特异性和严重破坏，但Mfn1缺陷的巨细胞是正常的。缺乏Mfn1或Mfn2的胚胎成纤维细胞显示不同类型的片段化线粒体，我们确定这种表型是由于线粒体融合严重减少。此外，我们发现，Mfn1和Mfn2形成同型和异型复合物，并显示，通过拯救突变细胞，同型复合物的融合功能。我们的结论是，Mfn1和Mfn2都有冗余和不同的功能，并在三个独立的分子复合物，以促进线粒体融合。引人注目的是，突变细胞中的一部分线粒体失去了膜电位。因此，线粒体融合对于胚胎发育是必不可少的，并且通过使线粒体之间的合作，对线粒体群体具有保护作用。
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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