Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations.
Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations.
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DOI：
10.1083/jcb.200611080
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发表时间：
2007-02-12
影响因子：
7.8
通讯作者：
Chan, David C
中科院分区：
文献类型：
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作者：
Detmer, Scott A;Chan, David C
Mfn 2是一种对线粒体融合很重要的寡聚线粒体蛋白，在Charcot-Marie-Tooth病（CMT）2A型（一种以轴突变性为特征的周围神经病）中发生突变。除了同源寡聚复合物，Mfn 2也与Mfn 1，但这种异源寡聚复合物的功能意义是未知的。同样未知的是，鉴于Mfn 2的广泛表达，CMT 2A中的Mfn 2突变为什么会导致细胞类型特异性缺陷。在这项研究中，我们表明，许多Mfn 2疾病突变体形成的同源寡聚复合物是线粒体融合的非功能性。然而，野生型Mfn 1通过形成异源寡聚复合物（包括在线粒体之间反式形成的复合物）来补充突变型Mfn 2。野生型Mfn 2不能与疾病等位基因互补。我们的研究结果突出了Mfn 1-Mfn 2异源寡聚复合物的功能重要性，以及两种线粒体融合蛋白在线粒体融合控制中的密切相互作用。此外，他们认为Mfn 1表达低的组织在CMT 2A中很脆弱，并且增加外周神经系统中Mfn 1表达的方法将使CMT 2A患者受益。
Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.