Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion
Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion
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DOI：
10.1091/mbc.e09-03-0252
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发表时间：
2009-08-01
影响因子：
3.3
通讯作者：
Chan, David C.
中科院分区：
文献类型：
--
作者：
Song, Zhiyin;Ghochani, Mariam;Chan, David C.
线粒体融合需要外膜和内膜的协调融合。三种大型 GTPases——OPA1 以及线粒体融合蛋白 Mfn1 和 Mfn2——对于哺乳动物线粒体的融合至关重要。 OPA1 在显性视神经萎缩（一种视神经退行性疾病）中发生突变。在酵母中，OPA1 直系同源物 Mgm1 是体外内膜融合所必需的；然而，缺乏 Mgm1 的酵母在体内既不表现出外膜融合，也不表现出内膜融合，因为这两个过程之间紧密耦合。我们发现，在体内 OPA1 缺失的小鼠细胞中，可以很容易地观察到外膜融合，但这些事件不会进展为内膜融合。在缺乏抑制素的细胞中也发现了类似的缺陷，而抑制素是 OPA1 正确加工所必需的。相反，双 Mfn 缺失细胞既不显示外膜融合，也不显示内膜融合。 OPA1 缺失细胞中的线粒体通常包含由单个外膜结合在一起的多个基质区室，这与外膜与内膜融合的解偶联一致。此外，与线粒体融合素和酵母 Mgm1 不同，相邻线粒体不需要 OPA1 来介导膜融合。这些结果表明，与酵母中的情况相反，哺乳动物线粒体融合蛋白和 OPA1 介导容易解偶联的不同连续融合步骤。
Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases-OPA1 and the mitofusins Mfn1 and Mfn2-are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast.