The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure
The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure
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DOI：
10.1074/jbc.m116.762567
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发表时间：
2017-04-28
影响因子：
4.8
通讯作者：
Yoon, Yisang
中科院分区：
文献类型：
--
作者：
Lee, Hakjoo;Smith, Sylvia B.;Yoon, Yisang
蛋白质视神经萎缩1（optic atrophy 1，OPA 1）是与线粒体内膜相关的动力蛋白相关蛋白，并且在线粒体内膜融合和嵴维持中起作用。内膜锚定的长OPA 1（L-OPA 1）经历蛋白水解切割，产生短OPA 1（S-OPA 1）。通常认为S-OPA 1是L-OPA 1的功能不重要的蛋白水解产物，因为在线粒体片段化和功能障碍中观察到由于L-OPA 1切割而导致的S-OPA 1的积累。然而，细胞在正常条件下含有L-OPA 1和S-OPA 1的混合物，这表明维持两种OPA 1形式的功能意义，但L-OPA 1和S-OPA 1在线粒体融合和能量学中的不同作用是不明确的。在这里，我们研究了线粒体融合和充满活力的活动，在细胞中拥有L-OPA 1单独，S-OPA 1单独，或L-OPA 1和S-OPA 1。使用线粒体融合测定，我们确定L-OPA 1赋予融合能力，而S-OPA 1不赋予。值得注意的是，我们发现，S-OPA 1单独没有L-OPA 1可以维持氧化磷酸化功能，判断生长在氧化磷酸化需要的媒体，呼吸测量，和呼吸复合物的水平。最引人注目的是，S-OPA 1单独维持正常的线粒体嵴结构，这通常被认为是含有L-OPA 1和S-OPA 1的OPA 1寡聚体的功能。此外，我们发现OPA 1的GT3活性对于维持嵴紧度和能量能力至关重要。我们的研究结果表明，与传统观念相反，S-OPA 1是完全有能力维持线粒体能量和嵴结构。
The protein optic atrophy 1 (OPA1) is a dynamin-related protein associated with the inner mitochondrial membrane and functions in mitochondrial inner membrane fusion and cristae maintenance. Inner membrane-anchored long OPA1 (L-OPA1) undergoes proteolytic cleavage resulting in short OPA1 (S-OPA1). It is often thought that S-OPA1 is a functionally insignificant proteolytic product of L-OPA1 because the accumulation of S-OPA1 due to L-OPA1 cleavage is observed in mitochondrial fragmentation and dysfunction. However, cells contain a mixture of both L-and S-OPA1 in normal conditions, suggesting the functional significance of maintaining both OPA1 forms, but the differential roles of L-and S-OPA1 in mitochondrial fusion and energetics are ill-defined. Here, we examined mitochondrial fusion and energetic activities in cells possessing L-OPA1 alone, S-OPA1 alone, or both L-and S-OPA1. Using a mitochondrial fusion assay, we established that L-OPA1 confers fusion competence, whereas S-OPA1 does not. Remarkably, we found that S-OPA1 alone without L-OPA1 can maintain oxidative phosphorylation function as judged by growth in oxidative phosphorylation-requiring media, respiration measurements, and levels of the respiratory complexes. Most strikingly, S-OPA1 alone maintained normal mitochondrial cristae structure, which has been commonly assumed to be the function of OPA1 oligomers containing both L-and S-OPA1. Furthermore, we found that the GTPase activity of OPA1 is critical for maintaining cristae tightness and thus energetic competency. Our results demonstrate that, contrary to conventional notion, S-OPA1 is fully competent for maintaining mitochondrial energetics and cristae structure.