The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission.
The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission.
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DOI：
10.1083/jcb.201308006
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发表时间：
2014-03-17
期刊：
影响因子：
--
通讯作者：
Langer T
中科院分区：
文献类型：
--
作者：
Anand R;Wai T;Baker MJ;Kladt N;Schauss AC;Rugarli E;Langer T
YEM 1 L和OMA 1对OPA 1的加工不利于线粒体融合，反而会驱动线粒体片段化，这对线粒体完整性和质量控制至关重要。线粒体的融合和结构依赖于动力蛋白样GTIPOPA 1，其活性受蛋白水解加工调节。YME 1 L和OMA 1在两个不同位点的组成性OPA 1切割导致长和短形式的OPA 1的积累并维持线粒体融合。应激诱导的OPA 1通过OMA 1加工将OPA 1完全转化为短的同种型，抑制融合，并触发线粒体片段化。在这里，我们分析了不同OPA 1形式在缺乏YME 1 L，OMA 1或两者的细胞中的功能。出乎意料的是，Oma 1的缺失恢复了缺乏YME 1 L的细胞中线粒体的微管形成、嵴形态发生和凋亡抗性。长OPA 1形式足以介导这些细胞中的线粒体融合。短OPA 1形式的表达促进线粒体片段化，这表明它们与分裂有关。一致地，GTP酶失活的短OPA 1形式与ER-线粒体接触位点和线粒体裂变机制部分共定位。因此，OPA 1加工对于融合是不利的，但协调线粒体的动态行为，并且对于线粒体完整性和质量控制是至关重要的。
OPA1 processing by YEM1L and OMA1 is dispensable for mitochondrial fusion and instead drives mitochondrial fragmentation, which is crucial for mitochondrial integrity and quality control. Mitochondrial fusion and structure depend on the dynamin-like GTPase OPA1, whose activity is regulated by proteolytic processing. Constitutive OPA1 cleavage by YME1L and OMA1 at two distinct sites leads to the accumulation of both long and short forms of OPA1 and maintains mitochondrial fusion. Stress-induced OPA1 processing by OMA1 converts OPA1 completely into short isoforms, inhibits fusion, and triggers mitochondrial fragmentation. Here, we have analyzed the function of different OPA1 forms in cells lacking YME1L, OMA1, or both. Unexpectedly, deletion of Oma1 restored mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in cells lacking YME1L. Long OPA1 forms were sufficient to mediate mitochondrial fusion in these cells. Expression of short OPA1 forms promoted mitochondrial fragmentation, which indicates that they are associated with fission. Consistently, GTPase-inactive, short OPA1 forms partially colocalize with ER–mitochondria contact sites and the mitochondrial fission machinery. Thus, OPA1 processing is dispensable for fusion but coordinates the dynamic behavior of mitochondria and is crucial for mitochondrial integrity and quality control.
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