Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion.
Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion.
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DOI：
10.1091/mbc.e20-09-0605
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发表时间：
2021-01-15
影响因子：
3.3
通讯作者：
Chan DC
中科院分区：
文献类型：
--
作者：
Wang R;Mishra P;Garbis SD;Moradian A;Sweredoski MJ;Chan DC
OPA1是动力蛋白超家族的一个大的GTP酶，它介导线粒体内膜的融合，调节嵴的形态，并维持呼吸链的功能。内膜锚定的长型OPA1(L-OPA1)被OMA1或YME1L蛋白水解酶降解，分别作用于切割位点S1和S2，产生短型(S-OPA1)。在小鼠和人类中，OPA1mRNA剪接形式的一半都被结构性加工成只产生S-OPA1。然而，S-OPA1在线粒体融合中的作用一直存在争议，因为在某些应激条件下，S-OPA1是线粒体融合所必需的。通过构建OPA1基因不再产生带有S2裂解位点的转录本的细胞，我们产生了一个简化的系统来鉴定新的YME1L依赖的S3位点，它介导了OPA1的结构性和完全切割。我们发现线粒体形态对L-OPA1和S-OPA1的比例高度敏感，表明S-OPA1调控线粒体融合。
OPA1, a large GTPase of the dynamin superfamily, mediates fusion of the mitochondrial inner membranes, regulates cristae morphology, and maintains respiratory chain function. Inner membrane–anchored long forms of OPA1 (l-OPA1) are proteolytically processed by the OMA1 or YME1L proteases, acting at cleavage sites S1 and S2, respectively, to produce short forms (s-OPA1). In both mice and humans, half of the mRNA splice forms of Opa1 are constitutively processed to yield exclusively s-OPA1. However, the function of s-OPA1 in mitochondrial fusion has been debated, because in some stress conditions, s-OPA1 is dispensable for fusion. By constructing cells in which the Opa1 locus no longer produces transcripts with S2 cleavage sites, we generated a simplified system to identify the new YME1L-dependent site S3 that mediates constitutive and complete cleavage of OPA1. We show that mitochondrial morphology is highly sensitive to the ratio of l-OPA1 to s-OPA1, indicating that s-OPA1 regulates mitochondrial fusion.