Department of Biological Chemistry, University of California, Los Angeles, 90095, USA.
J Cell Biol. 2009 Dec 28;187(7):959-66. doi: 10.1083/jcb.200906083.
The mammalian mitochondrial inner membrane fusion protein OPA1 is controlled by complex patterns of alternative splicing and proteolysis. A subset of OPA1 isoforms is constitutively cleaved by YME1L. Other isoforms are not cleaved by YME1L, but they are cleaved when mitochondria lose membrane potential or adenosine triphosphate. In this study, we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1. We find that OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function. We also find that OMA1 is normally cleaved from 60 to 40 kD by another as of yet unidentified protease. Loss of membrane potential causes 60-kD protein to accumulate, suggesting that OMA1 is attenuated by proteolytic degradation. We conclude that a proteolytic cascade controls OPA1. Inducible cleavage provides a mechanism for quality control because proteolytic inactivation of OPA1 promotes selective removal of defective mitochondrial fragments by preventing their fusion with the mitochondrial network.
哺乳动物线粒体内膜融合蛋白 OPA1 的表达受到复杂的选择性剪接和蛋白水解调控。YME1L 可对 OPA1 同种型的一部分进行组成性切割。其它同种型不会被 YME1L 切割，但在线粒体失去膜电位或三磷酸腺苷时会被切割。本研究表明，这种诱导性切割是由一种称为 OMA1 的锌金属蛋白酶介导的。我们发现 OMA1 的小干扰 RNA 可抑制诱导性切割，有助于保持融合能力，并减缓细胞凋亡的发生，表明 OMA1 控制着 OPA1 的切割和功能。我们还发现，另一种尚未鉴定的蛋白酶通常会将 OMA1 从 60 到 40 kD 进行切割。膜电位的丧失导致 60-kD 蛋白的积累，这表明 OMA1 被蛋白水解降解所减弱。我们得出结论，一个蛋白水解级联反应控制着 OPA1。诱导性切割提供了一种质量控制机制，因为 OPA1 的蛋白水解失活可通过阻止有缺陷的线粒体片段与线粒体网络融合来促进其选择性去除。
