Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria
Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria
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DOI：
10.1016/j.molcel.2017.06.013
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发表时间：
2017-08-03
期刊：
影响因子：
16
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
--
作者：
Vukotic, Milena;Nolte, Hendrik;Langer, Thomas
线粒体酰基甘油激酶（AGK）的突变会导致以白内障、肥厚性心肌病和骨骼肌病为特征的Syndrome综合征。AGK产生磷脂酸和溶血磷脂酸，它们是参与脂质信号传导和调节肿瘤进展的生物活性磷脂。然而，线粒体病理学的分子机制仍然是谜。确定其线粒体相互作用组，我们已经确定AGK作为线粒体内膜中的TIM22复合物的组成部分。AGK与TIMM22和TIMM29组装，并支持多跨膜蛋白亚组的输入。AGK作为TIM22复合物的亚基的功能不依赖于其激酶活性。然而，需要酶活性AGK来维持线粒体嵴形态发生和细胞的凋亡抗性。AGK作为脂质激酶和TIM22复合物的组成部分的双重功能揭示了磷脂代谢和线粒体蛋白生物合成的紊乱导致了SHP综合征的发病机制。
Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins. The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity. However, enzymatically active AGK is required to maintain mitochondrial cristae morphogenesis and the apoptotic resistance of cells. The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome.