粒体自噬
缺氧(环境)
细胞生物学
自噬
化学
生物
氧气
生物化学
细胞凋亡
有机化学
作者
Chih-Wei Chen,Ching‐Yuan Su,Chih‐Mao Huang,Xuan-Rong Huang,Margaret Cui,Tung Chao,Chun-Hsiang Fan,Chung-Te Ting,Yi-Wei Tsai,Kai‐Chien Yang,Ti‐Yen Yeh,Sung‐Tsang Hsieh,Yi-Ju Chen,Yuxi Feng,Tony Hunter,Zee-Fen Chang
标识
DOI:10.1038/s41467-024-46385-7
摘要
Abstract NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.
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