https://scholars.lib.ntu.edu.tw/handle/123456789/641502
Title: | NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia | Authors: | CHIH-WEI CHEN Su, Chi Huang, Chang Yu Huang, Xuan Rong Cuili, Xiaojing Chao, Tung Fan, Chun Hsiang Ting, Cheng Wei Tsai, Yi Wei KAI-CHIEN YANG Yeh, Ti Yen SUNG-TSANG HSIEH Chen, Yi Ju Feng, Yuxi Hunter, Tony ZEE-FEN CHANG |
Issue Date: | 1-Dec-2024 | Publisher: | Nature Research | Journal Volume: | 15 | Journal Issue: | 1 | Source: | Nature Communications | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641502 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-024-46385-7 |
Appears in Collections: | 分子醫學研究所 |
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