NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia

Chih-Wei Chen, Chi Su, Chang-Yu Huang, Xuan-Rong Huang, Xiaojing Cuili, Tung Chao, Chun-Hsiang Fan, Cheng-Wei Ting, Yi-Wei Tsai, Kai-Chien Yang, Ti-Yen Yeh, Sung-Tsang Hsieh, Yi-Ju Chen, Yuxi Feng, Tony Hunter and Zee-Fen Chang ()
Additional contact information
Chih-Wei Chen: National Taiwan University
Chi Su: National Taiwan University
Chang-Yu Huang: National Taiwan University
Xuan-Rong Huang: National Taiwan University
Xiaojing Cuili: National Taiwan University
Tung Chao: National Taiwan University
Chun-Hsiang Fan: National Taiwan University
Cheng-Wei Ting: National Taiwan University
Yi-Wei Tsai: National Taiwan University
Kai-Chien Yang: National Taiwan University
Ti-Yen Yeh: National Taiwan University
Sung-Tsang Hsieh: National Taiwan University
Yi-Ju Chen: Academia Sinica
Yuxi Feng: Heidelberg University
Tony Hunter: Salk Institute
Zee-Fen Chang: National Taiwan University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46385-7

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