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NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia

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...

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Main Authors: Chen, Chih-Wei (Author) , Su, Chi (Author) , Huang, Chang-Yu (Author) , Huang, Xuan-Rong (Author) , Cuili, Xiaojing (Author) , Chao, Tung (Author) , Fan, Chun-Hsiang (Author) , Ting, Cheng-Wei (Author) , Tsai, Yi-Wei (Author) , Yang, Kai-Chien (Author) , Yeh, Ti-Yen (Author) , Hsieh, Sung-Tsang (Author) , Chen, Yi-Ju (Author) , Feng, Yuxi (Author) , Hunter, Tony (Author) , Chang, Zee-Fen (Author)
Format: Article (Journal)
Language:English
Published: 13 March 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-20
ISSN:2041-1723
DOI:10.1038/s41467-024-46385-7
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-46385-7
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-46385-7
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Author Notes: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 & Zee-Fen Chang
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Summary: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.
Item Description:Gesehen am 27.11.2024
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-024-46385-7

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