期刊
CELL DEATH AND DIFFERENTIATION
卷 23, 期 7, 页码 1140-1151出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2015.160
关键词
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资金
- National Institutes of Health [P01HL114453, U19AI068021, NS076511, NS061817, ES020693, NS065789, AG026389, HL117880]
- National Institute of Occupational Safety and Health [OH008282]
- Human Frontier Science Program [HFSP-RGP0013/2014]
- Barth Syndrome Foundation of Canada
- Barth Syndrome Foundation of United States
- Fondation pour la Recherche Medicale (FRM) [DPM20121125557]
- CMIRA Explo'ra doc fellowship of the Region Rhone Alpes
- GEFLUC
- Natural Sciences and Engineering Council of Canada [9848]
Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.
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