Mitochondrial NM23-H4/NDPK-D Supports Cardiolipin Signaling to Eliminate Depolarized Mitochondria by Mitophagy

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Schlattner, Uwe | Jiang, Jianfei | Huang, Zhentai | Tyurina, Yulia | Desbourdes, Céline | Cottet-Rousselle, C. | Dar, Haider | Verma, Manish | Tyurina, Vladimir | Kapralov, Alexandr | Lacombe, Marie-Lise | Chu, Charleen | Mallampalli, Rama | Bayir, Hülya | Kagan, Valerian, E

Edité par CCSD -

International audience. The well-established function of the hexameric intermembrane space protein, NDPK-D/NM23-H4, is phosphotransfer activity as a nucleoside diphosphate kinase. However, recent data revealed a second function in lipid signaling that is involved in mitophagy, a critical process for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the mitochondrial surface was identified as a mitophageal signal, recognized by the microtubule-associated protein 1 light chain 3. Here we demonstrate that NDPK-D binds CL and facilitates its re-distribution to the outer mitochondrial membrane. We found that mitophagy induced by a protonophoric uncoupler, 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 which does not bind CL was inactive in promoting mitophagy. In situ proximity ligation assay showed that mitophagy-inducing CL transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, and OPA1 silencing favored NDPK-D supported CL transfer, implicating fission-fusion dynamics in mitophagy regulation.

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