NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

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, t...

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Published in:Cell death and differentiation 2016-07, Vol.23 (7), p.1140-1151
Main Authors: Kagan, V E, Jiang, J, Huang, Z, Tyurina, Y Y, Desbourdes, C, Cottet-Rousselle, C, Dar, H H, Verma, M, Tyurin, V A, Kapralov, A A, Cheikhi, A, Mao, G, Stolz, D, St Croix, C M, Watkins, S, Shen, Z, Li, Y, Greenberg, M L, Tokarska-Schlattner, M, Boissan, M, Lacombe, M-L, Epand, R M, Chu, C T, Mallampalli, R K, Bayır, H, Schlattner, U
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - drug effects
Bioenergetics
Biology
Carbonyl Cyanide m-Chlorophenyl Hydrazone - toxicity
Cardiolipins - analysis
Cardiolipins - metabolism
Cell death
Cell Line
Critical care
Free radicals
GTP Phosphohydrolases - metabolism
HeLa Cells
Humans
Kinases
Life Sciences
Lysosomes - metabolism
Lysosomes - pathology
Mice
Microtubule-Associated Proteins - metabolism
Mitochondria
Mitochondria - metabolism
Mitochondria - pathology
Mitochondrial Membranes - metabolism
Mitophagy - drug effects
Mutagenesis, Site-Directed
Nucleoside Diphosphate Kinase D - antagonists & inhibitors
Nucleoside Diphosphate Kinase D - genetics
Nucleoside Diphosphate Kinase D - metabolism
Occupational health
Original Paper
Oxidopamine - pharmacology
Protein Binding
Proteins
Quality control
RNA Interference
Rotenone - pharmacology
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2015.160