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

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  • 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.


  • Kagan, VE
  • Jiang, J
  • Huang, Z
  • Tyurina, YY
  • Desbourdes, C
  • Cottet-Rousselle, C
  • Dar, HH
  • Verma, M
  • Tyurin, VA
  • Kapralov, AA
  • Cheikhi, A
  • Mao, G
  • Stolz, D
  • St. Croix, CM
  • Watkins, S
  • Shen, Z
  • Li, Y
  • Greenberg, ML
  • Tokarska-Schlattner, M
  • Boissan, M
  • Lacombe, M-L
  • Epand, Richard
  • Chu, CT
  • Mallampalli, RK
  • Bayır, H
  • Schlattner, U

publication date

  • July 2016

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