NDPK-D (NM23-H4)-Mediated Externalization of Cardiolipin Enables Elimination of Depolarized Mitochondria by Mitophagy

Details

• Personal Author:
  Bayir H ; Boissan M ; Cheikhi A ; Chu CT ; Cottet-Rousselle C ; Dar HH ; Desbourdes C ; Epand RM ; Greenberg ML ; Huang Z ; Jiang J ; Kagan VE ; Kapralov AA ; Lacombe ML ; Li Y ; Mallampalli RK ; Mao G ; Schlattner U ; Shen Z ; St Croix CM ; Stolz D ; Tokarska-Schlattner M ; Tyurin VA ; Tyurina YY ; Verma M ; Watkins S
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Energy Metabolism Laboratories Lipids Lung Mutagens Occupational Health Respiratory System Safety
• Keywords:
  Adenocarcinomas Carbonyls Cell Biology Cell Death Cell Differentiation Cell Metabolism Cellular Effects Cellular Function Cellular Structures Cervical Cancer Gene Regulation Humans Laboratory Animals Lung Cells Metabolism Nucleosides Phagocytic Activity Phospholipids Physiological Function Physiological Response Proteins Ribonucleic Acids RNA Rotenone

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• ISSN:
  1350-9047
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Michigan ; OSHA Region 3 ; OSHA Region 5 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  23
• Issue:
  7
• NIOSHTIC Number:
  nn:20050882
• Citation:
  Cell Death Differ 2016 Jul; 23(7):1140-1151
• Contact Point Address:
  VE Kagan, Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA
• Email:
  Kagan@pitt.edu
• CAS Registry Number:
  6-Hydroxydopamine (CAS RN 1199-18-4) ; Carbonyl cyanide (m-chlorophenyl)hydrazone (CAS RN 555-60-2) ; Rotenone (CAS RN 83-79-4)
• Federal Fiscal Year:
  2016
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Cell Death and Differentiation
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:380da89eb4be96988002dccb1d6447d901fc716357eefacc7ea33424cfbc4585d9cabee5a9412a037b5124141a5efbbd42235573d77b6946985ee1b518cbc660
• Download URL:
  https://stacks.cdc.gov/view/cdc/211074/cdc_211074_DS1.pdf
• File Type:
  [PDF - 2.97 MB ]