Dual function of mitochondrial Nm23-H4 protein in phosphotransfer and intermembrane lipid transfer: a cardiolipin-dependent switch

Details

• Personal Author:
  Amoscato AA ; Boissan M ; Epand RF ; Epand RM ; Huang Z ; Jiang J ; Kagan VE ; Klein-Seetharaman J ; Lacombe M-L ; Mohammadyani D ; Ramirez S ; Schlattner U ; Seffouh A ; Tokarska-Schlattner M ; Tyurina YY ; Yanamala N
• Description:
  The nucleoside diphosphate kinase Nm23-H4/NDPK-D forms symmetrical hexameric complexes in the mitochondrial intermembrane space with phosphotransfer activity using mitochondrial ATP to regenerate nucleoside triphosphates. We demonstrate the complex formation between Nm23-H4 and mitochondrial GTPase OPA1 in rat liver, suggesting its involvement in local and direct GTP delivery. Similar to OPA1, Nm23-H4 is further known to strongly bind in vitro to anionic phospholipids, mainly cardiolipin, and in vivo to the inner mitochondrial membrane. We show here that such protein-lipid complexes inhibit nucleoside diphosphate kinase activity but are necessary for another function of Nm23-H4, selective intermembrane lipid transfer. Mitochondrial lipid distribution was analyzed by liquid chromatography-mass spectrometry using HeLa cells expressing either wild-type Nm23-H4 or a membrane binding-deficient mutant at a site predicted based on molecular modeling to be crucial for cardiolipin binding and transfer mechanism. We found that wild type, but not the mutant enzyme, selectively increased the content of cardiolipin in the outer mitochondrial membrane, but the distribution of other more abundant phospholipids (e.g. phosphatidylcholine) remained unchanged. HeLa cells expressing the wild-type enzyme showed increased accumulation of Bax in mitochondria and were sensitized to rotenone-induced apoptosis as revealed by stimulated release of cytochrome c into the cytosol, elevated caspase 3/7 activity, and increased annexin V binding. Based on these data and molecular modeling, we propose that Nm23-H4 acts as a lipid-dependent mitochondrial switch with dual function in phosphotransfer serving local GTP supply and cardiolipin transfer for apoptotic signaling and putative other functions. [Description provided by NIOSH]
• Subjects:
  Animals Biochemistry Energy Metabolism Enzymes Histocytochemistry Laboratories Lipids Mass Spectrometry Occupational Health Safety
• Keywords:
  Animal-studies Biochemical-analysis Cell-damage Cell-metabolism Cellular-structures Chemical-binding Cytochemistry Enzyme-activity Laboratory-animals Liquid-chromatography Liver-cells Liver-microsomal-metabolism Mass-spectrometry Metabolism Nucleosides Phospholipids Physiological-chemistry Protein-biochemistry Protein-chemistry Proteins

  More +
• ISSN:
  0021-9258
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  111-121
• Volume:
  288
• Issue:
  1
• NIOSHTIC Number:
  nn:20042264
• Citation:
  J Biol Chem 2013 Jan; 288(1):111-121
• Contact Point Address:
  Uwe Schlattner, Laboratory of Fundamental and Applied Bioenergetics, University Joseph Fourier, Inserm U1055, BP 53, F-38041 Grenoble Cedex 9, France
• Email:
  uwe.schlattner@ujf-grenoble.fr
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Journal of Biological Chemistry
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:8242caa12858a0783590a5868ec55909a14e6240bb7eadb8940ec62a82b7f55034fba85598d63d8fa161a98688eb07a0516ef012ccbb229f009f8af5b315716c
• Download URL:
  https://stacks.cdc.gov/view/cdc/194544/cdc_194544_DS1.pdf
• File Type:
  [PDF - 3.34 MB ]