Schlattner 2018 MiP2018

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Uwe Schlattner
Intramitochondrial nucleotide regeneration by NME/NDPK proteins – roles in mitochondrial dynamics, signaling and metastasis.

Link: MiP2018

Schlattner U, Tokarska-Schlattner M, Lacombe ML, Boissan M (2018)

Event: MiP2018

COST Action MitoEAGLE

Several NME proteins have NDP kinase (NDPK) activity and are thus a major source of cellular GTP. We have shown that mitochondrial NME4 localizing to the intermembrane space is using oxidatively synthesized ATP to regenerate NTPs and to stimulate respiration by the generated ADP [1]. Most importantly, NME4 is able to directly interact with and fuel the GTPase OPA1, thus supporting OPA1 functions in fusion and remodeling of the inner mitochondrial membrane MIM [2]. Both, OPA1 loss-of-function and silencing of NM23-H4, result in fusion defects that manifest in mitochondrial fragmentation [2]. We also identified a second function of NME4, which consists in intermembrane cardiolipin (CL) transfer triggered by pro-mitophagic or -apoptotic stimuli, leading to externalization of CL from the mitochondrial inner membrane to the mitochondrial surface [3,4]. There, CL acts a « eat me signal » for mitophagy or as a platform to assemble pro-apoptotic proteins. Our most recent data on HeLa cells reveal that ablating either of the two NME4 functions, phosphotransfer or CL transfer, triggers a morphogenic switch that leads to a metastasis-like cellular phenotype.


Bioblast editor: Plangger M, Kandolf G O2k-Network Lab: FR Grenoble Schlattner U


Labels:


Organism: Human  Tissue;cell: HeLa 





Affiliations

Schlattner U(1), Tokarska-Schlattner M(1), Lacombe ML(2), Boissan M(2)

  1. Univ Grenoble Alpes, Inserm U1055, Grenoble
  2. Univ Pierre et Marie, Curie and Saint-Antoine Research Center, INSERM UMR-S 938, Paris; France. - uwe.schlattner@ujf-grenoble.fr


References

  1. Tokarska-Schlattner M, Boissan M, Munier A, Borot C, Mailleau C, Speer O, Schlattner U, Lacombe ML (2008) The nucleoside diphosphate kinase D (NM23-H4) binds the mitochondrial inner membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration. J Biol Chem 283:26198-207.
  2. Boissan M, Montagnac G, Shen Q, Griparic L, Guitton J, Romao M, Sauvonnet N, Lagache T, Lascu I, Raposo G, Desbourdes C, Schlattner U, Lacombe ML, Polo S, van der Bliek AM, Roux A, Chavrier P (2014) Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science 344:1510-5.
  3. Schlattner U, Tokarska-Schlattner M, Ramirez Rios S, Seffouh A, Tyuina YY, Amoscato AA, Huang Z, Jiang J, Boissan M, Epand RF, Mohammadsanyi D, Klein-Seetharaman J, Epand RM, Lacombe ML, Kagan VE (2013) Dual function of mitochondrial Nm23-H4 protein in phosphotransfer and intermembrane lipid transfer: a cardiolpin switch. J Biol Chem 288:111-21.
  4. Kagan E, 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 ML, Epand RM, Chu CT, Mallampalli R, Bayir H, Schlattner U (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Diff 23:1140-51.