BMC Biology (Oct 2021)

The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor

  • Marie-Lise Lacombe,
  • Frederic Lamarche,
  • Olivier De Wever,
  • Teresita Padilla-Benavides,
  • Alyssa Carlson,
  • Imran Khan,
  • Anda Huna,
  • Sophie Vacher,
  • Claire Calmel,
  • Céline Desbourdes,
  • Cécile Cottet-Rousselle,
  • Isabelle Hininger-Favier,
  • Stéphane Attia,
  • Béatrice Nawrocki-Raby,
  • Joël Raingeaud,
  • Christelle Machon,
  • Jérôme Guitton,
  • Morgane Le Gall,
  • Guilhem Clary,
  • Cedric Broussard,
  • Philippe Chafey,
  • Patrice Thérond,
  • David Bernard,
  • Eric Fontaine,
  • Malgorzata Tokarska-Schlattner,
  • Patricia Steeg,
  • Ivan Bièche,
  • Uwe Schlattner,
  • Mathieu Boissan

DOI
https://doi.org/10.1186/s12915-021-01155-5
Journal volume & issue
Vol. 19, no. 1
pp. 1 – 29

Abstract

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Abstract Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

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