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Lacombe, Marie-Lise; Lamarche, Frederic; De Wever, Olivier; Padilla-Benavides, Teresita; Carlson, Alyssa; Khan, Imran; Huna, Anda; Vacher, Sophie; Calmel, Claire; Desbourdes, Céline; Cottet-Rousselle, Cécile; Hininger-Favier, Isabelle; Attia, Stéphane; Nawrocki-Raby, Béatrice; Raingeaud, Joël; Machon, Christelle; Guitton, Jérôme; Le Gall, Morgane; Clary, Guilhem; Broussard, Cedric; Chafey, Philippe; Thérond, Patrice; Bernard, David; Fontaine, Eric; [...]

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

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  • Media type: E-Article
  • Title: The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor
  • Contributor: Lacombe, Marie-Lise; Lamarche, Frederic; De Wever, Olivier; Padilla-Benavides, Teresita; Carlson, Alyssa; Khan, Imran; Huna, Anda; Vacher, Sophie; Calmel, Claire; Desbourdes, Céline; Cottet-Rousselle, Cécile; Hininger-Favier, Isabelle; Attia, Stéphane; Nawrocki-Raby, Béatrice; Raingeaud, Joël; Machon, Christelle; Guitton, Jérôme; Le Gall, Morgane; Clary, Guilhem; Broussard, Cedric; Chafey, Philippe; Thérond, Patrice; Bernard, David; Fontaine, Eric; [...]
  • imprint: Springer Science and Business Media LLC, 2021
  • Published in: BMC Biology
  • Language: English
  • DOI: 10.1186/s12915-021-01155-5
  • ISSN: 1741-7007
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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, <jats:italic>NME4</jats:italic> expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These data demonstrate <jats:italic>NME4</jats:italic> as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.</jats:p> </jats:sec>
  • Access State: Open Access