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The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor. 2021
Marie-Lise Lacombe, and
Frederic Lamarche, and
Olivier De Wever, and
Teresita Padilla-Benavides, and
Alyssa Carlson, and
Imran Khan, and
Anda Huna, and
Sophie Vacher, and
Claire Calmel, and
Céline Desbourdes, and
Cécile Cottet-Rousselle, and
Isabelle Hininger-Favier, and
Stéphane Attia, and
Béatrice Nawrocki-Raby, and
Joël Raingeaud, and
Christelle Machon, and
Jérôme Guitton, and
Morgane Le Gall, and
Guilhem Clary, and
Cedric Broussard, and
Philippe Chafey, and
Patrice Thérond, and
David Bernard, and
Eric Fontaine, and
Malgorzata Tokarska-Schlattner, and
Patricia Steeg, and
Ivan Bièche, and
Uwe Schlattner, and
Mathieu Boissan
Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. 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. 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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