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

• DOI: 10.1186/s12915-021-01155-5
• Publication Date: 2021-10-21T11:03:03Z
• Authors: Marie-Lise Lacombe; Frederic Lamarche; Olivier De Wever; Teresita Padilla-...; Alyssa Carlson; Imran Khan; Anda Huna; Sophie Vacher; Claire Calmel; Céline Desbourdes; Cécile Cottet-Rou...; Isabelle Hininger...; Stéphane Attia; Béatrice Nawrocki...; Joël Raingeaud; Christelle Machon; Jérôme Guitton; Morgane Le Gall; Guilhem Clary; Cedric Broussard; Philippe Chafey; Patrice Thérond; David Bernard; Eric Fontaine; Malgorzata Tokars...; Patricia Steeg; Ivan Bièche; Uwe Schlattner; Mathieu Boissan
• Keywords: Nucleoside-diphosphate kinase; Wild type

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