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

Abstract : 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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Submitted on : Friday, November 5, 2021 - 1:56:11 PM
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Marie-Lise Lacombe, Frederic Lamarche, Olivier de Wever, Teresita Padilla-Benavides, Alyssa Carlson, et al.. The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor. BMC Biology, BioMed Central, 2021, 19 (1), ⟨10.1186/s12915-021-01155-5⟩. ⟨hal-03403979⟩



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