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

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

doi:10.1186/s12915-021-01155-5

Abstract

BackgroundMitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane.ResultsWe 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.ConclusionsThese data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

Highlights

Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane
They present as a single strong band at the size of mature enzyme indicating a correct maturation of the NDPK-D variants (Additional file 1: Fig. S1A)
Collectively, our data reveal a prominent role of altered NDPK-D in crucial features of cancer metastasis such as loss of intercellular adhesion, migration, invasion, and epithelialmesenchymal transition (EMT)

Summary

Introduction

Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Metastasis, the final step in malignancy, is the cause of death for more than 90% of cancer patients. The first step in the metastatic cascade, i.e., the breakdown of epithelial intercellular adhesion and the acquisition of an invasive program allows epithelial cancer cells to breach the basement membrane and to invade stromal type I fibrillar collagen. These events are referred as epithelialmesenchymal transition (EMT) and are considered crucial events in malignancy yet they are poorly understood [2]. During EMT, epithelial cells loose some of their epithelial characteristics, including cell adhesion and cell polarity; cytoskeletal rearrangement occurs that leads to an increased motility and an invasive phenotype

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