Nucleoside diphosphate kinase D (NME4) is the first mitochondrial metastasis suppressor - Archive ouverte HAL
Article Dans Une Revue Biochimica biophysica acta (BBA) - Bioenergetics Année : 2022

Nucleoside diphosphate kinase D (NME4) is the first mitochondrial metastasis suppressor

Morgane Le Gall
  • Fonction : Auteur

Résumé

NDP-kinase D (NME4) is a mitochondrial protein with multiple functions in bioenergetics and signaling. NME4 mainly localizes to the mitochondrial intermembrane space, interacting with cardiolipin and the pro-fusion GTPase OPA1 at the inner membrane. Here, NME4 forms a metabolite channeling complex, generating GTP for maximal OPA1 efficiency and ADP to stimulate respiration. NME4 simultaneously interacts with outer membrane to favor intermembrane transfer of cardiolipin to the mitochondrial surface as a signal for mitophagy or apoptosis. Here, we deleted either its NDP kinase activity (H151N) or cardiolipin interaction (R90D) and expressed these mutants or wtNME4 in HeLa cells almost devoid of NME4 [1]. Both loss-of-function mutants independently led to similar, dominant-negative effects on mitochondrial structure and function: a metabolic shift with reduced complex-I-linked respiration and Krebs cycle activity together with increased aerobic glycolysis, downregulation of some mitochondrial proteins, altered sensitivity of mitochondrial permeability transition, increased oxidative stress, and mild energy stress (upregulated mitochondrial creatine and adenylate kinases and AMPK-signaling). Consistent with disturbed GTP-fueling of OPA1, mitochondrial network and mass were reduced. Importantly, mitochondrial alterations triggered a pro-invasive reprogramming that favors metastasis: overexpression of metastasis-related proteins, loss of cell-cell contacts, promoted epithelial-mesenchymal transition, and increased migratory/invasive potential. More metastases developed in immune-compromised mice when injected with mutant cells. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition or tumor aggressiveness, and represents a good prognosis factor for beneficial clinical outcome. Our study emphasizes a new role of mitochondria and mitochondria-nuclear retrograde signaling in metastasis. [1] M.L. Lacombe et al., The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor, BMC Biology, 19 (2022) 228-257.

Dates et versions

hal-04598513 , version 1 (03-06-2024)

Identifiants

Citer

Uwe Schlattner, Marie-Lise Lacombe, Frederic Lamarche, Olivier de Wever, Teresita Padilla-Benavides, et al.. Nucleoside diphosphate kinase D (NME4) is the first mitochondrial metastasis suppressor. Biochimica biophysica acta (BBA) - Bioenergetics, 2022, 1863, pp.148796. ⟨10.1016/j.bbabio.2022.148796⟩. ⟨hal-04598513⟩
30 Consultations
0 Téléchargements

Altmetric

Partager

More