engleski

NME6 negatively impacts mitochondrial respiration in tumor cell lines

The nucleoside diphosphate kinases (NDPK/NME/Nm23) family raised considerable interest after the discovery of metastasis suppressor role of NME1 in the early 2000. The enzymes catalyze the transfer of gamma phosphate from nucleoside triphosphates to nucleoside diphosphates (NDPK activity), thus maintaining locally the availability of nucleotides for cellular processes. Decades of investigation separated the family in two groups: Group I proteins (NME1-NME4) are highly similar and all display NDPK activity, while Group II proteins (NME5-NME9) are less homologous and are deficient of NDPK activity. Three members, NME3, NME4 and NME6 were shown to localize with mitochondria. The poorly studied NME6 was found to be overexpressed in colon and gastric carcinoma, as well as in colorectal cancer tissues. We recently published an extensive description of the human NME6 protein revealing, among other, that NME6 is enzymatically inactive but interacts with RCC1L in the mitochondrial matrix. RCC1L, a component of the mitochondrial-RNA maturation module (pseudouridylation module), is strongly associated with mitoribosome biogenesis and was found essential for oxidative phosphorylation, the final metabolic pathway of mitochondrial respiration. We showed that NME6 is ubiquitously expressed in a large panel of cancer cell lines with different tissues of origin, as well as in non-cancer cell lines using Western blot. We confirmed the mitochondrial localization of the protein by immunofluorescence and live cells imaging, and further refined it to the mitochondrial matrix localization using mitochondrial subfractionation. We described, using oxygraphy, its negative impact on mitochondrial respiration upon overexpression, directly linked with a decreased abundance of respiratory chain complexes at the protein level. Finally, we propose a joint role of NME6 and RCC1L within the mitochondrial matrix, affecting the abundance of respiratory chain complexes and eventually affecting the mitochondrial respiration.

Mitochondria ; NME6 ; Respiratory Chain

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