Because NDUFC2 underwent positive selection, we assessed the effect of directed mutagenesis of a positively selected amino acid within NDUFC2 on the interaction with its mtDNA-encoded partner ND4. Finally, we assessed the association of T2DM with mitonuclear genotype combinations, including NDUFC2 and mtDNA genetic backgrounds in Ashkenazi Jews. This evidence concerns the gene MT-ND4 and type 2 diabetes mellitus.