Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex i integrity and impacts human health

The mutation rate of the mitochondrial DNA (mtDNA), which is higher by an order of magnitude as compared with the nuclear genome, enforces tightmitonuclear coevolution tomaintainmitochondrial activities. Interruption of such coevolution plays a role in interpopulation hybrid breakdown, speciation events, and disease susceptibility. Previously, we found an elevated amino acid replacement rate andpositive selection in the nuclearDNA-encodedoxidative phosphorylation (OXPHOS)complex I subunitNDUFC2, a phenomenon important for the direct interaction of NDUFC2 with the mtDNA-encoded complex I subunit ND4. This finding underlines the importance of mitonuclear coevolution to physical interactions between mtDNA and nuclear DNA-encoded factors. Nevertheless, it remains unclear whether this interaction is important for the stability and activity of complex I. Here, we show that siRNA silencing of NDUFC2 reduced growth of human D-407 retinal pigment epithelial cells, significantly diminishedmitochondrialmembrane potential, and interfered with complex I integrity.Moreover, site-directedmutagenesis of a positively selected amino acid inNDUFC2significantly interfered with the interaction ofNDUFC2 with its mtDNA-encoded partnerND4. Finally,we showthat a genotype combination involving this amino acid (NDUFC2 residue 46) and themtDNA haplogroup HV likely altered susceptibility to type 2 diabetes mellitus in Ashkenazi Jews. Therefore, mitonuclear coevolution is important for maintaining mitonuclear factor interactions, OXPHOS, and for human health.