Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions.

Mitochondrial genome (mtDNA) mutation causes highly variable clinical features, and its pathogenesis is not fully understood. In this study, we analyzed the heteroplasmic mtDNA mutation C4936T (p.T156I) in ND2 of complex I and the homoplasmic mtDNA mutation A9181G (p.S219G) in ATPase 6 of complex V. Using cybrid technology, we found that in a high-glucose medium in which cultured cells mainly depend on anaerobic glycolysis for energy, the C4936T mutation inhibited cell growth by 50%. Oxygen consumption and reactive oxygen species production were also reduced by 60 and 75%, respectively. Because the subject also had conjunctiva carcinoma, we further tested whether the C4936T mutation was associated with tumor formation. In an anchorage-dependant growth test, we found that only cells with a high level of C4936T mutation formed colonies. In contrast, when the cells grew in a galactose medium in which cells were forced to generate ATP through oxidative phosphorylation, the C4936T mutation protected cells from apoptosis probably caused by the A9181G mutation. Our results suggest that the phenotype caused by mtDNA mutations may depend on the availability of the nutrients. This gene-environment interaction may contribute to the complexity of pathogenesis and clinical phenotypes caused by mtDNA mutation.