Mitochondrial protein TMEM70: key role in the biogenesis of ATP synthase verified in a mouse knockout model

Abstract

TMEM70 is a transmembrane protein localized in the inner mitochondrial membrane and involved in the biogenesis of the eukaryotic ATP synthase, but its molecular role in this process is still unknown. TMEM70 mutations cause isolated deficiency of ATP synthase often resulting in a fatal neonatal mitochondrial encephalocardiomyopathy in patients. Generation of Tmem70 knockout mice resulted in embryonically lethal Tmem70-/- embryos [1]. To obtain adult Tmem70-/- mice we generated the tamoxifen inducible knockout. The weight of mice dramatically decreased and they died by week 8 past Cre-mediated excision. Despite of the similar efficiency of Tmem70 deletion in liver and heart, blue native electrophoresis demonstrated more pronounced decrease of fully assembled F1Fo ATP synthase and accumulation of F1 subcomplex in liver than in heart. SDS electrophoresis showed more decreased level of F1-α subunit in liver, which has also impaired ATPase hydrolytic activity. Moreover the oxygen consumption induced by addition of cytochrome c indicated damaged liver mitochondria in the treated mice in comparison to controls. Most likely, this can be explained by slower turnover of ATP synthase in heart than in liver. In conclusion, induction of Tmem70 knockout in adult mice impairs primarily liver, contrasting with predominantly cardiologic presentation in human patients.