Inhibition of mitochondrial complex I impedes zygotic genome activation via PDH-histone modification retrograde signaling

Rotenone (RTN), an Insecticide that functions through inhibiting mitochondrial electron transport chain complex I, has been demonstrated to impair reproductive health in mammals. Nevertheless, its impact on the process of preimplantation development remains to be elucidated. In this study, the toxic effects of RTN on mouse preimplantation embryo development were determined by exposure to different concentrations of RTN. RTN exposure resulted in developmental arrest of mouse preimplantation embryos in a dose-dependent manner. Mechanistically, RTN treatment induced mitochondrial dysfunction, elevated ROS levels, severe DNA damage and developmental arrest at the 2-cell stage. Furthermore, RTN treatment resulted in the failure of nuclear localization of the mitochondrial TCA cycle enzyme, pyruvate dehydrogenase (PDH), and abnormalities in histone modifications. This, in turn, led to impaired zygotic genome activation and development beyond the 2-cell stage. In addition, dichloroacetic acid enhanced the nuclear localization of PDH in 2-cell embryo, thereby augmenting TCA flux and promoting preimplantation development. In conclusion, RTN has the potential to exert cytotoxic effects on mammalian reproduction, and electron transport chain complex I inhibitors should be used with caution when applied to the treatment of reproductive diseases. Furthermore, this study enhances our comprehension of the interplay between Mitochondrial Metabolism and epigenetic regulation in early embryos.