Mitoguardin-2 promotes cell proliferation by activating AKT and regulating Hippo/YAP1 signaling pathway in ovarian granulosa cells

Abstract Mitochondria have been identified to be involved in oxidative phosphorylation, lipid metabolism, cell death, and cell proliferation. Previous studies have demonstrated that Mitoguardin (Miga), a mitochondrial protein that governs mitochondrial fusion, mitochondria-ER contacts, lipid formation and autophagy, is crucial for ovarian endocrine and follicular development. Nevertheless, it remains uncertain whether Miga is implicated in the regulation of ovarian granulosa cell proliferation, which cellular signals are involved, and how they are regulated. This study revealed that mammalian MIGA1,-2 promotes cell proliferation and regulates the phosphorylation and localization of YAP1 in ovarian granulosa cells. The upregulation of MIGA2 resulted in a reduction of YAP1 activity, while the removal of MIGA2 led to an increase in YAP1 activity. Further analyses have indicated that MIGA1,-2 regulated YAP1 via the Hippo signaling pathway and regulate AKT activity in collaboration with YAP1. In addition, LPA was able to regulate MIGA2 expression and AKT activity by activating YAP1. In brief, our findings demonstrate that the mitochondrial protein MIGA2 regulates the Hippo/YAP1 signaling pathway and promotes AKT activity and cellular proliferation in ovarian granulosa cells, which may contribute to the molecular pathogenesis of reproductive endocrine disease such as polycystic ovary syndrome.