Decreased expression of IDH1 by chronic unpredictable stress suppresses proliferation and accelerates senescence of granulosa cells through ROS activated MAPK signaling pathways

Studies suggested that psychosocial stress was associated with female fertility decline, but the underlying mechanisms remained unclear. Granulosa cells (GCs) are important somatic cells to support follicular development and oocyte maturation. Herein, by using a mouse model of chronic unpredictable stress (CUS), we found that CUS induced oxidative stress damage in mouse ovaries, also inhibited GCs proliferation and accelerated GCs senescence. Isocitrate dehydrogenase-1 (IDH1), an antioxidant related gene by generating NADPH, was shown to be downregulated in GCs of CUS mice. Consistently, IDH1 knockdown inhibited cell proliferation and accelerated cellular senescence in KGN cells in vitro. In addition, IDH1 knockdown increased ROS content, induced autophagy activation and triggered cell cycle arrest in S and G2/M phases in KGN cells, which could be rescued by N-acetyl-l-cysteine (NAC), a ROS scavenger in these cells. Besides, IDH1 knockdown activated MAPK signaling pathways, including ERK, JNK and p38 signaling pathways in KGN cells, while NAC could suppress the activation. Through using inhibitors of MAPK signaling pathways, we showed that the activation of ERK pathway participated in autophagy related cell proliferation inhibition and cellular senescence, whereas JNK and p38 MAPK signaling pathways took part in regulation cell cycle arrest associated cell proliferation inhibitory and senescence in IDH1 knockdown KGN cells. Our findings suggested that downregulated expression of IDH1 induced by CUS has a physiological function in GCs proliferation and senescence through ROS activated MAPK signaling pathways, and improvement of IDH1 activity might be a beneficial therapeutic strategy for ovarian dysfunction.