Palmitic acid-induced insulin resistance triggers granulosa cell senescence by disruption of the UPRmt/mitophagy/lysosome axis

Abstract

Insulin resistance (IR) is the main pathological feature of polycystic ovary syndrome (PCOS), but the adverse impacts of IR on ovary and granulosa cells (GCs) are unknown. Therefore, the role of palmitic acid (PA) induced IR in GCs, and a mitochondrial proteostasis and mitochondrial homeostasis control system, the mitochondrial unfolded protein response (UPR^mt)/mitophagy/lysosome axis were investigated to uncover the side effect and the mechanism of IR on GCs. Our results revealed that IR in GC was successfully constructed by 100 μM PA treatment accompanied with cell senescence. In addition, mitochondrial function was impaired by IR-induced GC senescence accompanied by significantly increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential, and mitochondrial proteostasis was impaired by a dysfunctional UPR^mt and increased protein aggregation, leading to more unfolded and misfolded proteins accumulating in mitochondria. Mitochondrial homeostasis was maintained by the mitophagy/lysosome degradation system, although mitophagy was significantly increased, lysosomes were damaged; hence, malfunctional mitochondria were not cleared by the mitophagy/lysosome degradation system, more ROS were produced by malfunctional mitochondria. Therefore, accelerated GC senescence was triggered by excessive ROS, and reversed by the mitophagy inhibitor cyclosporin A (CsA) accompanied with reduced IR. Additionally, the mice were administered with PA, and results revealed that the accelerated ovarian aging was caused by PA, which might be attributed to GC senescence. In conclusion, GC senescence was triggered in PA-induced IR by disruption of the UPR^mt/mitophagy/lysosome axis, and IR induced GC senescence was reversed by the CsA.