Observation of Parthanatos Involvement in Diminished Ovarian Reserve Patients and Melatonin's Protective Function Through Inhibiting ADP-Ribose (PAR) Expression and Preventing AIF Translocation into the Nucleus.

Abstract

Diminished ovarian reserve (DOR) is characterized by the depletion of the ovarian pool, which leads to reductions in oocyte quality and quantity. Studies have suggested that ovarian reserve or ovarian aging is tightly related to apoptosis. However, the cell death mechanism is not comprehensively understood. Parthanatos, a type of poly [ADP-ribose] polymerase 1(PARP1)-dependent and apoptosis-inducing factor (AIF)-mediated cell death, plays a crucial role in various disorders. In the present study, we aimed to investigate whether parthanatos is involved in the pathogenesis of DOR. We recruited 40 patients (20 DOR patients and 20 normal ovarian reserve (NOR) patients) and examined PAR expression and AIF translocation in their isolated cumulus GCs (granulosa cells) by fluorescence microscopy. Our results demonstrated that PAR expression and AIF nuclear translocation were significantly higher in cumulus GCs of DOR patients, suggesting that PARP1-dependent cell death may be associated with DOR pathophysiology. Moreover, we tested the protective function of melatonin on hydrogen peroxide (H2O2)-induced parthanatos in human ovarian cancer (IGROV1) cells. Our results demonstrated that H2O2 treatment of IGROV1 cells led to excessive protein PARylation and AIF translocation into the nuclei. Melatonin effectively inhibits PARylation, blocks translocation of AIF into the nucleus, and consequently decreases the risk of parthanatos in cumulus GCs.