Autophagy regulates sex steroid synthesis in human ovary

Autophagy is an evolutionarily conserved process that aims to maintain the energy homeostasis of the cell by recycling long-lived proteins and organelles. Emerging data indicates that autophagy also regulates lipid metabolism in a process called lipophagy. Here we describe a novel role of autophagy in steroid biosynthesis in human ovary. Pharmacological inhibition or genetic interruption of autophagic process through silencing of autophagy genes (Beclin1 and ATG5) via siRNA technology significantly compromised steroidogenesis and resulted in a dose-dependent and progressive decline in basal and gonadotropin-stimulated progesterone (P4) production of the explant cultures of corpus luteum and the primary human granulosa cells. Blockage of autophagy was also associated with a marked cytoplasmic accumulation of the lipid droplets (LDs), which strongly co-localized with autophagy substrates (LC3 and SQSTM1/p62) and lysosome. Furthermore, we found that the expression of the autophagy genes, the co-localization of the LDs with autophagosome and lysosome are defective and, autophagy-mediated steroidogenesis are compromised in the corpora luteae of the patients who had clinically documented luteal phase defect due to their inability to produce P4 in sustainable levels to maintain pregnancy and prevent miscarriage. More interestingly, pharmacological induction of autophagy with rapamycin together with luteotropic hCG administration had a synergistic effect on steroidogenesis and autophagy and drastically corrected defective P4 production in the luteal GCs of these patients in vitro. Taken collectively these findings suggest that autophagy plays a pivotal role in basal and gonadotropin-stimulated steroidogenesis by promoting the association of the LDs with lysosome to deliver the lipid cargo within the LDs to lysosomes for degradation in order to release free cholesterol required for steroid synthesis in human ovary. Given that P4 hormone is essential for preparation of endometrium for implantation and maintenance of pregnancy, our findings may have significant clinical implications and open a new avenue in the treatment of infertility, pregnancy-related complications, and miscarriages in human.