Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

• Published in: Scientific reports Vol. 10; no. 1; p. 1021
• Main Authors: Salehi, Reza, Mazier, Hannah L., Nivet, Anne-Laure, Reunov, Arkadiy A., Lima, Patricia, Wang, Qi, Fiocco, Arianna, Isidoro, Ciro, Tsang, Benjamin K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2020; Nature Publishing Group
• Subjects: 13/2; 13/51; 14/28; 14/63; 631/443/494/2732/2730; 631/80/39/2346; 692/163/2743/2730; 692/699/2732/1577; 692/699/2732/2730; 82/80; 96/106; Androgens - pharmacology; Animals; Apoptosis; Apoptosis - physiology; Autophagy; Autophagy - physiology; Cell fate; Dihydrotestosterone; Dihydrotestosterone - pharmacology; Disease Models, Animal; Dynamin; Dynamins - metabolism; Female; Follicles; Gonadotropins; Gonadotropins - pharmacology; Granulosa cells; Granulosa Cells - metabolism; Humanities and Social Sciences; Lysosomes; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Mitochondrial Dynamics - physiology; multidisciplinary; Phagocytosis; Pituitary (anterior); Polycystic ovary syndrome; Polycystic Ovary Syndrome - pathology; Rats; Rats, Sprague-Dawley; Rodents; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-57672-w

In this study, we investigated in an androgenized rat model the involvement of autophagy and mitochondrial dynamics in granulosa cells in the pathogenesis of polycystic ovarian syndrome (PCOS) and its modulation by exogenous gonadotropin (eCG). We found 5α-dihydrotestosterone (DHT) treatment reduces ovarian length and weight with predominantly late antral and/or preovulatory stage follicles and no corpora lutea. DHT increased the population of large lysosomes (>50 micron) and macroautophagy, an event associated with granulosa cell apoptosis. Increased granulosa cell Dynamin Related Protein 1 (Drp1) content in the DHT group was accompanied by increased circular and constricted, but reduced rod-shaped, mitochondria. eCG eliminated all atypical follicles and increased the number of late antral and preovulatory follicles with less granulosa cell apoptosis. eCG-treated rats had a higher proportion of connected mitochondria, and in combination with DHT had a lower proportion of circular and constricted mitochondria than rats treated with DHT alone, suggesting that eCG induces mitochondrial fusion and attenuates fission in granulosa cells. In summary, we observed that DHT-induced up-regulation of Drp1 is associated with excessive mitochondrial fission, macroautophagy and apoptosis in granulosa cells at the antral stage of development in an androgenized rat model for PCOS, a response partially attenuated by exogenous gonadotropin.