Reza Salehi 1 , Hannah L Mazier 1 2 , Anne-Laure Nivet 1 2 , Arkadiy A Reunov 3 , Patricia Lima 1 , Qi Wang 1 , Arianna Fiocco 2 4 , Ciro Isidoro 5 , Benjamin K Tsang 6 7
Affiliations
1 Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada.
2 Department of Cellular & Molecular Medicine and Obstetrics & Gynecology, University of Ottawa, Ottawa, Canada.
3 Electron Microscopy Laboratory, University of Ottawa Heart Institute, Ottawa, Canada.
4 Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via P. Solaroli 17, 28100, Novara, Italy.
5 Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via P. Solaroli 17, 28100, Novara, Italy. ciro.isidoro@med.uniupo.it.
6 Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada. btsang@ohri.ca.
7 Department of Cellular & Molecular Medicine and Obstetrics & Gynecology, University of Ottawa, Ottawa, Canada. btsang@ohri.ca.
PMID: 31974436
PMCID: PMC6978404
DOI: 10.1038/s41598-020-57672-w
Sci Rep. 2020 Jan 23;10(1):1021. doi: 10.1038/s41598-020-57672-w.
Abstract
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.
