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.
Highlights
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
The etiology of PCOS remains elusive due to its complex and heterogeneous nature, granulosa cell apoptosis has been suggested to play an important role in follicular growth arrest associated with the pathogenesis of PCOS20,25,26
For the first time, the dysregulation of mitochondrial fission and fusion dynamics, and autophagy in a DHT-induced rat model that recapitulates many phenotypes of human PCOS
Summary
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 observed that DHT-induced up-regulation of Drp[1] 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. Our recent studies have shown that 5α-dihydrotestosterone (DHT)-implanted rat PCOS model mimics many of the phenotypes of the human PCOS, including increased body weight gain and disrupted estrus cyclicity, allowing us to examine the molecular and cellular basis of PCOS20–22 We employed this chronically androgenized rat model to determine if PCOS is associated with dysregulation in mitochondrial fission/fusion and autophagy, and to determine whether exogenous gonadotropin can modulate this dysregulation in vivo. Here we show that up-regulation in Drp[1] is associated with excessive mitochondrial fission and apoptosis in granulosa cells at the antral stage of follicular development and that these events were partially attenuated by exogenous gonadotropin
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