Abstract
Simple SummaryThe present study demonstrates that induction of autophagy-related proteins in corpus luteum is regulated by Akt/mTOR signaling and autophagy may exert influences on progesterone production by controlling the pool of lipid droplets in luteal cells during the luteal development of pregnant rats. Furthermore, mitophagy-related proteins were also induced during the initiation of luteal regression in pregnant rats, which may play an essential role in the maintenance of mitochondrial homeostasis. These findings will shed light on the role of autophagy during the luteal development of pregnant ovaries in vivo in mammals.The contribution of autophagy to catabolic balance has been well-established in various types of cells, whereas the involvement of autophagy in progesterone synthesis during rat pregnancy still remains unknown. Therefore, the present study was designed to evaluate the role of autophagy in progesterone production during the luteal development of pregnant rats. The results showed autophagy-related proteins was maintained at a low level on day 10 after pregnancy, significantly induced on day 16 and subsided to a relative low level on day 21, which was consistent with the changes of serum progesterone levels. The findings further indicated the contribution of autophagy to progesterone production was regulated by inactivation of Akt/mTOR signaling during the luteal development of pregnant rats in in vivo and in vitro experiments. Further investigations revealed autophagy may be involved in the surge of progesterone production in pregnant rats, as inhibition of autophagy by 3-MA compromised serum progesterone levels. Furthermore, 3-MA treatment also leveled down the number of lipid droplets in luteal cells, implying that autophagy may affect the production of progesterone by manipulating the formation of lipid droplets in luteal cells. In addition, the results suggested that mitophagy was mobilized during the primary stage of luteolysis and inhibition of autophagy promoted the increase of redundant mitochondrial and cytoplasmic cytochrome C in luteal cells of pregnant rats. Taken together, the present study indicated that autophagy-related proteins were induced by the inactivation of Akt/mTOR signaling and then contributed to the progesterone production possibly by affecting the formation of intracellular lipid droplets during the luteal development of pregnant rats. To our knowledge, this will provide a new insight into the important mechanism of autophagy regulating progesterone production in ovaries of pregnant mammals.
Highlights
Autophagy is an evolutionarily conserved cellular catabolic activity by degrading unessential or redundant parts of itself for recycling of building blocks, ensuring homeostasis of metabolism under stresses and contributing to survival of cells [1]
The results of LC-3 and LAMP-2 immunostaining demonstrated the obvious induction of autophagy and a significantly increased number of lysosomes in the corpus luteum (CL) on day 16 after pregnancy followed by a decrease on day 21 (Figure 1)
The expression levels of autophagic marker proteins including Beclin1, LC-3, and LAMP-2 were further detected by western blotting (Figure 2A–D), and it was found these proteins were significantly increased on day 16 and compromised on day 21 but still maintained at a high level compared with that on day 10 (Figure 2A–D), which corroborated the immunostaining findings of autophagy during the luteal development of pregnant rats (Figure 1)
Summary
Autophagy is an evolutionarily conserved cellular catabolic activity by degrading unessential or redundant parts of itself for recycling of building blocks, ensuring homeostasis of metabolism under stresses and contributing to survival of cells [1]. During this program, several essential proteins are involved in induction or degradation of autophagosomes, including Beclin1—a scaffold protein for autophagosome initiation, LC-3—a protein involved in autophagosome formation, and LAMP2—a protein involved in lysosome regulation. Studies have revealed that the level of autophagy in steroidogenic cells is higher than in other types of cells and aberrant regulation of autophagy is related to turbulent steroidogenesis [7]. Steroids exert influences on autophagy induction, suggesting sophisticated regulatory mechanisms between autophagy induction and steroid synthesis [4]
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