Reproduction in all systems is heavily influenced by nutrition and the metabolic state of the organism. Furthermore, metabolic syndrome is thought to be a major factor in a number of reproductive disorders in humans. For example, PolyCystic Ovary Syndrome (PCOS), the most common cause of infertility in women, is strongly associated with type-2 diabetes and obesity. However, despite these intimate relationships, the precise metabolic mechanisms that support reproduction remain poorly defined. Interestingly, as Drosophila eggs develop, nutrients accumulate in the germline in a coordinated stepwise manner. This stepwise accumulation, in conjunction with the advanced genetics available in Drosophila, provides an excellent system to investigate the roles of energy homeostasis during oocyte development and reproduction.
Using a combination of metabolomics, proteomics, and molecular genetics we have found that developing Drosophila follicles undergo a major metabolic transition after stage 10 that leads to massive glycogen accumulation. This transition leads to shift in the balance of glycolysis and gluconeogenesis that results in the build up of several glycolytic/gluconeogenesis intermediates as well as a subset of TCA intermediates. Intriguingly, this shift in carbohydrate metabolism is the result of germline mitochondria entering into a state of respiratory quiescence in the late stages of oogenesis. Mitochondria enter respiratory quiescence as a result of a dramatic remodeling of the electron transport chain (ETC). ETC remodeling and mitochondrial quiescence are triggered by a reduction in insulin/akt signaling, and mediated by glycogen synthase kinase 3 (GSK3). Using proteomic analysis of isolated germline mitochondria we have found that GSK3 induces respiratory quiescence by promoting a global shift in mitochondrial protein content. Intriguingly, we observed a similar glycogen and ETC remodeling in Xenopus oocytes, suggesting that remodeling the ETC and inducing carbohydrate storage are important and conserved aspects of the terminal stages of egg production. Collectively, our data indicates that GSK3-mediated ETC remodeling is a novel, but highly conserved, mechanism of mitochondrial regulation. Furthermore, these data provide valuable insights into the mechanistic links between metabolic syndrome and many reproductive disorders.