Abstract
Pyruvate dehydrogenase kinase (PDK) is known as a gatekeeper directing the carbon flux into glycolysis via inhibition of the pyruvate dehydrogenase complex. During syncytialization of placental trophoblasts, both ATP production and oxygen consumption are increased to meet enhanced energetic demands by syntiotrophoblasts. We hypothesized that down-regulation of PDK expression may play a central role in the switch from glycolysis to oxidative phosphorylation (OXPHOS) during syncytialization. By using primary human trophoblasts, we demonstrated that PDK4 was the dominating PDK isoform in human cytotrophoblasts, and its abundance was substantially decreased upon syncytialization, which was accompanied by decreases in lactate production and increases in ATP production. Knock-down of PDK4 expression reduced lactate production and increased ATP production, while over-expression of PDK4 increased lactate production and decreased ATP production, indicating that down-regulation of PDK4 is key to the shift from glycolysis to OXPHOS during syncytialization. Moreover, human chorionic gonadotropin (hCG)/cAMP/PKA pathway was demonstrated to be involved in the down-regulation of PDK4 expression upon syncytialization. Taken together, our findings disclosed that down-regulation of PDK4 is critical for the metabolic shift from glycolysis to OXPHOS during syncytialization, which may be a prerequisite for the proper implementation of syncytiotrophoblast functions.
Highlights
Carbohydrate metabolism is well-known as the most fundamental resource for biomass and bioenergy
Given that oxidative phosphorylation (OXPHOS) consumes abundant oxygen and produces more ATP molecules, we hypothesized that the carbohydrate catabolism might shift from glycolysis to OXPHOS during syncytialization to meet the enhanced energetic demands to accomplish the sophisticated functions of the syncytiotrophoblasts, and this transition might be a consequence of down-regulation of pyruvate dehydrogenase kinase (PDK) expression upon syncytialization
We have demonstrated that PDK4 is the dominant PDK isoform in human placental trophoblasts and its abundance is substantially decreased along with a reduction in PDHE1α phosphorylation during syncytialization
Summary
Carbohydrate metabolism is well-known as the most fundamental resource for biomass and bioenergy. Given that OXPHOS consumes abundant oxygen and produces more ATP molecules, we hypothesized that the carbohydrate catabolism might shift from glycolysis to OXPHOS during syncytialization to meet the enhanced energetic demands to accomplish the sophisticated functions of the syncytiotrophoblasts, and this transition might be a consequence of down-regulation of PDK expression upon syncytialization. We examined this hypothesis in an in vitro model of syncytialization of primary human placental trophoblasts[10, 11]
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