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.

中文翻译：

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PDK4的下调对于人类胎盘滋养细胞合体化过程中碳水化合物代谢的转换至关重要。

丙酮酸脱氢酶激酶（PDK）被称为守门员，通过抑制丙酮酸脱氢酶复合物引导碳通量进入糖酵解。在胎盘滋养细胞合胞体化过程中，ATP的产生和耗氧量都增加了，以满足合成滋养细胞对能量的需求增加。我们假设PDK表达的下调可能在合胞期间从糖酵解到氧化磷酸化（OXPHOS）的转变中起着核心作用。通过使用原代人类滋养细胞，我们证明了PDK4是人类滋养细胞中主要的PDK亚型，并且在合胞体化后其丰度大大降低，同时伴随着乳酸产量的减少和ATP产量的增加。降低PDK4表达可降低乳酸生成并增加ATP生成，而过表达PDK4可提高乳酸生成并降低ATP生成，这表明PDK4的下调是合胞期间从糖酵解转变为OXPHOS的关键。此外，人类绒毛膜促性腺激素（hCG）/ cAMP / PKA通路被证明与合胞化过程中PDK4表达的下调有关。综上所述，我们的发现表明，PDK4的下调对于合胞体化过程中从糖酵解到OXPHOS的代谢转变至关重要，这可能是正确实施合体滋养层细胞功能的先决条件。这表明PDK4的下调是在合胞体化过程中从糖酵解转变为OXPHOS的关键。此外，人类绒毛膜促性腺激素（hCG）/ cAMP / PKA通路被证明与合胞化过程中PDK4表达的下调有关。综上所述，我们的发现表明，PDK4的下调对于合胞体化过程中从糖酵解到OXPHOS的代谢转变至关重要，这可能是正确实施合体滋养层细胞功能的先决条件。这表明PDK4的下调是在合胞体化过程中从糖酵解转变为OXPHOS的关键。此外，人类绒毛膜促性腺激素（hCG）/ cAMP / PKA通路被证明与合胞化过程中PDK4表达的下调有关。综上所述，我们的发现揭示，PDK4的下调对于合胞体化过程中从糖酵解到OXPHOS的代谢转变至关重要，这可能是正确实施合体滋养层细胞功能的先决条件。