Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts
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...
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doaj-20adde03dac6496d951312af854126992020-12-08T01:49:00ZengNature Publishing GroupScientific Reports2045-23222017-08-017111010.1038/s41598-017-09163-8Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental TrophoblastsXiaohui Liu0Rujuan Zuo1Yirong Bao2Xiaoxian Qu3Kang Sun4Hao Ying5Shanghai First Maternity and Infant Hospital, Tongji University School of MedicineCenter for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai First Maternity and Infant Hospital, Tongji University School of MedicineShanghai First Maternity and Infant Hospital, Tongji University School of MedicineCenter for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai First Maternity and Infant Hospital, Tongji University School of MedicineAbstract 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.https://doi.org/10.1038/s41598-017-09163-8 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaohui Liu Rujuan Zuo Yirong Bao Xiaoxian Qu Kang Sun Hao Ying |
spellingShingle |
Xiaohui Liu Rujuan Zuo Yirong Bao Xiaoxian Qu Kang Sun Hao Ying Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts Scientific Reports |
author_facet |
Xiaohui Liu Rujuan Zuo Yirong Bao Xiaoxian Qu Kang Sun Hao Ying |
author_sort |
Xiaohui Liu |
title |
Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts |
title_short |
Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts |
title_full |
Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts |
title_fullStr |
Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts |
title_full_unstemmed |
Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts |
title_sort |
down-regulation of pdk4 is critical for the switch of carbohydrate catabolism during syncytialization of human placental trophoblasts |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-08-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-017-09163-8 |
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