Metabolism and homeostasis of energy in trophoblast cells of the placenta: from development to disease

The placenta is a highly metabolic organ essential for fetal growth by mediating nutrient transport, hormone production, and immunological regulation. These functions depend on continuous and efficient adenosine triphosphate (ATP) supply, primarily generated through glycolysis and oxidative phosphorylation. However, due to high turnover of ATP and multi-step de novo synthesis, these pathways may not always meet the rapid and localized energy demands of trophoblast cells. The phosphagen system, comprising creatine kinase (CK), creatine (Cr), and phosphocreatine (PCr), provides a rapid ATP-buffering mechanism, yet its role in placental biology remains poorly understood. This review synthesizes current knowledge on ATP production and buffering across trophoblast subtypes drawing from in vitro, ex vivo, and transcriptomic studies. We highlight emerging data on the contribution of the Cr-CK-PCr system to ATP homeostasis in trophoblasts and its dynamic regulation across gestation. Dysregulation of this system, including altered creatine metabolism and CK expression, is observed in pregnancy disorders such as preeclampsia, fetal growth restriction, and gestational diabetes. We also examine evidence from animal models supporting maternal creatine supplementation as a potential strategy to enhance placental efficiency and fetal outcomes. Finally, we propose that new models, including trophoblast stem cells and organoids, could be leveraged in the future to further elucidate creatine's role in early placental development and disease. A deeper understanding of placental energy metabolism and buffering may reveal new therapeutic avenues to improve maternal-fetal health.