Low level of lactate and trophoblast dysfunction mediated by SNAI1/PDK1 contributes to miscarriage

Abstract

Introduction

Although the significance of metabolic remodelling in maintaining homeostasis at the maternal–foetal interface has been established, research on its implications in miscarriage remains limited.

Methods

Immunofluorescence, qRT-PCR, and western blotting were used to detect the expression of SNAI1 in miscarriage and normal villi. The function of the zinc-finger transcription factor SNAI1 was evaluated in three-dimensional (3D) trophoblast spheroids. Lactate production assays and western blotting were performed to investigate the effect of SNAI1 on lactate production and pyruvate dehydrogenase kinase 1 (PDK1) expression. Immunofluorescence and western blotting were used to detect the effect of lactate on SNAI1 expression. Furthermore, the role of PDK1 in miscarriage was confirmed in clinical samples.

Results

The expression of SNAI1 is significantly downregulated in the villi of patients with miscarriages. SNAI1 promotes proliferation, invasion, and inhibits apoptosis of HTR8/SVneo 3D spheroids. The glycolytic enzyme PDK1 has been identified as a downstream target of SNAI1 and plays a crucial role in regulating lactate production in trophoblasts. Lactate upregulates SNAI1 expression and promotes its nuclear localisation. Furthermore, the expression of PDK1 was downregulated in the villi of patients with miscarriage.

Discussion

Trophoblast spheroids may serve as reliable models to investigate the placenta. The regulatory mechanisms mediated by SNAI1/PDK1 in miscarriage have been elucidated. We provide new clues regarding the mechanism of miscarriage from a metabolic perspective and present evidence supporting lactate as a potential diagnostic marker.