Hyperglycemia-induced α-Klotho downregulation impairs mitophagy and promotes placental dysfunction in T2DM pregnancies

Abstract

Introduction

Placental dysfunction in pregnancies complicated by type 2 diabetes mellitus (T2DM) is associated with adverse maternal and fetal outcomes. α-Klotho, a multifunctional anti-aging protein, plays a critical role in maintaining cellular homeostasis, but its role in T2DM-induced placental dysfunction remains poorly understood.

Methods

Placental tissues from T2DM pregnancies and normoglycemic controls were analyzed for α-Klotho expression using qRT-PCR, Western blot, and immunohistochemistry. BeWo trophoblast cells were cultured under normoglycemic and hyperglycemic conditions, with α-Klotho knockdown and overexpression to explore its regulatory effects. Transcriptomic analysis was conducted to identify affected pathways, and markers of mitophagy and reactive oxygen species (ROS) were analyzed.

Results

α-Klotho expression was significantly reduced in the placentas of T2DM pregnancies and in trophoblast cells under hyperglycemic conditions. Transcriptomic analysis identified pathways related to mitochondrial dysfunction and impaired mitophagy as key processes regulated by α-Klotho. Hyperglycemia and α-Klotho knockdown suppressed mitophagy, while ROS production was increased, further exacerbating oxidative stress. Overexpression of α-Klotho restored mitophagy and mitigated ROS activation.

Discussion

This study reveals that α-Klotho downregulation contributes to T2DM-induced placental dysfunction by impairing mitophagy and increasing oxidative stress. These findings provide new insights into the molecular mechanisms underlying placental abnormalities in diabetic pregnancies and highlight α-Klotho as a potential therapeutic target.