SIRT3 impairment and MnSOD hyperacetylation in trophoblast dysfunction and preeclampsia

Abstract

Preeclampsia (PE) is a prevalent obstetric disorder that affects 2–8 % of pregnancies worldwide. Trophoblasts, which are crucial functional cells in the placenta, play a significant role in the development of PE due to inadequate invasion. Sirtuin 3 (SIRT3) is an NAD⁺ − dependent mitochondrial deacetylase, that positively modulates energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. However, the role of SIRT3 in trophoblast dysfunction and the pathogenesis of PE remains unclear. In this study, we aim to investigate the functional role of SIRT3 in PE and explore the underlying mechanism. Our results demonstrated that human PE placentas exhibited reduced expression of SIRT3. In vitro experiments showed that hypoxia promoted SIRT3 expression, while oxidative stress inhibited SIRT3 expression in HTR-8/SVneo cells. The reduced SIRT3 expression inhibited the proliferation and migration of trophoblast cells while also increasing levels of reactive oxygen species and inflammatory factors. As a deacetylase, SIRT3 deficiency increased the acetylation level of manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme, subsequently reducing its activity. These effects associated with reduced SIRT3 expression could be reversed by treatment with MnSOD mimetics TEMPO and overexpression of MnSOD. All these results suggested that diminished SIRT3 expression leaded to MnSOD hyperacetylation and inactivation, contributing to trophoblast dysfunction and the pathogenesis of PE.