SIRT2 通过促进线粒体的生物生成和功能减轻先兆子痫的症状

SIRT2 alleviates pre-eclampsia via prompting mitochondrial biogenesis and function

SIRT2 通过促进线粒体的生物生成和功能减轻先兆子痫的症状

Authors: Ruirui Hou, Xiaoyan Yang, Qi Xu, Can Shen, Longbiao Zhang, Binbin Huang, Yuanyuan Yang, Zhen Yu, Zongzhi Yin, Yunxia Cao, Xiaoqing Peng

Source: Life Sciences

DOI: 10.1016/j.lfs.2025.123566

Abstract

Aims: Pre-eclampsia (PE) globally impacts 2-8 % of pregnancies and is a leading cause of neonatal and maternal morbidity and mortality. Recent studies found the association between mitochondrial dysfunction and deficient motility of trophoblast cells in PE. Lower expressions of mitochondrial biogenesis related proteins (i.e. PGC1α, NRF1 and TFAM) and SIRT2 have recently been found. However, the regulative role of SIRT2 on the protein expression and acetylation of PGC1α and its influence on trophoblast migration and invasion in PE have never been investigated.

Materials and methods: The alterations in protein expressions of SIRT2 and PGC1α/NRF1/TFAM were examined in the placenta from pregnant women with and without PE. The role of SIRT2 on mitochondrial biogenesis and mitochondrial morphology/function was explored in trophoblast cell, and the findings were confirmed in the LPS-induced PE mice with adeno-associated virus transfection system.

Key findings: We demonstrated the lower protein expressions of SIRT2 and PGC1α/NRF1/TFAM and mitochondrial dysfunction in PE patients and mice compared with counterparts. Moreover, overexpression of SIRT2 enhanced the protein expressions of PGC1α and deacetylated PGC1α, and further facilitating mitochondrial function and motility of trophoblast cells. In vivo, overexpression of SIRT2 attenuated the PE-like symptoms and adverse pregnancy outcomes in LPS-induced PE mice via promoting mitochondrial biogenesis.

Significance: Above findings suggest that SIRT2 might be a potential interventive target against PE via improving deacetylation of PGC1α and mitochondrial biogenesis and function.

Keywords: Mitochondria/pathology; Mitochondrial dynamics; Pre-eclampsia; Sirtuin 2.

摘要

目的：子痫前期（PE）影响全球 2-8% 的妊娠，是新生儿和孕产妇发病和死亡的主要原因。最近的研究发现，子痫前期妊娠线粒体功能障碍与滋养层细胞运动能力不足有关。最近发现线粒体生物生成相关蛋白（即 PGC1α、NRF1 和 TFAM）和 SIRT2 的表达较低。然而，SIRT2 对 PE 中 PGC1α 蛋白表达和乙酰化的调节作用及其对滋养层细胞迁移和侵袭的影响尚未得到研究。

材料和方法：研究了患有和未患有 PE 的孕妇胎盘中 SIRT2 和 PGC1α/NRF1/TFAM 蛋白表达的变化。在滋养层细胞中探讨了 SIRT2 对线粒体生物生成和线粒体形态/功能的作用，并在腺相关病毒转染系统 LPS 诱导的 PE 小鼠中证实了这些发现。

主要发现：我们发现 PE 患者和小鼠的 SIRT2 和 PGC1α/NRF1/TFAM 蛋白表达量较低，线粒体功能也较弱。此外，过表达 SIRT2 可提高 PGC1α 和去乙酰化 PGC1α 的蛋白表达量，进一步促进线粒体功能和滋养层细胞的运动。在体内，SIRT2的过表达通过促进线粒体的生物生成，减轻了LPS诱导的PE小鼠的PE样症状和不良妊娠结局。

意义：上述研究结果表明，SIRT2可通过改善PGC1α的去乙酰化及线粒体的生物生成和功能，成为抗PE的潜在干预靶点。

关键词：线粒体/病理学；线粒体动力学；子痫前期；Sirtuin 2