Xu Jiao, Wang Xiaoyin, Qin Ziyi, Liu Jing, Chen Jin, Li Qianrong, Wang Xuemei, Zhuang Lin
Department of Obstetrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Biochem Biophys Res Commun. 2025 Jul 17;778:152379. doi: 10.1016/j.bbrc.2025.152379.
Preeclampsia is characterized by placental hypoxia and metabolic reprogramming toward glycolysis, leading to increased lactate production and protein lactylation. This study investigated the role of heat shock protein 60 (Hsp60) lactylation in preeclampsia pathophysiology. Using placental tissue microarrays and HTR-8/SVneo trophoblast cells, we found that Hsp60 undergoes aberrant lactylation in preeclamptic placentas, particularly under hypoxic conditions. Through in silico prediction and site-directed mutagenesis, we identified K469 and K473 as the primary lactylation sites on Hsp60. Functional studies revealed that Hsp60 lactylation promotes mitochondrial fission by modulating Drp1 phosphorylation, increases mitochondrial ROS production, and sensitizes trophoblasts to apoptosis. Expression of the delactylation-mimetic K469R/K473R mutant significantly attenuated hypoxia-induced mitochondrial fragmentation, preserved mitochondrial membrane potential, reduced cytochrome c release and caspase-3 activation, and maintained trophoblast invasive capacity. Furthermore, we demonstrated that Hsp60 lactylation is regulated by histone deacetylases and p300 acetyltransferase. These findings identify Hsp60 lactylation as a novel mechanism linking metabolic adaptation to mitochondrial dysfunction in preeclampsia. Targeting Hsp60 lactylation or its regulatory enzymes may represent a potential therapeutic strategy for preventing trophoblast dysfunction and improving outcomes in preeclampsia.
子痫前期的特征是胎盘缺氧以及代谢重编程转向糖酵解，导致乳酸生成增加和蛋白质乳酰化。本研究调查了热休克蛋白60（Hsp60）乳酰化在子痫前期病理生理学中的作用。使用胎盘组织芯片和HTR-8/SVneo滋养层细胞，我们发现Hsp60在子痫前期胎盘中发生异常乳酰化，尤其是在缺氧条件下。通过计算机预测和定点诱变，我们确定K469和K473是Hsp60上的主要乳酰化位点。功能研究表明，Hsp60乳酰化通过调节Drp1磷酸化促进线粒体分裂，增加线粒体活性氧生成，并使滋养层细胞对凋亡敏感。去乳酰化模拟物K469R/K473R突变体的表达显著减弱了缺氧诱导的线粒体碎片化，维持了线粒体膜电位，减少了细胞色素c释放和caspase-3激活，并保持了滋养层细胞的侵袭能力。此外，我们证明Hsp60乳酰化受组蛋白脱乙酰酶和p300乙酰转移酶调节。这些发现确定Hsp60乳酰化是子痫前期中连接代谢适应与线粒体功能障碍的一种新机制。靶向Hsp60乳酰化或其调节酶可能代表一种预防滋养层细胞功能障碍和改善子痫前期结局的潜在治疗策略。
