内质网
神经毒性
MFN2型
线粒体
化学
细胞生物学
生物
生物化学
毒性
线粒体融合
线粒体DNA
有机化学
基因
作者
Yi Zhao,Yuan‐Hang Chang,Hao-Ran Ren,Ming Lou,Fuwei Jiang,Jia-Xin Wang,Ming‐Shan Chen,Shuo Liu,Yu-Sheng Shi,Hongmei Zhu,Jin‐Long Li
标识
DOI:10.1021/acs.jafc.3c07752
摘要
Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER–mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood–brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER–mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
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