Mono-2-ethylhexyl phthalate drives progression of PINK1-parkin-mediated mitophagy via increasing mitochondrial ROS to exacerbate cytotoxicity

• Published in: Redox biology Vol. 38; p. 101776
• Main Authors: Xu, Jian, Wang, Liming, Zhang, Lihuan, Zheng, Fang, Wang, Fang, Leng, Jianhang, Wang, Keyi, Héroux, Paul, Shen, Han-Ming, Wu, Yihua, Xia, Dajing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021; Elsevier
• Subjects: Cell death; Cytotoxicity; Diethylhexyl Phthalate - analogs & derivatives; Humans; MEHP; Mitochondria; Mitochondrial ROS; Mitophagy; Phthalic Acids; PINK1-Parkin-mediated mitophagy; Protein Kinases - genetics; Reactive Oxygen Species; Research Paper; Ubiquitin-Protein Ligases - genetics; Mitochondrial ROS; Cytotoxicity; MEHP; Cell death; PINK1-Parkin-mediated mitophagy
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2020.101776

Phthalate ester plasticizers are used to improve the plasticity and strength of plastics. One of the most widely used and studied, di-2-ethylhexyl phthalate (DEHP), has been labeled as an endocrine disruptor. The major and toxic metabolic derivative of DEHP, mono-2-ethylhexyl phthalate (MEHP), is capable of interfering with mitochondrial function, but its mechanism of action on mitophagy remains elusive. Here, we report that MEHP exacerbates cytotoxicity by amplifying the PINK1-Parkin-mediated mitophagy pathway. First, MEHP exacerbated mitochondrial damage induced by low-dose CCCP via increased reactive oxygen species (ROS) production, decreased mitochondrial membrane potential (MMP), and enhanced fragmentation in mitochondria. Second, co-exposure to MEHP and CCCP (“MEHP-CCCP”) induced robust mitophagy. Mechanistically, MEHP-CCCP stabilized PINK1, increased the level of phosphorylated ubiquitin (pSer 65-Ub), and led to Parkin mitochondrial translocation and activation. Third, MEHP-CCCP synergistically caused more cell death, while inhibition of mitophagy, either through chemical or gene silencing, reduced cell death. Finally and importantly, co-treatment with N-acetyl cysteine (NAC) completely counteracted the effects of MEHP-CCCP, suggesting that mitochondrial ROS played a vital role in this process. Our results link mitophagy and MEHP cytotoxicity, providing an insight into the potential roles of endocrine disrupting chemicals (EDCs) in human diseases such as Parkinson's disease. [Display omitted] •Mono-2-ethylhexyl phthalate (MEHP) exacerbates mitochondrial damage induced by low-dose CCCP.•Co-exposure to MEHP and CCCP (MEHP-CCCP) induces robust mitophagy in a PINK1-Parkin-dependent pathway.•Mitophagy promotes MEHP-CCCP-induced cell death.•ROS mediate MEHP-CCCP-induced mitophagy and cytotoxicity.