Mono-2-ethylhexyl phthalate drives progression of PINK1-parkin-mediated mitophagy via increasing mitochondrial ROS to exacerbate cytotoxicity
Jian Xu,
Liming Wang,
Lihuan Zhang,
Fang Zheng,
Fang Wang,
Jianhang Leng,
Keyi Wang,
Paul Héroux,
Han-Ming Shen,
Yihua Wu,
Dajing Xia
Affiliations
Jian Xu
Department of Toxicology of School of Public Health, And Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, PR China
Liming Wang
Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China
Lihuan Zhang
Department of Toxicology of School of Public Health, And Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
Fang Zheng
Department of Toxicology of School of Public Health, And Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
Fang Wang
Department of Toxicology of School of Public Health, And Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
Jianhang Leng
Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, PR China
Keyi Wang
Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, PR China
Paul Héroux
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Canada
Han-Ming Shen
Faculty of Health Sciences, University of Macau, Macau SAR, China
Yihua Wu
Department of Toxicology of School of Public Health, And Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Corresponding author.
Dajing Xia
Department of Toxicology of School of Public Health, And Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Corresponding author.
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.
