Journal
REDOX BIOLOGY
Volume 38, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2020.101776
Keywords
MEHP; Mitochondrial ROS; PINK1-Parkin-mediated mitophagy; Cytotoxicity; Cell death
Categories
Funding
- National Natural Science Foundation of China [81773016, 21976155, 31471297]
- Zhejiang Provincial Natural Science Foundation of China [LY18C060001, LY18H160062]
- Medical Health Science and Technology Project of Hangzhou Municipal Health Commission [A20200097]
- Zhejiang University Cancer Center
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MEHP exacerbates cytotoxicity by amplifying the PINK1-Parkin-mediated mitophagy pathway, leading to increased mitochondrial damage and robust mitophagy. Co-treatment with N-acetyl cysteine (NAC) counteracted the effects of MEHP-CCCP, suggesting that mitochondrial ROS played a vital role in this process. The findings provide insights into the potential roles of endocrine disrupting chemicals (EDCs) in human diseases such as Parkinson's disease.
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, coexposure 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.
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