Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells
- Authors
- Park, Jae Hyeon; Ko, Juyeon; Hwang, Jungwook; Koh, Hyun Chul
- Issue Date
- Dec-2015
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Chlorpyrifos; Dynamin-related protein 1; p53; Mitochondrial-division inhibitor-1; Reactive oxidative species; Mitogen-activated protein kinase
- Citation
- NEUROTOXICOLOGY, v.51, pp.145 - 157
- Indexed
- SCIE
SCOPUS
- Journal Title
- NEUROTOXICOLOGY
- Volume
- 51
- Start Page
- 145
- End Page
- 157
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/155725
- DOI
- 10.1016/j.neuro.2015.10.008
- ISSN
- 0161-813X
- Abstract
- Recent studies have demonstrated that dynamin-related protein 1 (Drp1), a mitochondrial fission protein, mediates mitochondria-dependent apoptosis through mitochondrial division. However, little is known about the mechanism by which Drp1 modulates apoptosis in response to chlorpyrifos (CPF)-induced toxicity. In this study, we determined that CPF-induced mitochondrial apoptosis is mediated by Drp1 translocation in SH-SY5Y human neuroblastoma cells. Our results showed that CPF treatment induced intrinsic apoptosis by activating caspase-9, caspase-3, and cytochrome c release in SH-SY5Y cells. Cytosolic Drp1 translocated to the mitochondria in CPF-treated cells and was phosphorylated at Ser616. Treating cells with CPF induced the generation of reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs). Inhibiting this ROS generation and MAPK activation abolished CPF-induced expression of phospho-Drp1. Furthermore, Drp1 was required for p53 to translocate to the mitochondria under CPF-induced oxidative stress. Treating cells with mitochondrial-division inhibitor-1 (mdivi-1), which blocks Drp1 translocation, increased the viability of CPF-treated cells by abrogating Drp1 translocation and caspase-3 activation. Specifically, pretreating cells with mdivi-1 inhibited Bax translocation to the mitochondria by blocking p53 signaling. Taken together, these data reveal a novel mechanism by which Drp1 activates mitochondrial-dependent apoptosis and indicate that inhibiting Dpr1 function can protect against CPF-induced cytotoxicity. We propose that inhibiting Drp1 is a possible therapeutic approach for pesticide-induced toxicity when hyperactivated Drp1 contributes to pathology.
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