title: Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Seoul, South Korea; Hanyang Biomedical Research Institute, Seoul, South Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Hanyang Biomedical Research Institute, Seoul, South Korea.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Ko
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. Electronic address: jwhwang@hanyang.ac.kr.
authors.forename: Jungwook
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Seoul, South Korea; Hanyang Biomedical Research Institute, Seoul, South Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. Electronic address: hckoh@hanyang.ac.kr.
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Koh
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004390:Chlorpyrifos / Q000633:toxicity*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D004390:Chlorpyrifos
keywords: Chlorpyrifos; Dynamin-related protein 1; Mitochondrial-division inhibitor-1; Mitogen-activated protein kinase; Reactive oxidative species; p53