Tags

Type your tag names separated by a space and hit enter

Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells.
Neurotoxicology. 2015 Dec; 51:145-57.N

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+Show Affiliations

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.Hanyang Biomedical Research Institute, Seoul, South Korea.Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. Electronic address: jwhwang@hanyang.ac.kr.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26598294

Citation

Park, Jae Hyeon, et al. "Dynamin-related Protein 1 Mediates Mitochondria-dependent Apoptosis in Chlorpyrifos-treated SH-SY5Y Cells." Neurotoxicology, vol. 51, 2015, pp. 145-57.
Park JH, Ko J, Hwang J, et al. Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells. Neurotoxicology. 2015;51:145-57.
Park, J. H., Ko, J., Hwang, J., & Koh, H. C. (2015). Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells. Neurotoxicology, 51, 145-57. https://doi.org/10.1016/j.neuro.2015.10.008
Park JH, et al. Dynamin-related Protein 1 Mediates Mitochondria-dependent Apoptosis in Chlorpyrifos-treated SH-SY5Y Cells. Neurotoxicology. 2015;51:145-57. PubMed PMID: 26598294.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells. AU - Park,Jae Hyeon, AU - Ko,Juyeon, AU - Hwang,Jungwook, AU - Koh,Hyun Chul, Y1 - 2015/10/24/ PY - 2015/07/02/received PY - 2015/10/21/revised PY - 2015/10/21/accepted PY - 2015/11/25/entrez PY - 2015/11/26/pubmed PY - 2016/10/13/medline KW - Chlorpyrifos KW - Dynamin-related protein 1 KW - Mitochondrial-division inhibitor-1 KW - Mitogen-activated protein kinase KW - Reactive oxidative species KW - p53 SP - 145 EP - 57 JF - Neurotoxicology JO - Neurotoxicology VL - 51 N2 - 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. SN - 1872-9711 UR - https://www.unboundmedicine.com/medline/citation/26598294/Dynamin_related_protein_1_mediates_mitochondria_dependent_apoptosis_in_chlorpyrifos_treated_SH_SY5Y_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-813X(15)30008-5 DB - PRIME DP - Unbound Medicine ER -