title: PPAR-γ activation attenuates deltamethrin-induced apoptosis by regulating cytosolic PINK1 and inhibiting mitochondrial dysfunction.
abstract: Central events in the mitochondrial-dependent cell death pathway include the disruption of mitochondrial membrane potential, which causes the release of apoptogenic molecules leading to cell death. Based on the cytotoxic mechanism of deltamethrin (DLM), we examined the neuroprotective mechanisms of rosiglitazone (RGZ), which is against DLM-induced neuronal cell death. In this study, we found that DLM induces apoptosis in SH-SY5Y cells as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, neuronal cell death in response to DLM was due to mitochondrial dependent-apoptosis pathways since DLM increased cytochrome c release into the cytosol and activated caspase-9. DLM exposure reduced PINK1 expression, and pretreatment with RGZ significantly reduced cytochrome c release and caspase-9 activation. RGZ also attenuated the reduction of complex I activity, mitochondrial membrane potential, and ATP levels. Pretreatment with RGZ significantly enhanced PINK1 expression in DLM-exposed cells. In addition, RGZ increased cytosolic PINK1 by inhibiting mitochondrial translocation of PINK1. Interestingly, RGZ fails to rescue DLM-induced mitochondrial dysfunction both in PINK1 knockdown and PPAR-γ antagonist treated cells. Results from this study suggest that RGZ exerts anti-apoptotic effects against DLM-induced cytotoxicity by attenuation of mitochondrial dysfunction through cytosolic PINK1-dependent signaling pathways.
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Hanyang Biomedical Research Institute, Seoul, Republic of Korea.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Ko
authors.affiliation: Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Yun Sun
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea. Electronic address: hckoh@hanyang.ac.kr.
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Koh
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D053144:Cell Nucleus Shape / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007306:Insecticides / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000633:toxicity; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011722:Pyrethrins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000633:toxicity; D034622:RNA Interference; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D042967:Electron Transport Complex I; D007004:Hypoglycemic Agents; D007306:Insecticides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009570:Nitriles; D047495:PPAR gamma; D011494:Protein Kinases; D011722:Pyrethrins; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D000099202:PTEN-Induced Putative Kinase; C457499:2-chloro-5-nitrobenzanilide; C017180:decamethrin
keywords: Apoptosis; Deltamethrin; Mitochondrial dysfunction; PINK1; Rosiglitazone