title: Melatonin prevents the dynamin-related protein 1-dependent mitochondrial fission and oxidative insult in the cortical neurons after 1-methyl-4-phenylpyridinium treatment.
abstract: Mitochondrial dysfunction and oxidative stress are involved in the pathogenesis of Parkinson's disease (PD). Mitochondrial morphology is dynamic and precisely regulated by the mitochondrial fission and fusion machinery. Aberrant mitochondrial fragmentation controlled by the mitochondrial fission protein, dynamin-related protein 1 (Drp1), may result in cell death. Our previous results showed that melatonin protected neurons by inhibiting oxidative stress in a 1-methyl-4-phenylpyridinium (MPP(+) )-induced PD model. However, the effect of melatonin on mitochondrial dynamics remains uncharacterized. Herein, we investigated the effect of melatonin and the role of Drp1 on MPP(+) -induced mitochondrial fission in rat primary cortical neurons. We found that MPP(+) induced a rapid increase in the ratio of GSSG:total glutathione (a marker of oxidative stress) and mitochondrial fragmentation, Drp1 upregulation within 4 hours, and finally resulted in neuron loss 48 hours after the treatment. Neurons overexpressing wild-type Drp1 promoted mitochondrial and nuclear fragmentation; however, neurons overexpressing dominant-negative Drp1(K38A) or cotreated with melatonin exhibited significantly reduced MPP(+) -induced mitochondrial fragmentation and neuron death. Moreover, melatonin cotreatment prevented an MPP(+) -induced high ratio of GSSG and mitochondrial Drp1 upregulation. The prevention of mitochondrial fission by melatonin was not found in neurons transfected with wild-type Drp1. These results provide a new insight that the neuroprotective effect of melatonin against MPP(+) toxicity is mediated by inhibiting the oxidative stress and Drp1-mediated mitochondrial fragmentation.
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jih-Ing
authors.initials: JI
authors.lastname: Chuang
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: I-Ling
authors.initials: IL
authors.lastname: Pan
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chiu-Ying
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Department of Parasitology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jyh Wei
authors.initials: JW
authors.lastname: Shin
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008550:Melatonin / Q000494:pharmacology*; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C519851:Dnm1l protein, rat; D034281:Dynamins; D008550:Melatonin; D015655:1-Methyl-4-phenylpyridinium
keywords: Parkinson's diseases; dynamin-related protein 1; melatonin; mitochondrial fission; oxidative stress