title: The cyclophilin D/Drp1 axis regulates mitochondrial fission contributing to oxidative stress-induced mitochondrial dysfunctions in SH-SY5Y cells.
abstract: Oxidative stress plays a central role in the pathogenesis of various neurodegenerative diseases. Increasing evidences have demonstrated that structural abnormalities in mitochondria are involved in oxidative stress related nerve cell damage. And Drp1 plays a critical role in mitochondrial dynamic imbalance insulted by oxidative stress-derived mitochondria. However, the status of mitochondrial fusion and fission pathway and its relationship with mitochondrial properties such as mitochondrial membrane permeability transition pore (mPTP) have not been fully elucidated. Here, we demonstrated for the first time the role of Cyclophilin D (CypD), a crucial component for mPTP formation, in the regulation of mitochondrial dynamics in oxidative stress treated nerve cell. We observed that CypD-mediated phosphorylation of Drp1 and subsequently augmented Drp1 recruitment to mitochondria and shifts mitochondrial dynamics toward excessive fission, which contributes to the mitochondrial structural and functional dysfunctions in oxidative stress-treated nerve cells. CypD depletion or over expression accompanies mitochondrial dynamics/functions recovery or aggravation separately. We also demonstrated first time the link between the CypD to mitochondrial dynamics. Our data offer new insights into the mechanism of mitochondrial dynamics which contribute to the mitochondrial dysfunctions, specifically the role of CypD in Drp1-mediated mitochondrial fission. The protective effect of CsA, or other molecules affecting the function of CypD hold promise as a potential novel therapeutic strategy for governing oxidative stress pathology via mitochondrial pathways.
authors.affiliation: Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Anqi
authors.initials: A
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
authors.forename: Xueqi
authors.initials: X
authors.lastname: Gan
authors.affiliation: Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Ruiqi
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: shionaries@126.com.
authors.forename: Chao
authors.initials: C
authors.lastname: You
mesh_terms: D045744:Cell Line, Tumor; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D034281:Dynamins; D005452:Fluoresceins / Q000032:analysis; D005456:Fluorescent Dyes / Q000032:analysis; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053858:Metabolic Networks and Pathways; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D015854:Up-Regulation
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D016572:Cyclosporine; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D021983:Cyclophilins; C007740:fluorexon
keywords: Cyclophilin D; Drp1; Mitochondrial fission and fusion; Oxidative stress; SH-SY5Y cells