title: Hypoxic preconditioning-induced mitochondrial protection is not disrupted in a cell model of mtDNA T8993G mutation-induced F1F0-ATP synthase defect: the role of mitochondrial permeability transition.
abstract: Transient opening of the mitochondrial permeability transition pore plays a crucial role in hypoxic preconditioning-induced protection. Recently, the cyclophilin-D component of the mitochondrial permeability transition pore has been shown to interact with and regulate the F1F0-ATP synthase. However, the precise role of the F1F0-ATP synthase and the interaction between cyclophilin-D and F1F0-ATP synthase in the mitochondrial permeability transition pore and hypoxic preconditioning remain uncertain. Here we found that a 1-h hypoxic preconditioning delayed apoptosis and improved cell survival after stimulation with various apoptotic inducers including H2O2, ionomycin, and arachidonic acid in mitochondrial DNA T8993G mutation (NARP) osteosarcoma 143B cybrids, an F1F0-ATP synthase defect cell model. This hypoxic preconditioning protected NARP cybrid cells against focal laser irradiation-induced oxidative stress by suppressing reactive oxygen species formation and preventing the depletion of cardiolipin. Furthermore, the protective functions of transient opening of the mitochondrial permeability transition pore in both NARP cybrids and wild-type 143B cells can be augmented by hypoxic preconditioning. Disruption of the interaction between cyclophilin-D and F1F0-ATP synthase by cyclosporin A attenuated the mitochondrial protection induced by hypoxic preconditioning in both NARP cybrids and wild-type 143B cells. Our results demonstrate that the interaction between cyclophilin-D and F1F0-ATP synthase is important in the hypoxic preconditioning-induced cell protection. This finding improves our understanding of the mechanism of mitochondrial permeability transition pore opening in cells in response to hypoxic preconditioning, and will be helpful in further developing new pharmacological agents targeting hypoxia-reoxygenation injury and mitochondria-mediated cell death.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pharmacology, and Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Mei-Jie
authors.initials: MJ
authors.lastname: Jou
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan. Electronic address: tipeng@cgmh.org.tw.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Peng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000494:pharmacology; D002308:Cardiolipins / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002678:Chimera; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D000081406:Peptidyl-Prolyl Isomerase F; D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D015759:Ionomycin; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; D021983:Cyclophilins
keywords: Cyclophilin-D; F1F0-ATP synthase; Free radicals; Hypoxic preconditioning; Mitochondria; NARP