title: Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice.
abstract: Chronic ethanol consumption increases sensitivity of the mitochondrial permeability transition (MPT) pore induction in liver. Ca(2+) promotes MPT pore opening, and genetic ablation of cyclophilin D (CypD) increases the Ca(2+) threshold for the MPT. We used wild-type (WT) and CypD-null (CypD(-/-)) mice fed a control or an ethanol-containing diet to investigate the role of the MPT in ethanol-mediated liver injury. Ca(2+)-mediated induction of the MPT and mitochondrial respiration were measured in isolated liver mitochondria. Steatosis was present in WT and CypD(-/-) mice fed ethanol and accompanied by increased terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive nuclei. Autophagy was increased in ethanol-fed WT mice compared with ethanol-fed CypD(-/-) mice, as reflected by an increase in the ratio of microtubule protein 1 light chain 3B II to microtubule protein 1 light chain 3B I. Higher levels of p62 were measured in CypD(-/-) than WT mice. Ethanol decreased mitochondrial respiratory control ratios and select complex activities in WT and CypD(-/-) mice. Ethanol also increased CypD protein in liver of WT mice. Mitochondria from control- and ethanol-fed WT mice were more sensitive to Ca(2+)-mediated MPT pore induction than mitochondria from their CypD(-/-) counterparts. Mitochondria from ethanol-fed CypD(-/-) mice were also more sensitive to Ca(2+)-induced swelling than mitochondria from control-fed CypD(-/-) mice but were less sensitive than mitochondria from ethanol-fed WT mice. In summary, CypD deficiency was associated with impaired autophagy and did not prevent ethanol-mediated steatosis. Furthermore, increased MPT sensitivity was observed in mitochondria from ethanol-fed WT and CypD(-/-) mice. We conclude that chronic ethanol consumption likely lowers the threshold for CypD-regulated and -independent characteristics of the ethanol-mediated MPT pore in liver mitochondria.
authors.affiliation: Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: King
authors.forename: Telisha M
authors.initials: TM
authors.lastname: Swain
authors.forename: Zhengkuan
authors.initials: Z
authors.lastname: Mao
authors.forename: Uduak S
authors.initials: US
authors.lastname: Udoh
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Oliva
authors.forename: Angela M
authors.initials: AM
authors.lastname: Betancourt
authors.forename: Corrine E
authors.initials: CE
authors.lastname: Griguer
authors.forename: David R
authors.initials: DR
authors.lastname: Crowe
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lesort
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Bailey
mesh_terms: D000818:Animals; D001343:Autophagy; D020013:Calcium Signaling; D019069:Cell Respiration; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D000431:Ethanol; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism; D005838:Genotype; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling; D010641:Phenotype; D013997:Time Factors
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D000431:Ethanol; D021983:Cyclophilins
keywords: alcohol; cyclophilin D; liver; mitochondria; permeability transition pore