title: Effects of oxidative alcohol metabolism on the mitochondrial permeability transition pore and necrosis in a mouse model of alcoholic pancreatitis.
abstract: OBJECTIVE
  Opening of the mitochondrial permeability transition pore (MPTP) causes loss of the mitochondrial membrane potential (ΔΨm) and, ultimately, adenosine triphosphate depletion and necrosis. Cells deficient in cyclophilin D (CypD), a component of the MPTP, are resistant to MPTP opening, loss of ΔΨm, and necrosis. Alcohol abuse is a major risk factor for pancreatitis and is believed to sensitize the pancreas to stressors, by poorly understood mechanisms. We investigated the effects of ethanol on the pancreatic MPTP, the mechanisms of these effects, and their role in pancreatitis.
  
  
  METHODS
  We measured ΔΨm in mouse pancreatic acinar cells incubated with ethanol alone and in combination with physiologic and pathologic concentrations of cholecystokinin-8 (CCK). To examine the role of MPTP, we used ex vivo and in vivo models of pancreatitis, induced in wild-type and CypD(-/-) mice by a combination of ethanol and CCK.
  
  
  RESULTS
  Ethanol reduced basal ΔΨm and converted a transient depolarization, induced by physiologic concentrations of CCK, into a sustained decrease in ΔΨm, resulting in reduced cellular adenosine triphosphate and increased necrosis. The effects of ethanol and CCK were mediated by MPTP because they were not observed in CypD(-/-) acinar cells. Ethanol and CCK activated MPTP through different mechanisms-ethanol by reducing the ratio of oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, as a result of oxidative metabolism, and CCK by increasing cytosolic Ca(2+). CypD(-/-) mice developed a less-severe form of pancreatitis after administration of ethanol and CCK.
  
  
  CONCLUSIONS
  Oxidative metabolism of ethanol sensitizes pancreatic mitochondria to activate MPTP, leading to mitochondrial failure; this makes the pancreas susceptible to necrotizing pancreatitis.
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California; Institute of General and Experimental Biology, Russian Academy of Sciences, Siberian Branch, Ulan-Ude, Russian Federation.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shalbueva
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Mareninova
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gerloff
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California.
authors.forename: Jingzhen
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Waldron
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California. Electronic address: agukovsk@ucla.edu.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000493:pharmacokinetics* / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019512:Pancreatitis, Alcoholic / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000431:Ethanol