title: The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease.
abstract: Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver.
  
  
  
  For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined.
  
  
  
  Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration.
  
  
  
  Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the attenuation of hypoxic stress.
authors: Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: aking125@kennesaw.edu.
authors: Adrienne L
authors: AL
authors: King
authors: Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: sushdheer@yahoo.com.
authors: Sudheer K
authors: SK
authors: Mantena
authors: Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: kellyandringa@uabmc.edu.
authors: Kelly K
authors: KK
authors: Andringa
authors: Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: telishaswain@uabmc.edu.
authors: Telisha
authors: T
authors: Millender-Swain
authors: Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: Kimberly.dunhamsnary@queensu.ca.
authors: Kimberly J
authors: KJ
authors: Dunham-Snary
authors: Departments of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: coliva@uabmc.edu.
authors: Claudia R
authors: CR
authors: Oliva
authors: Departments of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: cegriguer@uabmc.edu.
authors: Corinne E
authors: CE
authors: Griguer
authors: Departments of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: shannonbailey@uabmc.edu.
authors: Shannon M
authors: SM
authors: Bailey
mesh_terms: D000818:Animals; D015415:Biomarkers; D019069:Cell Respiration; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009569:Nitric Oxide / Q000378:metabolism; D001678:Organelle Biogenesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000431:Ethanol; D012436:S-Adenosylmethionine; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I
keywords: Alcohol; Hypoxia; Liver; Mitochondria; Nitric oxide; S-Adenosylmethionine