title: Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations.
abstract: Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD(+) and NADH levels (∼2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD(+), the rate-limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver.
authors.affiliation: University of Southern California Research Center for Liver Diseases and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9121, USA. derickh@usc.edu
authors.forename: Derick
authors.initials: D
authors.lastname: Han
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ybanez
authors.forename: Heather S
authors.initials: HS
authors.lastname: Johnson
authors.forename: Jeniece N
authors.initials: JN
authors.lastname: McDonald
authors.forename: Lusine
authors.initials: L
authors.lastname: Mesropyan
authors.forename: Harsh
authors.initials: H
authors.lastname: Sancheti
authors.forename: Gary
authors.initials: G
authors.lastname: Martin
authors.forename: Alanna
authors.initials: A
authors.lastname: Martin
authors.forename: Atalie M
authors.initials: AM
authors.lastname: Lim
authors.forename: Lily
authors.initials: L
authors.lastname: Dara
authors.forename: Enrique
authors.initials: E
authors.lastname: Cadenas
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000222:Adaptation, Physiological / Q000187:drug effects*; D000428:Alcohol Drinking / Q000009:adverse effects* / Q000378:metabolism / Q000473:pathology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000494:pharmacology; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013312:Stress, Physiological / Q000187:drug effects; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002492:Central Nervous System Depressants; D045222:Electron Transport Chain Complex Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009243:NAD; D000431:Ethanol; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde