Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice
BIOGENESIS, REMODELING, AND FUNCTIONAL ALTERATIONS*
- Derick Han‡,1,
- Maria D. Ybanez‡,
- Heather S. Johnson‡,
- Jeniece N. McDonald‡,
- Lusine Mesropyan‡,
- Harsh Sancheti§,
- Gary Martin¶,
- Alanna Martin¶,
- Atalie M Lim‡,
- Lily Dara‡,
- Enrique Cadenas§,
- Hidekazu Tsukamoto‖ and
- Neil Kaplowitz‡
- From the ‡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,
- the §Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089,
- the ¶Department of Biology, Occidental College, Los Angeles, California 90041, and
- the ‖Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, University of Southern California Keck School of Medicine and Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90089-9121
- ↵1 To whom correspondence should be addressed: Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 101, Los Angeles, CA 90089-9121. Tel.: 323-442-3239; Fax: 323-442-5425; E-mail: derickh{at}usc.edu.
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.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health Grant AA016911 (to D. H.), AA14428 (to N. K.), and P50AA11999 (to H. T.).
- Received April 30, 2012.
- Revision received October 18, 2012.
- © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
