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Free Radic Biol Med. 2017 Jan;102:100-110. doi: 10.1016/j.freeradbiomed.2016.11.020. Epub 2016 Nov 17.

Mitochondrial remodeling in the liver following chronic alcohol feeding to rats.

Author information

1
Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA. Electronic address: dhan@kgi.edu.
2
University of Southern California Research Center for Liver Diseases and Southern California Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA.
3
W.M. Keck Science Department, Scripps College, Claremont, CA 91711, USA.
4
Department of Biology, Occidental College, Los Angeles, CA 90041, USA.
5
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
6
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0303, USA.
7
Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA.

Abstract

The feeding of alcohol orally (Lieber-DeCarli diet) to rats has been shown to cause declines in mitochondrial respiration (state III), decreased expression of respiratory complexes, and decreased respiratory control ratios (RCR) in liver mitochondria. These declines and other mitochondrial alterations have led to the hypothesis that alcohol feeding causes "mitochondrial dysfunction" in the liver. If oral alcohol feeding leads to mitochondrial dysfunction, one would predict that increasing alcohol delivery by intragastric (IG) alcohol feeding to rats would cause greater declines in mitochondrial bioenergetics in the liver. In this study, we examined the mitochondrial alterations that occur in rats fed alcohol both orally and intragastrically. Oral alcohol feeding decreased glutamate/malate-, acetaldehyde- and succinate-driven state III respiration, RCR, and expression of respiratory complexes (I, III, IV, V) in liver mitochondria, in agreement with previous results. IG alcohol feeding, on the other hand, caused a slight increase in glutamate/malate-driven respiration, and significantly increased acetaldehyde-driven respiration in liver mitochondria. IG feeding also caused liver mitochondria to experience a decline in succinate-driven respiration, but these decreases were smaller than those observed with oral alcohol feeding. Surprisingly, oral and IG alcohol feeding to rats increased mitochondrial respiration using other substrates, including glycerol-3-phosphate (which delivers electrons from cytoplasmic NADH to mitochondria) and octanoate (a substrate for beta-oxidation). The enhancement of glycerol-3-phosphate- and octanoate-driven respiration suggests that liver mitochondria remodeled in response to alcohol feeding. In support of this notion, we observed that IG alcohol feeding also increased expression of mitochondrial glycerol phosphate dehydrogenase-2 (GPD2), transcription factor A (TFAM), and increased mitochondrial NAD+-NADH and NADP+-NADPH levels in the liver. Our findings suggest that mitochondrial dysfunction represents an incomplete picture of mitochondrial dynamics that occur in the liver following alcohol feeding. While alcohol feeding causes some mitochondrial dysfunction (i.e. succinate-driven respiration), our work suggests that the major consequence of alcohol feeding is mitochondrial remodeling in the liver as an adaptation. This mitochondrial remodeling may play an important role in the enhanced alcohol metabolism and other adaptations in the liver that develop with alcohol intake.

KEYWORDS:

Alcohol; Liver; Mitochondria; Remodeling; Respiration

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