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.
Highlights
Mitochondrial respiration plays an important role in alcohol metabolism by regenerating NADϩ needed for alcohol/acetaldehyde metabolism
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 (ϳ2-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-1␣
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
Summary
Mitochondrial respiration plays an important role in alcohol metabolism by regenerating NADϩ needed for alcohol/acetaldehyde metabolism. Results: Chronic alcohol feeding caused many mitochondrial alterations, such as increased mitochondrial respiration, that enhanced acetaldehyde metabolism. One study showed some enhancement of mitochondrial respiration in the liver of mice fed alcohol orally [20], whereas another study found that alcohol feeding to mice increases complex I levels in liver mitochondria [21] These studies suggest that chronic alcohol feeding to mice may trigger mitochondrial alterations as an adaptive response, which needs to be further explored. The decline in mitochondrial respiration is accompanied by a decline in respiratory complex proteins in the liver of rats fed alcohol orally [25, 26] This suggests that alcohol feeding to mice and rats may induce different types of mitochondrial alterations in the liver. The hypothesis that liver mitochondria respond to the increased demands of alcohol metabolism by undergoing adaptive plastic changes was examined in this work
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