Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide

Abstract

Chronic alcohol consumption is a well-known risk factor for hepatic injury, and mitochondrial damage plays a significant role in this process. Nitric oxide (NO) is an important modulator of mitochondrial function and is known to inhibit mitochondrial respiration. However, the impact of chronic alcohol consumption on NO-dependent control of liver mitochondrial function is unknown. This study examines the effect of alcohol exposure on liver mitochondria in a rat model and explores the interaction of NO and mitochondrial respiration in this context. Mitochondria were isolated from the liver of both control and ethanol-fed rats after 5 to 6 weeks of alcohol consumption. Mitochondria isolated from ethanol-treated rats showed a significant decrease in state 3 respiration and respiratory control ratio that was accompanied by an increased sensitivity to NO-dependent inhibition of respiration. In conclusion, we show that chronic alcohol consumption leads to increased sensitivity to the inhibition of respiration by NO. We propose that this results in a greater vulnerability to hypoxia and the development of alcohol-induced hepatotoxicity.

Mitochondrial alterations in livers of Sod1−/− mice fed alcohol

“…We did not detect any significant decreases in the rate of respiration in mitochondria of wild type and knockout mice by ethanol as found with rat liver mitochondria. This possible species difference in sensitivity of mitochondrial respiration to ethanol has also been reported by others (30). However, ethanol enhanced the uncoupling of respiration and oxidative phosphorylation in mitochondria of Sod1 −/− mice (but not in wild type mice) as detected by increased rates of respiration in state 4 and lowering of the respiratory control and the ADP/O ratio with glutamate plus malate as substrate.…”

Caspase 1 Activation Is Protective against Hepatocyte Cell Death by Up-regulating Beclin 1 Protein and Mitochondrial Autophagy in the Setting of Redox Stress

“…The results are consistent with increased mitochondrial ROS in caspase 1 Ϫ/Ϫ hepatocytes and suggest increased mitochondria-triggered cell death because of caspase 1 deficiency. To assess mitochondrial content in vivo, we measured the activity of citrate synthase, a mitochondrial enzyme relatively resistant to oxidative modification that, therefore, can be used as an indicator of mitochondrial content (31). We found that the mitochondrial content was decreased significantly in Ϫ/Ϫ hepatocytes transfected with vector or mouse caspase 1 plasmid after normoxia or hypoxia for 2 and 6 h. E, beclin1 mRNA levels in hepatocytes after normoxia or 6 h of hypoxia.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Moreover, NO regulates mitochondrial respiration through reversible binding at the redoxactive heme site in cytochrome c oxidase [99][100][101] and affects mitochondrial biogenesis through interactions with soluble guanylate cyclase [102]. Studies have shown that mitochondria from chronic alcohol-fed animals are more sensitive to the inhibitory effect of NO on respiration [90,103]. While it is known that chronic alcohol consumption results in cytochrome c oxidase defects [82,90,104], it is likely that this alteration in NO responsiveness may be due to alcohol-dependent changes in interactions of NO with sites other than Complex IV.…”