Increased Production of Reactive Oxygen Species by Rat Liver Mitochondria After Chronic Ethanol Treatment

Kukielka, E.; Dicker, Elisa; Cederbaum, Arthur I.

doi:10.1006/abbi.1994.1127

Cited by 147 publications

(77 citation statements)

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“…This could be a result of decreased complex I (NADH dehydrogenase) activity or decreased amounts of ubiquinone. Ubiquinone functions as an antioxidant, which may be important in ethanol toxicity [39]. It has been found to be decreased in the plasma of human alcoholic subjects [40] and that free radical damage can decrease the amount of ubiquinone in the mitochondrial membrane and thereby diminish substrate oxidations [41].…”

Section: Impaired B-oxidation As a Cause Of Alcoholic Steatosismentioning

confidence: 99%

Multiple biochemical effects in the pathogenesis of alcoholic fatty liver

Eaton

Record²,

Bartlett

1997

Eur J Clin Investigation

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Abstract. The pathogenesis of alcoholic fatty liver is unknown, but several causes have been proposed based on biochemical findings. These include the metabolism of alcohol leading to a shift in the cytosolic [NAD þ ]/ [NADH] ratio to reduction, which in turn causes a direct inhibition of b-oxidation and enhanced triacylglycerol formation via the [glycerol-3-phosphate]/[dihydroxyacetone phosphate] ratio. There are also chronic effects of ethanol on hepatic enzyme activities. Thus, increased activity of phosphatidate phosphohydrolase, an increased amount of fatty acid binding protein, decreased secretion of very low-density lipoprotein and impairment of the respiratory chain as a result of decreased protein synthesis or decreased amounts of ubiquinone could all lead to fat accumulation and steatosis. The interplay of each of these with nutritional and genetic factors would then lead to the heterogeneity of the severity and characteristics of the steatosis observed in human alcoholics.

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Section: Impaired B-oxidation As a Cause Of Alcoholic Steatosismentioning

confidence: 99%

Multiple biochemical effects in the pathogenesis of alcoholic fatty liver

Eaton

Record²,

Bartlett

1997

Eur J Clin Investigation

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“…Acute ethanol treatment of rat hepatocytes increased ROS production in mitochondria, produced depolarization of the mitochondrial membrane which resulted in a mitochondrial permeability transition (MPT) and caused Bax translocation from cytosol to mitochondria; these effects led to subsequent formation of Bax-VDAC complexes, release of cytochrome c, caspase 3 activation, and apoptosis (6)(7)(8). Chronic alcohol consumption induced inhibition of complexes I and III of the mitochondrial electron transport chain, impaired the rate of ATP synthesis, decreased levels of ATP and increased ROS production in rat liver (9,10). Mitochondria isolated from rats chronically fed ethanol exhibited a markedly increased sensitivity to MPT induction caused by a variety of agents implicated in both necrotic (Ca 2+ ) and apoptotic (ceramide, GD3 ganglioside, and Bax) forms of cell death (11).…”

Section: Introductionmentioning

confidence: 99%

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

Kessova

Cederbaum

2007

Free Radical Biology and Medicine

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Chronic alcohol consumption induced liver injury in Cu, Zn-superoxide dismutase -deficient mice (Sod1 −/− ) with extensive centrilobular necrosis and inflammation and a reduction of hepatic ATP content. Mechanisms by which ethanol decreased ATP in these mice remain unclear. We investigated alterations in mitochondria of Sod1 −/− mice produced by chronic ethanol treatment. These mitochondria had an increase in state 4 oxygen consumption with succinate and especially with glutamate plus malate compared to pair-fed Sod1 −/− mice or mitochondria from wild type mice fed dextrose or ethanol. This uncoupling was associated with a decrease in ADP/O and respiratory control ratios, a decline in mitochondrial membrane potential, enhanced mitochondrial permeability transition and decreased aconitase activity. Total thiols and uncoupling protein 2 levels were elevated in the pair-fed Sod1 −/− mitochondria, perhaps an adaptive response to oxidant stress. However, no such increases were found with the ethanol-fed Sod1 −/− mitochondria suggesting a failure to develop these adaptations. The mitochondria from the ethanol-fed Sod1 −/− mice had elevated levels of cleaved Bax, Bak, Bcl-xl and adenine nucleotide translocator. Immunoprecipitation studies revealed increased association of Bax and Bak with the adenine nucleotide translocator. ADP-ATP exchange was very low in the ethanol-fed Sod1 −/− mitochondria. These results suggest that ethanol treatment of Sod1 −/− mice, produces uncoupling and a decline in Δψ, swelling, increased association of proapoptotic proteins involved in the permeability transition and decreased adenine nucleotide translocator activity, which may be responsible for the decline in ATP levels and development of necrosis in this model of alcohol-induced liver injury.

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“…One of the primary sites manifesting damage brought on by ethanol is the mitochondria. [3][4][5][6] Mitochondria isolated from ethanolfed rats are known to be deficient in respiratory-chain components and ATP production during periods of stress, and they show damage to mitochondrial DNA. 7,8 Such effects of ethanol on mitochondrial function may result in lipid peroxidation and impairment of ATP production during exposure to stresses such as hypoxia or inflammatory cytokines, leading to further injury of the mitochondria and cell.…”

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confidence: 99%