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Mitochondrial alterations in livers of Sod1-/- mice fed alcohol
Irina G Kessova1, Arthur I Cederbaum
1Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, Box 1603, One Gustave L. Levy Place, New York, NY 10029, USA.
Abstract:
Chronic alcohol consumption induced liver injury in Cu,Zn-superoxide dismutase-deficient mice (Sod1-/-), with extensive centrilobular necrosis and inflammation and a reduction in 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 mitochondria from 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 Deltapsi, 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.
Insights
Chronic alcohol consumption damages the liver in copper, zinc-superoxide dismutase-deficient mice (Sod1-/-). Ethanol disrupts mitochondrial function, leading to liver injury by impairing ATP production and promoting cell death.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Chronic alcohol consumption is a major cause of liver injury.
- Copper, zinc-superoxide dismutase-deficient (Sod1-/-) mice exhibit severe liver damage following ethanol exposure.
- The precise mechanisms by which ethanol reduces hepatic ATP levels in Sod1-/- mice are not fully understood.
Purpose of the Study:
- To investigate the alterations in mitochondrial function in Sod1-/- mice subjected to chronic ethanol treatment.
- To elucidate the role of mitochondrial dysfunction in alcohol-induced liver injury in this model.
Main Methods:
- Mitochondrial respiration studies using succinate and glutamate plus malate.
- Assessment of mitochondrial membrane potential, permeability transition, and aconitase activity.
- Analysis of protein levels, including uncoupling protein 2, Bax, Bak, Bcl-xl, and adenine nucleotide translocator, using Western blotting and immunoprecipitation.
Main Results:
- Ethanol-fed Sod1-/- mitochondria exhibited increased State 4 oxygen consumption, indicative of uncoupling.
- A decrease in ADP/O ratios, respiratory control, mitochondrial membrane potential, and aconitase activity was observed.
- Ethanol-induced liver injury was associated with increased proapoptotic proteins (Bax, Bak) and reduced adenine nucleotide translocator activity, impairing ADP-ATP exchange.
Conclusions:
- Ethanol treatment in Sod1-/- mice leads to mitochondrial uncoupling, loss of membrane potential, and enhanced permeability transition.
- Increased association of proapoptotic proteins with the adenine nucleotide translocator contributes to impaired ATP synthesis.
- These mitochondrial dysfunctions are key factors in the development of alcohol-induced liver injury and necrosis in Sod1-/- mice.
