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Chronic ethanol feeding causes controversial changes of functional parameters of rat liver mitochondria

Name
Irina
Surname
Odinokova
Scientific organization
ITEB RAS
Academic degree
PhD
Position
Staff scientist
Scientific discipline
Life Sciences & Medicine
Topic
Chronic ethanol feeding causes controversial changes of functional parameters of rat liver mitochondria
Abstract
Chronic ethanol consumption causes liver disease and the earliest pathophysiological changes take place at the level of mitochondria. We studied the effect of chronic ethanol feeding on the parameters of rat liver mitochondria. We showed that chronic ethanol consumption decreased mitochondrial respiratory control ratio, but improved their ability to retain calcium and delayed mPTP opening. We suppose that changes in structural and/or regulatory components of mPTP could be an adaptive mechanism protected mitochondria from oxidative stress during chronic ethanol treatment.
Keywords
Chronic ethanol consumption, liver mitochondria, mPTP
Summary

Chronic ethanol expose is known to be associated with a range of liver disorders – hepatic steatosis, alcoholic hepatitis, hepatic fibrosis and cirrhosis. Some of the earliest pathophysiological changes take place at the mitochondrial level. We studied the effect of prolonged ethanol feeding on the parameters of rat liver mitochondria. Two groups of Wistar rats received Lieber-DeCarli liquid diet, where ethanol was added to yield a 5% (w/v) dose, and ethanol was isocalorically replaced with maltose/dextrin in control diet. Control rats were pair fed to their ethanol counterparts for 10 weeks. Experimental and control animals consumed 85-100 kkal per day and alcoholic rats received about 17 grams of ethanol per kg of body weight. The following mitochondrial parameters were measured: mitochondrial respiration, membrane potential, Ca2+ transport and mitochondrial swelling. We showed that rate of mitochondrial respiration of ethanol-fed rats increased at state 2 and decreased at state 3 leading to reduction in respiratory control ratio by 35%. Interestingly, Ca2+-capacity of mitochondria isolated from ethanol rats increased, their membrane potential was more stable, and rate of mitochondrial swelling was decelerated. Thus, in our experiments we observed that mitochondria from ethanol-treated rats improved their ability to retain Ca2+ and mPTP opening was delayed, which is opposite to the literature data. We supposed that changes in structural and/or regulatory components of mPTP during chronic ethanol consumption could be the reason for the resistance of mitochondria to damaging conditions. Several mitochondrial proteins related to mPTP were tested using Western blot assay (subunit c of FoF1-ATPase, VDAC1, VDAC3, CNP, TSPO, Bcl-xL). It was found that level of subunit c of FoF1-ATPase was significantly increased in mitochondria from ethanol-fed rats, furthermore the level of phosphorylated form of subunit c was also higher in ethanol mitochondria compare to control ones. Earlier we showed that induction of mPTP opening in rat liver and brain mitochondria correlated with Ca2+ and CsA-sensitive dephosphorylation of subunit c of FoF1-ATPase and subunit c might be a structural or regulatory component of mPTP. Thus increase of phosphorylated subunit c level could be an adaptive mechanism protected rat liver mitochondria from oxidative stress during chronic ethanol treatment.