Journal Articles

Zinc Deficiency Contributes to Alcohol Consumption-Induced Defect of Mitochondrial Electron Transport Chain and Overproduction of Reactive Oxygen Species in the Live of Rats

June 01, 2016

Qian Sun 1,2, Wei Zhong 2, Wenliang Zhang 2, Xinguo Sun 2 and Zhanxiang Zhou 1,2 (2016). Zinc Deficiency Contributes to Alcohol Consumption-Induced Defect of Mitochondrial Electron Transport Chain and Overproduction of Reactive Oxygen Species in the Live of Rats. The FASEB Journal, 30(1).

Author Affiliations

1. Nutrition, UNCG, KANNAPOLIS, NC
2. Center for translational biomedical research, UNCG, KANNAPOLIS, NC

Abstract

Clinical studies demonstrated that patients with alcoholic liver disease (ALD) have decreased hepatic zinc levels; however the effect of zinc deficiency on the function of hepatic mitochondria has not been well studied. The present study was undertaken to determine if zinc deficiency causes mitochondrial electron transport chain (ETC) defect and if defected ETC function could increase hepatic oxidative stress. Adult male Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol liquid diet for 5 months. Chronic alcohol exposure significantly increased hepatic levels of triacylglycerol and free fatty acid and induced apoptotic cell death. Zinc levels in both the whole liver and the purified hepatic mitochondria were significantly reduced by alcohol exposure in association with perturbed expression of zinc transporters. Chronic alcohol exposure also increased the levels of 4-hydroxynonenal (4HNE) in the whole liver as well as the purified mitochondria. The expression of hepatic mitochondrial respiratory complex I, III, IV, and V were repressed by chronic alcohol exposure, which was in consistence with a significant decrease of the hepatic ATP production. Examination of the mitochondrial biogenesis markers demonstrated that chronic alcohol exposure significantly decreased AMPK, PGC1α, NRF1 and TFAM levels in association with downregulation of mitochondrial DNA expression. In order to define the link between zinc deficiency and the defect of mitochondrial respiratory complexes, HepG2 cells were treated with zinc chelator, TPEN, for 6h. Experimental zinc deficiency significantly decreased the protein levels of mitochondrial respiratory complex I, III, and IV. In addition, p-AMPK, PGC1α, NRF1 and TFAM levels as well as mitochondrial DNA expression were significantly decreased by TPEN treatment. Consequently, mitochondrial respiratory complex I, III, or IV was silenced by corresponding shRNA, respectively. HepG2 cells with decreased expression of complex I, III, or IV by gene manipulation exhibited a decrease in mitochondrial membrane potential and an increase in free radical production compared to the cells transfected with scrambled shRNA. These results suggest that hepatic zinc deficiency critically mediates alcohol-diminished mitochondrial biogenesis and mitochondrial DNA levels which, at least partially, accounts for alcohol-induced defect of mitochondrial ETC and overproduction of reactive oxygen species.

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