These authors contributed equally to this study.
Steatohepatitis/Metabolic Liver Disease
Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis†
Article first published online: 24 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 1, pages 153–163, July 2011
How to Cite
Chacko, B. K., Srivastava, A., Johnson, M. S., Benavides, G. A., Chang, M. J., Ye, Y., Jhala, N., Murphy, M. P., Kalyanaraman, B. and Darley-Usmar, V. M. (2011), Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis. Hepatology, 54: 153–163. doi: 10.1002/hep.24377
Funding: This study was supported by the National Institutes of Health [grant number AA013395] to V.D.U. Dr. Michael P. Murphy holds patents related to the area of mitochondria-targeted antioxidants as therapies and serves on the scientific advisory board of Antipodean Pharmaceuticals Inc. that develops and commercializes MitoQ.
- Issue published online: 24 JUN 2011
- Article first published online: 24 JUN 2011
- Accepted manuscript online: 21 APR 2011 07:49AM EST
- Manuscript Accepted: 8 APR 2011
- Manuscript Received: 16 NOV 2010
Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. Conclusion: These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization. (HEPATOLOGY 2011;)