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FEBS Lett. 2014 Jan 3;588(1):175-83. doi: 10.1016/j.febslet.2013.11.033. Epub 2013 Dec 4.

TNF-α mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-κB activation in liver cells.

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Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Department of Medical Statistics, University of Goettingen, Goettingen, Germany.
Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:


Development of hepatocellular carcinoma (HCC) is accompanied by a continuous increase in reactive oxygen species (ROS) levels. To investigate the primary source of ROS in liver cells, we used tumor necrosis factor-alpha (TNF-α) as stimulus. Applying inhibitors against the respiratory chain complexes, we identified mitochondria as primary source of ROS production. TNF-α altered mitochondrial integrity by mimicking a mild uncoupling effect in liver cells, as indicated by a 40% reduction in membrane potential and ATP depletion (35%). TNF-α-induced ROS production activated NF-κB 3.5-fold and subsequently enhanced migration up to 12.7-fold. This study identifies complex I and complex III of the mitochondrial respiratory chain as point of release of ROS upon TNF-α stimulation of liver cells, which enhances cell migration by activating NF-κB signalling.


CCCP; H(2)DCF-DA; HBV; HCV; Hepatocellular carcinoma (HCC); Hepatocytes; Liver cancer; Mitochondria; N-acetylcysteine; NAC; NF-κB; ROS; Reactive oxygen species (ROS); TMRE; TNF-α; carbonyl cyanide m-chlorophenyl hydrazine; dichlorofluorescein diacetate; hepatitis B virus; hepatitis C virus; reactive oxygen species; tetramethylrhodamine ethyl ester; tumor necrosis factor-alpha

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