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.
Keywords: 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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