title: TNF-α mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-κB activation in liver cells.
abstract: 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.
authors: Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: L
authors: L
authors: Kastl
authors: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors: S W
authors: SW
authors: Sauer
authors: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors: T
authors: T
authors: Ruppert
authors: Department of Medical Statistics, University of Goettingen, Goettingen, Germany.
authors: T
authors: T
authors: Beissbarth
authors: Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: M S
authors: MS
authors: Becker
authors: Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: D
authors: D
authors: Süss
authors: Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: P H
authors: PH
authors: Krammer
authors: Division of Immunogenetics, Tumour Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: k.guelow@dkfz.de.
authors: K
authors: K
authors: Gülow
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D012194:RNA-Directed DNA Polymerase; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: C435491:BCS1L protein, human; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014475:Uncoupling Agents; D012402:Rotenone; D000968:Antimycin A; D009245:NADH Dehydrogenase; D012194:RNA-Directed DNA Polymerase; D000074183:ATPases Associated with Diverse Cellular Activities; C506342:NDUFAF1 protein, human; D014450:Electron Transport Complex III
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