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.
FEBS Lett. 2014 Jan 3;588(1):175-83. doi: 10.1016/j.febslet.2013.11.033. Epub 2013 Dec 4.
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.
肝癌（HCC）的发展伴随着活性氧（ROS）水平的持续升高。为了研究肝细胞中 ROS 的主要来源，我们使用肿瘤坏死因子-α（TNF-α）作为刺激物。应用呼吸链复合物抑制剂，我们发现线粒体是 ROS 产生的主要来源。TNF-α 通过模拟肝细胞中轻微的解偶联效应来改变线粒体的完整性，这表现为膜电位降低 40%和 ATP 耗竭（35%）。TNF-α 诱导的 ROS 产生使 NF-κB 激活 3.5 倍，随后迁移增强高达 12.7 倍。这项研究确定了线粒体呼吸链的复合物 I 和复合物 III 是 TNF-α 刺激肝细胞时 ROS 释放的关键点，通过激活 NF-κB 信号通路增强细胞迁移。
