Mitochondrial reactive oxygen species trigger hypoxia-induced transcription

DOI Web Site 被引用文献37件
  • N. S. Chandel
    Departments of Medicine, Pathology, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637
  • E. Maltepe
    Departments of Medicine, Pathology, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637
  • E. Goldwasser
    Departments of Medicine, Pathology, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637
  • C. E. Mathieu
    Departments of Medicine, Pathology, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637
  • M. C. Simon
    Departments of Medicine, Pathology, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637
  • P. T. Schumacker
    Departments of Medicine, Pathology, Biochemistry and Molecular Biology, Molecular Genetics and Cell Biology and The Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637

抄録

<jats:p> Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl <jats:sub>2</jats:sub> ) in Hep3B cells. However, neither the mechanism of cellular O <jats:sub>2</jats:sub> sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O <jats:sub>2</jats:sub> sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show ( <jats:italic>i</jats:italic> ) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O <jats:sub>2</jats:sub> ) or CoCl <jats:sub>2</jats:sub> incubation, ( <jats:italic>ii</jats:italic> ) Hep3B cells depleted of mitochondrial DNA (ρ <jats:sup>0</jats:sup> cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; ( <jats:italic>iii</jats:italic> ) ρ <jats:sup>0</jats:sup> cells increase ROS generation in response to CoCl <jats:sub>2</jats:sub> and retain the ability to induce expression of these genes; and ( <jats:italic>iv</jats:italic> ) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl <jats:sub>2</jats:sub> in wild-type cells, and abolish the response to CoCl <jats:sub>2</jats:sub> in ρ° cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl <jats:sub>2</jats:sub> activates transcription by stimulating ROS generation via a mitochondria-independent mechanism. </jats:p>

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