Mitochondrial reactive oxygen species trigger hypoxia-induced transcription

N. S. Chandel, E. Maltepe, E. Goldwasser, C. E. Mathieu, M. C. Simon, P. T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1434 Scopus citations

Abstract

Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular O2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O2 sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (ρ0 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; (iii) ρ0 cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in ρ0 cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.

Original languageEnglish (US)
Pages (from-to)11715-11720
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number20
DOIs
StatePublished - Sep 29 1998

ASJC Scopus subject areas

  • General

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