FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression

Cell Death Differ. 2012 Jun;19(6):968-79. doi: 10.1038/cdd.2011.179. Epub 2011 Dec 2.

Abstract

Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase/Akt pathway, and are key regulators of the cell cycle, apoptosis and response to oxidative stress. FOXOs have been shown to have tumour suppressor function and are important for stem cell maintenance. We have performed a detailed analysis of the transcriptional programme induced in response to Forkhead-box protein O3a (FOXO3a) activation. We observed that FOXO3a activation results in the repression of a large number of nuclear-encoded genes with mitochondrial function. Repression of these genes was mediated by FOXO3a-dependent inhibition of c-Myc. FOXO3a activation also caused a reduction in mitochondrial DNA copy number, expression of mitochondrial proteins, respiratory complexes and mitochondrial respiratory activity. FOXO3a has been previously implicated in the detoxification of reactive oxygen species (ROS) through induction of manganese-containing superoxide dismutase (SOD2). We observed that reduction in ROS levels following FOXO3a activation was independent of SOD2, but required c-Myc inhibition. Hypoxia increases ROS production from the mitochondria, which is required for stabilisation of the hypoxia-inducible factor-1α (HIF-1α). FOXO3a activation blocked the hypoxia-dependent increase in ROS and prevented HIF-1α stabilisation. Our data suggest that FOXO factors regulate mitochondrial activity through inhibition of c-Myc function and alter the hypoxia response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Hypoxia
  • Cell Line, Tumor
  • DNA, Mitochondrial / metabolism
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Oxidative Stress
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Superoxide Dismutase / metabolism

Substances

  • DNA, Mitochondrial
  • FOXO1 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • superoxide dismutase 2