Elevated mitochondrial reactive oxygen species generation affects the immune response via hypoxia-inducible factor-1alpha in long-lived Mclk1+/- mouse mutants

J Immunol. 2010 Jan 15;184(2):582-90. doi: 10.4049/jimmunol.0902352. Epub 2009 Dec 9.

Abstract

Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1alpha, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1(+/-) mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1(+/-) mutant mice in the C57BL/6J background displayed increased basal and induced expression of HIF-1alpha in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-alpha. Mutant macrophages showed increased classical and decreased alternative activation, and mutant mice were hypersensitive to LPS. Consistent with these observations in vivo, knock-down of Mclk1 in murine RAW264.7 macrophage-like cells induced increased mitochondrial ROS as well as elevated expression of HIF-1alpha and secretion of TNF-alpha. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1alpha, which, in turn, is necessary for increased TNF-alpha secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1alpha activity and demonstrate that changes in mitochondrial function within physiologically tolerable limits modulate the immune response. Our results further suggest that altered immune function through a limited increase in HIF-1alpha expression can positively impact animal longevity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / biosynthesis
  • Energy Metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology*
  • Immunity*
  • Liver / metabolism
  • Longevity
  • Macrophages / metabolism
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / immunology
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics*
  • Mixed Function Oxygenases
  • Mutation
  • Reactive Oxygen Species / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Mixed Function Oxygenases
  • Coq7 protein, mouse