Cited by 123Mitochondrial Function and PathologyGenetics, Aging, and Longevity in Model OrganismsRedox biology and oxidative stress

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1 +/− Mouse Mutants

Wang, Dantong, Malo, Danielle, Hekimi, Siegfried·2010·The Journal of Immunology

Abstract

Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1α, 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-1α in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-α. 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-1α and secretion of TNF-α. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1α, which, in turn, is necessary for increased TNF-α secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1α 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-1α expression can positively impact animal longevity.

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Crossref · 10.4049/jimmunol.0902352

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Authors
Wang, D., Malo, D., & Hekimi, S.
Affiliations
  • McGill University (CA)
  • Department of Biology
Corresponding author
  • Wang, Dantong
  • Hekimi, Siegfried
Venue
The Journal of Immunology
Published
2009-12-27
Volume
184
Issue
2
Pages
582-590
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W1544021262
Cited by
123
References
46
Citations by year
2025: 2 · 2024: 10 · 2023: 5 · 2022: 9 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 4 · 2017: 7 · 2016: 11 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 13
FWCI
4.02
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (15461_3)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
mitochondrial reactive oxygen species, hypoxia-inducible factor-1α, ubiquinone biosynthesis, macrophage polarization, TNF-α, inflammatory cytokines, antioxidant peptides, longevity, immune response, RAW 264.7 macrophages
MeSH terms
Animals, Cell Line, Energy Metabolism, Mixed Function Oxygenases, Immunity, Liver, Longevity, Macrophages, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Mutation, Tumor Necrosis Factor-alpha, Cytokines, Reactive Oxygen Species, Mitochondrial Proteins, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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