The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1 +/− Mouse Mutants
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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“and indeed, part of the fitness of Clk1+/− mice is attributed to the ability of mitochondrial ROS to modulate HIF function and inflammation 98.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [98]
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Metadata
- 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
- Publisher
- Oxford University Press (OUP)
- 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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