Cited by 99Metal-Catalyzed Oxygenation MechanismsEpigenetics and DNA MethylationGenetics, Aging, and Longevity in Model Organisms

2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process

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Salminen, Antero, Kauppinen, Anu, Kaarniranta, Kai·2015·Cellular and Molecular Life Sciences

Abstract

Recent studies have revealed that the members of an ancient family of nonheme Fe(2+)/2-oxoglutarate-dependent dioxygenases (2-OGDO) are involved in the functions associated with the aging process. 2-Oxoglutarate and O2 are the obligatory substrates and Fe(2+) a cofactor in the activation of 2-OGDO enzymes, which can induce the hydroxylation of distinct proteins and the demethylation of DNA and histones. For instance, ten-eleven translocation 1-3 (TET1-3) are the demethylases of DNA, whereas Jumonji C domain-containing histone lysine demethylases (KDM2-7) are the major epigenetic regulators of chromatin landscape, known to be altered with aging. The functions of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD1-3) as well as those of collagen hydroxylases are associated with age-related degeneration. Moreover, the ribosomal hydroxylase OGFOD1 controls mRNA translation, which is known to decline with aging. 2-OGDO enzymes are the sensors of energy metabolism, since the Krebs cycle intermediate 2-oxoglutarate is an activator whereas succinate and fumarate are the potent inhibitors of 2-OGDO enzymes. In addition, O2 availability and iron redox homeostasis control the activities of 2-OGDO enzymes in tissues. We will briefly elucidate the catalytic mechanisms of 2-OGDO enzymes and then review the potential functions of the above-mentioned 2-OGDO enzymes in the control of the aging process.

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  • Germline mutations in L2HGDH and D2HGDH cause L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria.

    “The cause of these so-called 2-hydroxyglutaric acidurias (2HGAs) was attributed to germline mutations in L-2-HG dehydrogenase (L2HGDH) and D-2-HG dehydrogenase (D2HGDH), the mitochondrial enzymes responsible for the conversion of 2-HG to α-KG and thus its breakdown107-109.”

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Authors
Salminen, A., Kauppinen, A., & Kaarniranta, K.
Affiliations
University of Eastern Finland (FI)
Corresponding author
Kaarniranta, Kai
Venue
Cellular and Molecular Life Sciences
Published
2015-06-29
Volume
72
Issue
20
Pages
3897-3914
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
OpenAlex
W1010999108
Cited by
99
References
216
Citations by year
2026: 6 · 2025: 4 · 2024: 9 · 2023: 12 · 2022: 11 · 2021: 7 · 2020: 12 · 2019: 6 · 2018: 10 · 2017: 10 · 2016: 9 · 2015: 3
FWCI
0.42
Type
journal article
Language
en
Open access
Locations
  • Cellular and Molecular Life Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Kuopion Yliopistollinen Sairaala
Topics
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
2-oxoglutarate-dependent dioxygenase, aging, energy metabolism, oxygen availability, iron homeostasis, histone demethylation, DNA demethylation, mRNA translation, epigenetic regulation
MeSH terms
Aging, Animals, Hypoxia, Energy Metabolism, Homeostasis, Iron, Oxygen, Protein Biosynthesis, DNA Methylation, Epigenesis, Genetic, Dioxygenases

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