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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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Abstract

Recent studies have revealed that the members of an ancient family of nonheme Fe2+/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 Fe2+ 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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Acknowledgments

This study was financially supported by the grants from the Academy of Finland, VTR funding from Kuopio University Hospital, the Finnish Cultural Foundation, and the Alfred Kordelin Foundation.

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Authors and Affiliations

  1. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Antero Salminen

  2. Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Anu Kauppinen & Kai Kaarniranta

  3. Department of Ophthalmology, Kuopio University Hospital, P.O.B. 100, 70029, Kuopio, Finland

    Anu Kauppinen & Kai Kaarniranta

Authors
  1. Antero Salminen
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  2. Anu Kauppinen
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  3. Kai Kaarniranta
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Correspondence to Kai Kaarniranta.

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Salminen, A., Kauppinen, A. & Kaarniranta, K. 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process. Cell. Mol. Life Sci. 72, 3897–3914 (2015). https://doi.org/10.1007/s00018-015-1978-z

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  • DOI: https://doi.org/10.1007/s00018-015-1978-z

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