Oxygen and 2-oxoglutarate sensing enzymes as novel therapeutic targets in metabolic, neurological and other disease

2-Oxoglutarate-dependent dioxygenase (2OGDD) enzymes share the same mechanism and cofactors but act on different substrates. 2OGDDs can sense hypoxia (deficiency of oxygen) and changes in metabolite and iron levels.

Project information

Project duration


Project funder

Biocenter Oulu

Project coordinator

University of Oulu

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Project description

The aim of this project is to deliver new information on contribution of selected 2OGDDs to normal physiology and disease mechanisms, and to discover new treatment options for metabolic, neurological and other diseases exploiting modulation of the 2OGDDs. We focus on obesity and neurodegenerative diseases that are increasing rapidly, having limited treatment options and causing high burden to individuals and the society. The project uses molecular, biochemical and cellular methodologies, systemic studies in experimental animals using preclinical disease models and translation to human context.

Key publications

Ollonen T, Kurkela M, Laitakari A, Sakko S, Dimova EY, Koivisto H, Myllyharju J, Tanila H, Serpi R, and Koivunen P: Activation of the hypoxia response protects mice from amyloid-b accumulation. Cell. Mol. Life Sci., 79:432, 2022.

Tapio J, Halmetoja R, Dimova EY, Mäki JM, Laitala A., Walkinshaw G, Myllyharju J, Serpi R, and Koivunen P: Contribution of HIF-P4H isoenzyme inhibition to metabolism indicates major beneficial effects being conveyed by HIF-P4H-2 antagonism. J. Biol., Chem., 298:102222, 2022.

Määttä J, Serpi R, Hörkkö S, Myllyharju J, Dimova EY, and Koivunen P: Genetic ablation of P4H-TM reduces atherosclerotic plaques in mice. Arterioscler. Thromb. Vasc. Biol.,41: 2128-2140, 2021.

Auvinen J, Tapio J, Karhunen V, Kettunen J, Serpi R, Dimova EY, Gill D, Soininen P, Tammelin T, Mykkänen J, Puukka K, Kähönen M, Raitoharju E, Lehtimäki T, Ala-Korpela M, Raitakari OT, Keinänen-Kiukaanniemi S, Järvelin M-R, and Koivunen P: Systematic evaluation of association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia. Sci. Adv. 7: eabi4822, 2021.

Tapio J, Vähänikkilä H, Kesäniemi YA, Ukkola O, and Koivunen P: Higher hemoglobin levels are an independent risk factor for adverse metabolism and higher mortality in a 20-year follow-up. Sci. Rep., 11: 19936, 2021.

Röning T, Magga J, Laitakari A, Halmetoja R, Tapio J, Dimova EY, Szabo Z, Rahtu-Korpela L, Kemppi A, Walkinshaw G, Myllyharju J, Koivunen P, and Serpi R: Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy. J. Mol. Cell. Cardiol., 164: 148-155, 2021.

Myllykoski M, Sutinen A, Koski MK, Kallio JP, Raasakka A, Myllyharju J, Wierenga RK, and Koivunen P: Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains. J. Biol. Chem., 296: 100197, 2021.

Laitakari A, Huttunen R, Kuvaja P, Hannuksela P, Szabo Z, Heikkilä M, Kerkelä R, Myllyharju J, Dimova EY, Serpi R, and Koivunen P: Systemic long-term inactivation of hypoxia-inducible factor prolyl 4-hydroxylase 2 ameliorates aging-induced changes in mice without affecting their life span. FASEB J., 34: 5590-5609, 2020.

Laitakari A, Tapio J, Mäkelä KA, Herzig K-H, Dengler F, Gylling H, Walkinshaw G, Myllyharju J, Dimova EY, Serpi R, and Koivunen P: HIF-P4H-2 downregulates hepatic fructose intake, induces thermogenesis and protects against NAFLD. J. Mol. Med., 98(5):719-731, 2020.

Chakraborty AA, Laukka T, Myllykoski M, Meng Y, Meier S, Jennigs RB, Creech A, Herbert ZT, McBrayer SK, Olenchock BA, Jaffe JD, Haigs M, Rameen B, Signoretti S, Koivunen P*, and Kaelin WG Jr*: Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. *Equal contribution. Science, 363:1217-1222, 2019.