2-oxoglutarate-dependent dioxygenases in health and disease

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

101A, Leena Palotie hall

Topic of the dissertation

2-oxoglutarate-dependent dioxygenases in health and disease

Doctoral candidate

Medical candidate Tuulia Ala-Nisula

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM & Hypoxia

Subject of study

Medicine

Opponent

Professor Henna Tyynismaa, University of Helsinki

Custos

Professor Peppi Karppinen, University of Oulu

Visit thesis event

Add event to calendar

2-oxoglutarate-dependent dioxygenases in health and disease

Aerobic organisms require oxygen for cellular functions, growth and homeostasis. Reduced oxygen levels, or hypoxia, activate the hypoxia-inducible factor (HIF), in response to which an organism enhances the oxygen supply to its tissues by angiogenesis and shifts its energy metabolism to favour glycolysis over oxidative phosphorylation in order to reduce oxygen demand.

HIF is regulated by the HIF prolyl 4-hydroxylases (HIF-P4H-1-3), the inhibition of which has been shown to be an effective treatment for renal anemia. Since HIF-P4H inhibitors have shown promising effects on metabolic health in preclinical trials, we examined the effect of roxadustat, a pan-HIF-P4H inhibitor, on human myotubes from donors with normal glucose tolerance or type 2 diabetes mellitus. Roxadustat was found to activate the HIF pathway, increase glycolysis and reduce mitochondrial respiration in human myotubes.

Transmembrane prolyl 4-hydroxylase (P4H-TM) is regarded as a fourth HIF-P4H as it acts on HIFα, and mutations in its gene are linked to HIDEA syndrome, characterized by hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities. Since P4H-TM deficiency has been shown to protect mice against atherosclerosis, suggesting a potential metabolic effect, we set out to study the effect of this deficiency on metabolism in mice. P4h-tm−/− mice showed alterations in energy metabolism, day-night activity rhythm, glucose metabolism, neuromuscular function, and respiration, and the symptoms observed in them resembled those in HIDEA patients, making this a valuable model for studying the HIDEA syndrome and developing targeted therapies.

The phytanoyl-CoA dioxygenase domain containing 1 (PHYHD1) is a less studied member of the 2-oxoglutarate-dependent dioxygenase family, and has been associated with Alzheimer’s disease, some cancers and immune cell functions. We investigated the subcellular localization, substrate candidates and kinetic parameters of PHYHD1. It is localized in both the nucleus and cytoplasm, and although the primary substrate remains unknown, mRNA was found to bind and inhibit its reaction. In an uncoupled reaction, PHYHD1 was activated by citrate, suggesting allosteric activation. Interactome analyses linked PHYHD1 to cell division and RNA metabolism, and phenotypic analyses to carbohydrate metabolism. Thus it may act as a novel oxygen sensor regulated by mRNA and citrate.
Last updated: 9.12.2024