Post-translational prolyl 4-hydroxylation - Hypoxia-inducible factor 3 in erythropoietin signaling and collagen modification in bone physiology

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Auditorium F101 of the Faculty of Biochemistry and Molecular Medicine

Topic of the dissertation

Post-translational prolyl 4-hydroxylation - Hypoxia-inducible factor 3 in erythropoietin signaling and collagen modification in bone physiology

Doctoral candidate

Licentiate of Medicine Jussi-Pekka Tolonen

Faculty and unit

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

Subject of study

Biochemistry

Opponent

Professor Geert Carmeliet, KU Leuven

Custos

Professor Johanna Myllyharju, University of Oulu

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A hydroxylation reaction regulates red blood cell production and bone tissue

The doctoral dissertation explored the multifaceted roles of 2-oxoglutarate dependent (2-OGDD) enzymes in cellular metabolism. One key function of the enzymes is to monitor the intracellular oxygen content. As the oxygen concentration drops, 2-OGDD enzymes trigger massive changes in cellular function to increase oxygen availability. This ‘hypoxia response’ consists of changes in the expression of up to thousands of genes. On the other hand, 2-OGDD enzymes regulate the structure and heat resistance of collagens, which are responsible for tissue strength.

One of the events in the ‘hypoxia response’ is an increase in red blood cell production. For example, reduced oxygen levels inside liver cells increase the secretion of the erythropoietin hormone, EPO, which regulates red blood cell production. The first part of the dissertation showed that the secretion of EPO is driven by multiple intracellular messengers. One of the messengers regulated by 2-OGDD enzymes is Hypoxia Inducible Factor (HIF)-3, previously thought to suppress the ‘hypoxia response’. However, based on the results published in the dissertation, HIF-3 is able to multiply EPO production alongside other HIF proteins. The second part of the dissertation shows that a disruption of collagen-handling 2-OGDD enzymes weakens bone structure and causes osteoporosis. The amount of cancellous bone in genetically engineered mice was half of that observed in normal mice. The osteoporosis was caused by a deceleration of collagen production and a smaller number of bone-producing osteoblasts.

The first small-molecule 2-OGDD inhibitor has been authorized in China last year. It is used to treat anemia, or hemoglobin deficiency, caused by chronic kidney disease. The drug initiates the secretion of EPO in the liver, from where EPO is transported to the bone marrow to boost red blood cell and hemoglobin production. The newly published dissertation study clarifies the details of erythropoietin secretion. The study also sheds light on the side effects of long-term use of 2-OGDD inhibitors, such as in bone tissue, where a disruption of the hydroxylation reaction causes osteoporosis.
Last updated: 19.9.2019