On 31 May at 10 Rando Porosk will defend his doctoral thesis „The role of oxidative stress in Wolfram syndrome 1 and hypothermia“.
Senior Research Fellow Kalle Kilk (PhD (Neurochemistry), Institute of Biomedicine and Translational Medicine) University of Tartu,
Senior Research Fellow Riina Mahlapuu (PhD (Bioorganic Chemistry), Institute of Biomedicine and Translational Medicine) University of Tartu,
Professor Ursel Soomets (PhD (Neurochemistry), Institute of Biomedicine and Translational Medicine) University of Tartu.
senior lecturer Margit Mahlapuu (PhD), University of Gothenburg, Gothenburg, Sweden.
The deficiency in WFS1 gene causes Wolfram syndrome (WS), which represents a valuable disease model currently available for identifying markers associated with endoplasmic reticulum (ER) stress, juvenile-onset diabetes and neurodegeneration. Another important factor is that WS arises from mutation of a single gene, which makes it a good model for teasing out the mechanisms of ER dysfunction than other multifactorial conditions like diabetes and oxidative stress. Studying oxidative stress and metabolic profiling of Wfs1-deficient mice under hyperglycemic conditions to find therapies aimed at reducing stress in patients or those at risk for developing diabetes. Also this might give new insight of the association between the Wfs1 and its functions.
The metabolomic characterization of Wfs1-deficient mice revealed a broad spectrum of metabolic complications and affected glutathione redox status in the knock-out mice. At the whole organism level, the glucose use, gluconeogenesis and anaerobic glycolysis appear to be increased in the early stages of the disease, but later the energy demand is satisfied by intensified lipolysis. Furthermore, in the blood and liver tissue of KO mice, the progression of the WS exceeds hypouricemia into hyperuricemia. In the pancreas and heart tissue young mice, glycosuria preceded hyperglycemia, which implied to kidney dysfunction.
The concentration of GSH was generally decreased in KO Wfs1-deficient mice, but a slight upregulation of GSH in the liver is probably an attempt to control ER stress. In the liver and heart the activity of glutathione peroxidase was increased and the activity of glutathione reductase was decreased in KO mice compared to WT littermates. In the kidneys KO mice, the activity of both enzymes increased.
The antioxidants had the highest effect improving the glutathione status in the liver and heart tissue of Wfs1-deficient mice. In the liver tissue, the studied antioxidants mainly reduced the acitivity of GR and GPx in older mice and inversely in the younger littermates.
Hypothermia induced the highest level of total glutathione in wild-type mouse embryonic fibroblasts and HeLa cells, whereas the concentration of oxidized glutathione was decreased or remained unchanged, respectively.