We analyze heteroplasmy and modifications in mtDNA. Mitochondrial activity is measured in various materials using Seahorse and oxygraphy analyses, and enzymatic and cellular assays are used to characterize the metabolism of branched-chain amino acids. In collaboration with the Structural Biology Research Group, we develop inhibitors for enzymes that metabolize branched-chain amino acids.
We collaborate with the Section for Metabolic Disorders, which has a national function for the diagnostics of patients with mitochondrial diseases and other conditions caused by defects in the metabolism of branched-chain amino acids.
Longterm goals
Mitochondria are fascinating organelles. We are curious about how mitochondrial activity is adapted to mtDNA (and vice versa). The breakdown of branched-chain amino acids (leucine, valine, and isoleucine) is catalyzed by mitochondrial enzymes, which in some cases also associates to nucleic acids. This indicates that metabolic activity is either regulated by - or regulates- RNA/DNA processes. Mitochondrial flux of metabolites generates reduced cofactors that are oxidized by the ETC at a rate that is limited by the biochemical capacity of the ETC but is most often constrained by the availability of metabolites and oxygen (cellular environment) as well as the type of mitochondria.
We study the underlying cellular causes of congenital metabolic diseases, including mitochondrial diseases, and other conditions where the metabolism of branched-chain amino acids is affected. The group is involved in collaborative projects driven by the group's expertise in mitochondria.
Projects
Metabolism of branched-chain amino acids
We have established methods to evaluate the cellular and mitochondrial effects of defects in the metabolism of branched-chain amino acids (BCAA). These are used to study Maple Syrup Urine Disease (MSUD), a rare congenital disorder caused by mutations in the BCKD complex, leading to ineffective breakdown of the BCAA, resulting in their accumulation as well as (toxic) intermediates and the lack of production of branched-chain fatty acids. An associated congenital defect in BCKDK (which limits the rate of BCKD) conversely leads to critically low concentrations of BCAA.
BCAA Metabolism as a Pharmacological Target Against Pancreatic Cancer
The metabolism of branched-chain amino acids is essential for the proliferation of pancreatic cancer cells, and these cells express high levels of the mitochondrial BCAT2 transaminase. We collaborate on developing inhibitors against BCAT2 and investigate why this metabolic pathway is important for cancer cells under tumor-relevant conditions.
Peripheral Mitochondrial Function in Huntington's Disease (HD)
HD is a neurodegenerative disorder strongly associated with mitochondrial dysfunction. In collaboration with two Czech groups, we have observed altered mitochondrial activity in lymphocytes from HD patients and in fibroblasts from a pig model of HD. This indicates that peripheral tissue can be used in monitoring the disease and during future treatment.
Mitochondrial Involvement in Age-related Macular Degeneration (AMD)
AMD is associated with elevated BCAA, and we postulate that changes in this metabolic pathway underlie the disease. We also identify biomarkers that can be used as quality markers for cells intended for transplantation.
Mitochondrial Precision Medicine
Mitochondrial capacity varies significantly among healthy individuals. This means that biochemical ETC diagnostic is challenging, identifying determinants for variability in mitochondrial biochemical complex activity. Large natural variability among healthy individuals makes it difficult to diagnose based on biochemical activity. We investigate whether this variability stems from post-translational modifications (oxidative damage, lipid changes, etc.) or genetic variants in mtDNA.
Huntington’s disease
Huntington’s disease is a neurodegenerative disorder with association to mitochondrial dysfunction. We’ve found that progression of disease correlates with DNA integrity in peripheral mononuclear blood cells, and speculate that onset of disease is dictated by individual mitochondrial capacity.
Adult Macular Degeneration (AMD)
We investigate whether mitochondrial aberrations in Retinal Epithelial Pigmental cells cause metabolic changes that underlie AMD.
Personalized mitochondrial function
Mitochondrial capacity varies greatly among healthy individuals. This implies that diagnosing mitochondrial disease based on biochemical ETC analysis is challenging. It also indicates that healthy individuals may have different predispositions to diseases associated with bioenergetic impairment. We investigate which genetic and post-translational factors contribute to this variation, and whether it can predispose individuals to disease.
Collaboration
- Bjørn Dalhus, University of Oslo
- Goran Petrovski, University of Oslo and Oslo University Hospital
- Kristin Ørstavik, Oslo University Hospital
- Arild Rustan, University of Oslo and Oslo
- Vigdis Aas, Oslo Met
- Magnar Bjørås, University of Oslo and Oslo University Hospital
- Katja Elgstøen, Oslo University Hospital
- Caroline Verbeke, University of Oslo and Oslo University Hospital
- Hana Hansikova, 1st Charles University in Prague and General University Hospital in Prague, Tsjekkia
- Zdenka Ellederova & Jan Motlik, Institute of Animal Physiology and Genetics, Libechov, Czech Republic
- Xavier Muñoz, The Institute of Microelectronics of Barcelona (IMB-CNM-CSIC), Spania
