Neurometabolism Research Unit
The research in NeuroMet is focused on energy and amino acid metabolism in the mammalian brain. Primary mouse cell culture systems of neurons and astrocytes from cerebral cortex or cerebellum are extensively employed. In addition, organotypical hippocampal cultures, acutely isolated cortical prisms, isolated mitochondria and cell lines are applied as model systems. An array of 3H, 15N and 13C isotopes is utilized in the mapping of metabolic pathways and their regulation. HPLC and mass spectrometry are key analytical tools combined with biochemical assays, protein biochemistry, molecular biology and fluorescence-based assays and imaging techniques.
Neuronal Bioenergetics Coupling between neuronal activation and generation of metabolic energy in the form of ATP is seminal for matching energy demand and production which is essential for brain function. Neurons are expensive in energetic terms and depolarization induces massive energy consumption, suggesting the presence of a coupling mechanism priming the energy-generating machinery towards a maximal and fast response. We are currently investigating a putative fast feed-forward link between activation of post-synaptic NMDA receptors and mitochondrial ATP output. This project is currently funded by the Danish Medical Research Council.
Astrocytic Bioenergetics The mammalian brain contains limited amounts of glycogen compared to muscle and liver and it is largely only present in astrocytes. However small the glycogen pool is, it is indeed highly dynamic; it is being degraded and rebuild continuously. We believe that glycogen is important for a number of astrocytic functions by providing fuel for key cellular processes and as precursor for biosynthetic reactions. Current projects are aimed at understanding the biochemistry of how glycogen turnover is regulated by receptor and non-receptor coupled intracellular signaling processes and to identify the cellular processes that rely on breakdown of glycogen as a source of metabolic energy. These projects are currently funded by the Lundbeck & Hørslev Foundations.
Glutamate Dehydrogenase Glutamate dehydrogenase (GDH) catalyzes the oxidation-dependent interconversion of glutamate and α-ketoglutarate releasing or fixating ammonia in the process. Residing in the mitochondrial matrix of both neurons and astrocytes, it plays an important role at the crossroad between amino acid homeostasis and energy metabolism. Interestingly, GDH exists in two isozymes in the primate and human brains whereas rodents have only one isozyme. What this means for brain cell metabolism is currently being investigated as is the role played by GDH in a number of settings including hepatic encephalopathy, a syndrome caused in part by elevated levels of blood ammonia. In addition, GDH may participate in so-called hetero-enzyme complexes with a number of key enzymes in mitochondria which is the object of an on-going project. Projects within this theme is currently funded by the Lundbeck Foundation.
- NeuroMet alumni
- Completed B.Sc., M.Sc. and Ph.D. projects
- Current funding
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Dadsetan S., Kukolj E., Bak L.K., Sørensen M., Ott P., Vilstrup H., Schousboe A., Keiding S., Waagepetersen H.S. (2013) Brain alanine formation as an ammonia scavenging pathway during hyperammonemia: effects of glutamine synthetase inhibition in rats and astrocyte-neuron co-cultures. J. Cereb. Blood Flow Metab. In press
Pajęcka K., Nielsen C.W., Hauge A., Zaganas I., Bak L.K., Schousboe A., Plaitakis A., Waagepetersen H.S. (2013) Glutamate dehydrogenase isoforms with N-terminal (His)6- or FLAG-tag retain their kinetic properties and cellular localization. Neurochem. Res. In press
Müller M.S., Obel L.F., Waagepetersen H.S., Schousboe A., Bak L.K. (2013) Complex actions of ionomycin in cultured cerebellar astrocytes affecting both calcium-induced calcium release and store-operated calcium entry. Neurochem Res. 38(6):1260-1265.
Zaganas I., Pajęcka K., Nielsen C.W., Schousboe A., Waagepetersen H.S., Plaitakis A. (2013) The effect of pH and ADP on ammonia affinity for human glutamate dehydrogenases. Metab Brain Dis. 28(2):127-131.
Dadsetan S., Sørensen M., Bak L.K., Vilstrup H., Ott P., Schousboe A., Jalan R., Keiding S., Waagepetersen H.S. (2013) Interorgan metabolism of ornithine phenylacetate – a novel strategy for treatment of hyperammonemia. Biochem Pharmacol. 85(1):115-23.
Dam G., Keiding S., Munk O.L., Ott P., Vilstrup H., Bak L.K., Waagepetersen H.S., Schousboe A., Sørensen M. (2013) Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology. 57(1):258-65.
Bak L.K., Waagepetersen H.S., Sørensen M., Ott P., Vilstrup H., Keiding S., Schousboe A. (2013) Role of branched chain amino acids in cerebral ammonia homeostasis related to hepatic encephalopathy. Metab Brain Dis. 28(2):209-215.