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Energy metabolism

There is an intense crosstalk between metabolism and signalling cascades regulating cell survival, proliferation, and differentiation. One of the first scientists who have found evidence for the regulating role of the energy metabolism was Otto Warburg whose concepts dating back to the 1920s have gained much attention in the last years. The so-called Warburg effect (aerobic glycolysis) describes a metabolic shift of cancer cells from aerobic to anaerobic energy production, i.e. instead of using mitochondrial respiratory chain cancer cells generate energy mainly via glycolysis. Numerous current studies have demonstrated that this metabolic shift is indeed distinctive of the majority of tumour entities. However, it has become clear that the Warburg effect is not restricted to cancer cells but is occurring in fast proliferating healthy cells and cells under environmental and energetic stress. We aim to unravel the mechanisms underlying bioenergetic plasticity in conditions that are typically associated with metabolic adaption, i.e. cancer, heart insufficiency, immune metabolism, and inborn errors of metabolism.


Metabolic remodeling in heart failure

Heart consumes more energy than any other organs to carry out its function. Normally more than 95% of ATP in the heart is generated from oxidative phosphorylation in the mitochondria. Failing to produce an adequate amount of energy causes mechanical failure. Generally the failing heart increases its reliance on glucose as the energy source with reduced oxidative metabolism (Warburg phenotype). In addition to the glucose reliance, the increase of other glucose metabolism pathways including pentose phosphate pathway, hexosamine biosynthesis pathway and anaplerosis are found in hypertrophied heart. We are studying the mechanism underlying this phenomenon in zebrafish and mouse models focussing on ER-linked modulation of hexosamine biosynthesis pathway.

Mitarbeiter

Bei-Tzu Wang
Sven W. Sauer

Projektförderung


Immune metabolism

Activation of immune cells induces a Warburg effect-like metabolic shift. This metabolic adaption is uniformly observed in T cells, B cells, M1 macrophages, dentritic cells, and granulocytes. We have recently identified ADP-dependent glucokinase (ADPGK) as a central modulator of immune metabolism. In our project we are aiming to characterize the basic bioenergetics phenotype of activated immune cells and to pinpoint the role of ADPGK in their bioenergetics plasticity. In this context, we are also studying the metabolic crosstalk of leukemic cell with their microenvironment. To this end we are using different cell culture models as well as Adpgk-deficient zebrafish and mice.

Mitarbeiter

Amol Tandon
Bei-Tzu Wang
Roland Imle
Sven W. Sauer

Projektförderung


Inborn errors of metabolism

2-Aminoadipic and 2-oxoadipic aciduria and glutaric aciduria type I are two disorders of lysine metabolism characterized by the accumulation of the name-giving metabolites 2-aminoadipic and 2-oxoadipic acid and glutaric acid respectively. Only glutaric aciduria type I presents with clinical symptoms, i.e. severe degeneration of basal ganglia, which are induced by the accumulating metabolites. We have recently identified mutations of DHTKD1 to cause 2-aminoadipic and 2-oxoadipic aciduria. This protein is a new subcomplex of the Krebs cycle protein 2-oxoglutarate dehydrogenase complex providing a link between this major pathway of energy homeostasis and lysine degradation with yet unknown implications. Of note, DHTKD1 is the enzymatic step before the protein deficient in glutaric aciduria type I and pharmacological inhibition of DHTKD1 is likely to prevent accumulation of toxic metabolites in this disease. Therefore, the aims of our study are (1) to unravel the role and function of a DHTKD1 containing 2-oxoglutarate dehydrogenase complex in cellular metabolism and (2) to design therapeutic strategies for glutaric aciduria type I via DHTKD1 inhibition using patient cells as well as Gcdh- and Dhtkd1-deficient mice and zebrafish.

Mitarbeiter

Yipin Wu
Deepthi Ediga
Sven Sauer
Stefan Kölker

Projektförderung
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