Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) | Beutenbergstr. 11 | 07745 Jena | Building FLI 1 | Room Nucleus
24.10.2019
- 16:00 Uhr
ARC Colloquium: Modelling for young and old: Tackling the Complexity of Fatty Acid Oxidation in Metabolic Disease
Prof. Dr. Barbara M. Bakker | Systems Medicine of Metabolism and Signaling | University Medical Centre Groningen
Barbara Bakker is Professor for Medical Systems Biology at the University Medical Centre Groningen and holds also a position as Associate Professor in Molecular Cell Physiology, VU University Amsterdam. Her group is specialized in: Systems Biology of Metabolic Networks and Metabolic Disease; Computational models of metabolic networks; Fluxomics; Metabolomics; Enzyme kinetics.
Abstract: Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Although the reactions and enzymes involved have been known for decades, the dynamic regulation of the pathway is not well understood. Deregulation of mFAO plays a pivotal role in many diseases, including age-related multifactorial diseases, such as diabetes, but also rare inherited mFAO deficiencies. Symptoms differ between individuals even with the same primary disease mutation. We therefore embarked on a systems biology program combining wet-lab biochemistry and computational modelling, to understand the dynamics, control, and robustness of the mFAO pathway in health and disease.
Enzymes in lipid metabolism, including those in the mFAO, typically recognize a class of substrates, rather than a unique substrate. In the case of mFAO there is limited specificity to the carbon chain-length of the substrate. This substrate promiscuity gives rise to a complex network of feedback and feedforward competitive inhibition. We developed and validated a dynamic model of the mFAO based on detailed biochemical kinetics. Model simulations showed that substrate promiscuity may trigger a vicious cycle in which coenzyme A (CoA) esters sequester so much CoA that it becomes limiting and the flux drops. Targeted proteomics and metabolomics are used to model individual patients. Initial personalized simulations suggest that we can explain the difference in disease severity between individual patients suffering from inherited enzyme deficiencies, thus providing a basis for a personalized medicine approach.
In the talk, I will highlight our ongoing research into mitochondrial fatty-acid oxidation and its surrounding metabolic pathways, how to translate our findings to clinical symptoms, and applications in inherited diseases as well as type 2 diabetes.
We cordially invite interested guests.
Beutenbergstr. 11