BBB seminar: Barbara Bakker
Robustness of fatty-acid oxidation in health and disease
Department of Pediatrics, Systems Medicine of Metabolism and Signalling, University Medical Centre Groningen, The Netherlands
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. Inherited mFAO defects reduce the capability of patients to cope with metabolic challenges, such as overnight fasting, cold, or infections. Medium-chain acyl-CoA dehydrogenase (MCAD) deficient patients provide an extreme example. Often, these children are apparently healthy, but they run the risk of a sudden and life-threatening drop in blood glucose levels, sometimes leading to sudden infant death. Clearly, the catalytic capacity of the pathway is sufficient under non-challenging conditions, but the metabolic function is not robust.
We use a systems biology approach, combining wet-lab biochemistry and computational modelling, to understand the dynamics, control, and robustness of the mFAO pathway. Fatty acids are degraded in multiple cycles of reactions. Typically, each mFAO enzyme is involved in subsequent cycles and accepts substrates of different fatty-acid chain lengths. This substrate promiscuity gives rise to a complex network of feedback and feedforward competitive inhibition. During fasting, this may trigger a vicious cycle in which coenzyme A (CoA) esters sequester so much CoA that it becomes limiting and the flux drops. Based on a computational model, a mouse model, patient data, and targeted proteomics and metabolomics data, we unravelled this vicious cycle. The computational model can explain the difference in disease severity between individual patients, providing a basis for a personalised medicine approach. Our ongoing work is focused on the interplay between mFAO and CoA metabolism and on the role of this metabolic network in biological ageing.
Chairperson: Mathias Ziegler <firstname.lastname@example.org>, Department of Molecular Biology