Thesis (Ph.D)


Mathematical modelling of mammalian mitochondrial metabolism

Abstract

This project is in the area of “Computational Biology” or “Systems Biology”. Mathe-matical modelling is a method to study a biological system using computer-aided tools. A mathematical model of any biological system consists of a set of biochemical (or other) reactions – complete with reaction mechanisms, substrate, product, and e˙ector concentrations, enzyme activities etc., specific to the system. Such models utilize relevant experimental data as parameters and/or variables in the reaction equations. In heart, mitochondrial energy metabolism involving utilization of dietary carbo-hydrates and fats bears a crucial importance for the normal physiological function of the cardiac muscle. The mammalian liver-specific tricarboxylic acid cycle (TCA) model developed within the Cell Systems Modelling Group (CSMG) was used to study and understand the basic functional properties of a tissue-specific TCA cycle model system and to form a knowledge base. Based on this knowledge, we successfully constructed a mammalian heart-specific TCA cycle model using heart-specific enzyme kinetics data from published literature. Analysis of the heart TCA cycle model (HRTTCA) showed that it needs an input from the malate-aspartate shuttle reactions and therefore a mammalian heart-specific malate-aspartate shuttle model was built. Analysis of the malate-aspartate shuttle model revealed that in order to supply the heart TCA cycle with anaplerotic input, the cytosolic NADH/NAD+ couple must vary dynamically and therefore a glycolysis model was built. Once, all the models were studied in detail, the three were combined to form a fully extended model of heart TCA cycle. Structural analysis of the fully extended model shows that there are more than 278 elementary modes in the extended model that use di˙erent combinations of 37 reactions. Kinetic analysis of the model shows significant findings that reveal its response to changes in various enzyme activities. This project will lead to improved understanding of the responses of mammalian heart mitochondrial metabolism to perturbations such as varying cellular demand for energy (ATP) and substrates (e.g. Pyruvate (Pyr)). The invaluable addition of Malate (Mal)-Aspartate (Asp) shuttle reactions as well as glucolysis reactions has hopefully generated a more physiologically relevant model system. In future, we plan to adapt the simulation to represent the dynamics of hyperpolarized 13C labelling, using the experimental data generated with hyperpolarized 13C Pyr as a metabolic tracer. This enables non-invasive, real-time visualization of the biochemical mechanisms under normal as well as abnormal conditions.

Attached files

Authors

Ghaisas, A

Oxford Brookes departments

Faculty of Health and Life Sciences
Department of Biological and Medical Sciences

Dates

Year: 2015


© Ghaisas, A
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