Metabolism and Transport

Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation

Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and scavenging are not well understood. To deepen our understanding of these processes, a computer model was developed to integrate the biophysical processes of oxidative phosphorylation and ROS generation. The model was calibrated with experimental data obtained from isolated rat heart mitochondria subjected to physiological conditions and workloads.

Enzyme and Transporter Models

Models of biochemical systems—including signaling pathways, electrophysiological systems, and cellular metabolism—are built from models of individual components such as enzymes, transporters, and ion channels. This databank of open source of component models uses a consistent notation, obeying a common set of criteria, with clear documentation and links to the primary literature. Code modules for enzymes and transporters can be downloaded in CellML or MATLAB, for use with the BISEN package.

Quantitative Assessment of Ca2+ Uptake in Isolated Cardiac Mitochondria

Cardiac mitochondria play a crucial role in buffering and shaping cytosolic Ca2+ oscillations. They also meet the beat-to-beat energy demand of the heart by Ca2+-dependent stimulation of mitochondrial dehydrogenases (e.g, pyruvate dehydrogenase, α-ketoglutarate dehydrogenase etc.). To date, a number of Ca2+ uptake pathways have been identified with the Ca2+ uniporter (CU) positioned as the major player.

Cellular Regulatory Control in Hepatocyte Metabolism

Thermodynamic-based constraints on biochemical fluxes and concentrations are applied in concert with mass balance of fluxes in glycogenesis and glycogenolysis in a model of hepatic cell metabolism. Constraint-based modeling methods that facilitate predictions of reactant concentrations, reaction potentials, and enzyme activities are introduced to identify putative regulatory and control sites in biological networks by computing the minimal control scheme necessary to switch between metabolic modes.

Mitochondrial Na+/Ca2+ Exchanger Kinetics

The paper first characterizes the kinetics of mitochondrial Ca2+uniporter, Na+/Ca2+ exchanger, and Na+/H+ exchanger (i.e., the kinetics of mitochondrial Na+– Ca2+ cycle), and then integrates these kinetic models into our existing biophysical model of mitochondrial respiratory system and oxidative phosphorylation. The integrated model is used to analyze data on the Na+ dose-dependent dynamics of mitochondrial Ca2+ to determine the stoichiometry of mitochondrial Na+/Ca2+ exchanger, as a 3Na+/Ca2+ exchanger.


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