MITODYN: An Open Source Software for Quantitative Modeling of Mitochondrial and Cellular Energy Metabolic Flux Dynamics in Health and Disease.

Mitochondrial respiratory chain (RC) transforms the reductive power of NADH or FADH2 oxidation into a proton gradient between the matrix and cytosolic sides of the inner mitochondrial membrane, that ATP synthase uses to generate ATP. This process constitutes a bridge between carbohydrates' central metabolism and ATP-consuming cellular functions. Moreover, the RC is responsible for a large part of reactive oxygen species (ROS) generation that play signaling and oxidizing roles in cells. Mathematical methods and computational analysis are required to understand and predict the possible behavior of this metabolic system. Here we propose a software tool that helps to analyze individual steps of respiratory electron transport in their dynamics, thus deepening understanding of the mechanism of energy transformation and ROS generation in the RC. This software's core is a kinetic model of the RC represented by a system of ordinary differential equations (ODEs). This model enables the analysis of complex dynamic behavior of the RC, including multistationarity and oscillations. The proposed RC modeling method can be applied to study respiration and ROS generation in various organisms and naturally extended to explore carbohydrates' metabolism and linked metabolic processes.

Unveiling a key role of oxaloacetate-glutamate interaction in regulation of respiration and ROS generation in nonsynaptic brain mitochondria using a kinetic model.

Glutamate plays diverse roles in neuronal cells, affecting cell energetics and reactive oxygen species (ROS) generation. These roles are especially vital for neuronal cells, which deal with high amounts of glutamate as a neurotransmitter. Our analysis explored neuronal glutamate implication in cellular energy metabolism and ROS generation, using a kinetic model that simulates electron transport details in respiratory complexes, linked ROS generation and metabolic reactions. The analysis focused on the fact that glutamate attenuates complex II inhibition by oxaloacetate, stimulating the latter's transformation into aspartate. Such a mechanism of complex II activation by glutamate could cause almost complete reduction of ubiquinone and deficiency of oxidized form (Q), which closes the main stream of electron transport and opens a way to massive ROS generating transfer in complex III from semiquinone radicals to molecular oxygen. In this way, under low workload, glutamate triggers the respiratory chain (RC) into a different steady state characterized by high ROS generation rate. The observed stepwise dependence of ROS generation on glutamate concentration experimentally validated this prediction. However, glutamate's attenuation of oxaloacetate's inhibition accelerates electron transport under high workload. Glutamate-oxaloacetate interaction in complex II regulation underlies the observed effects of uncouplers and inhibitors and acceleration of Ca2+ uptake. Thus, this theoretical analysis uncovered the previously unknown roles of oxaloacetate as a regulator of ROS generation and glutamate as a modifier of this regulation. The model predicted that this mechanism of complex II activation by glutamate might be operative in situ and responsible for excitotoxicity. Spatial-time gradients of synthesized hydrogen peroxide concentration, calculated in the reaction-diffusion model with convection under a non-uniform local approximation of nervous tissue, have shown that overproduction of H2O2 in a cell causes excess of its level in neighbor cells.