Kinetic and thermodynamic regulation of mitochondrial energy metabolism and ROS production

Abstract

We have developed a thermodynamically balanced kinetic model of mitochondrial adenosine triphosphate (ATP) production and concomitant reactive oxygen species (ROS) production. The model is comprised of modules simulating the kinetics of: (1) transporters and exchangers of phosphate, adenine nucleotides, and tricarboxylic acid (TCA) cycle intermediates, (2) the catalytic steps of the TCA cycle, via which substrates are oxidized to generate the reducing equivalents NADH and FADH2, (3) the donation of electrons to the electron transport chain (ETC) by these reducing equivalents and the subsequent redox transfer through the four complexes of the ETC, (4) the pumping of protons out of the matrix coupled to the ETC, which energetically finances the maintenance of an electrical potential across the inner mitochondrial membrane (IMM), (5) the transduction of membrane potential to synthesize ATP via the F0F1-ATPase, and (6) the generation of ROS by various complexes of the ETC.