title: Integrating mitochondrial energetics, redox and ROS metabolic networks: a two-compartment model.
abstract: To understand the mechanisms involved in the control and regulation of mitochondrial reactive oxygen species (ROS) levels, a two-compartment computational mitochondrial energetic-redox (ME-R) model accounting for energetic, redox, and ROS metabolisms is presented. The ME-R model incorporates four main redox couples (NADH/NAD(+), NADPH/NADP(+), GSH/GSSG, Trx(SH)(2)/TrxSS). Scavenging systems-glutathione, thioredoxin, superoxide dismutase, catalase-are distributed in mitochondrial matrix and extra-matrix compartments, and transport between compartments of ROS species (superoxide: O(2)(⋅-), hydrogen peroxide: H(2)O(2)), and GSH is also taken into account. Model simulations are compared with experimental data obtained from isolated heart mitochondria. The ME-R model is able to simulate: i), the shape and order of magnitude of H(2)O(2) emission and dose-response kinetics observed after treatment with inhibitors of the GSH or Trx scavenging systems and ii), steady and transient behavior of ΔΨ(m) and NADH after single or repetitive pulses of substrate- or uncoupler-elicited energetic-redox transitions. The dynamics of the redox environment in both compartments is analyzed with the model following substrate addition. The ME-R model represents a useful computational tool for exploring ROS dynamics, the role of compartmentation in the modulation of the redox environment, and how redox regulation participates in the control of mitochondrial function.
authors: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore Maryland, USA.
authors: Jackelyn M
authors: JM
authors: Kembro
authors: Miguel A
authors: MA
authors: Aon
authors: Raimond L
authors: RL
authors: Winslow
authors: Brian
authors: B
authors: O'Rourke
authors: Sonia
authors: S
authors: Cortassa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002451:Cell Compartmentation; D019069:Cell Respiration; D003198:Computer Simulation; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D053858:Metabolic Networks and Pathways; D008929:Mitochondria, Heart / Q000378:metabolism*; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015203:Reproducibility of Results; D013379:Substrate Specificity; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D009243:NAD; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D005978:Glutathione