Integrating mitochondrial energetics, redox and ROS metabolic networks: A two-compartment model.

JACKELYN M. KEMBRO; MIGUEL A. AON; RAIMOND L. WINSLOW; BRIAN OROURKE; SONIA CORTASSA

BIOPHYSICAL JOURNAL

CELL PRESS

Lugar: United States; Año: 2013 vol. 104 p. 332 - 343

0006-3495

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: O2.-, hydrogen peroxide: H2O2), 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 H2O2 emission and dose-response kinetics observed after treatment with inhibitors of the GSH or Trx scavenging systems; and ii) steady and transient behavior of membrane potential 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.