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.

The capillary bed offers the largest hemodynamic resistance to the cortical blood supply

“…A pH sensitive computation of oxygen binding kinetics using the Adair et al 89 model may be an appropriate step forward. A more complex model 90 of oxygen and glucose metabolism could also shed insight into the controlling factors for CMRO.…”

Protective Mechanisms of Mitochondria and Heart Function in Diabetes

“…As a mild oxidant, H 2 O 2 reacts with cysteine (Cys) residues in proteins, a reaction modulated by the local environment (e.g., pH) (59). Multiple biochemical networks that control cell cycle, stress response, cell migration and adhesion, energy metabolism, redox balance, cell contraction, and ion channels can be influenced by H 2 O 2 (59,62,66,105).…”

“…1). These scavenging systems continuously offset ROS generation from the respiratory chain and other sites (105). The glutathione peroxidase/glutathione reductase system removes H 2 O 2 using GSH as an electron source, and the thioredoxin peroxidase/thioredoxin reductase system uses electrons from thioredoxin [Trx(SH) 2 ].…”

Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

“…To avoid misinterpretation, herein the term "redox" refers to the four main redox couples: NADH/NAD ϩ , NADPH/NADP ϩ , GSH/GSSG, and TrxSH 2 /TrxSS (21,36). Little information is available on the mechanistic interactions between hyperglycemia and FAs on redox status in T2DM myocardium, although compelling evidence about the critical role played by perturbed cellular/mitochondrial redox, compromised mitochondrial energetics and elevated ROS at the origin of contractile impairment in diabetes, has been reported (1,51).…”