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A biophysically based mathematical model for the kinetics of mitochondrial Na+-Ca2+ antiporter.

ABSTRACT: Sodium-calcium antiporter is the primary efflux pathway for Ca(2+) in respiring mitochondria, and hence plays an important role in mitochondrial Ca(2+) homeostasis. Although experimental data on the kinetics of Na(+)-Ca(2+) antiporter are available, the structure and composition of its functional unit and kinetic mechanisms associated with the Na(+)-Ca(2+) exchange (including the stoichiometry) remains unclear. To gain a quantitative understanding of mitochondrial Ca(2+) homeostasis, a biophysical model of Na(+)-Ca(2+) antiporter is introduced that is thermodynamically balanced and satisfactorily describes a number of independent data sets under a variety of experimental conditions. The model is based on a multistate catalytic binding mechanism for carrier-mediated facilitated transport and Eyring's free energy barrier theory for interconversion and electrodiffusion. The model predicts the activating effect of membrane potential on the antiporter function for a 3Na(+):1Ca(2+) electrogenic exchange as well as the inhibitory effects of both high and low pH seen experimentally. The model is useful for further development of mechanistic integrated models of mitochondrial Ca(2+) handling and bioenergetics to understand the mechanisms by which Ca(2+) plays a role in mitochondrial signaling pathways and energy metabolism.

SUBMITTER: Pradhan RK

PROVIDER: S-EPMC2808480 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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A biophysically based mathematical model for the kinetics of mitochondrial Na+-Ca2+ antiporter.

Pradhan Ranjan K RK Beard Daniel A DA Dash Ranjan K RK

Biophysical journal 20100101 2

Sodium-calcium antiporter is the primary efflux pathway for Ca(2+) in respiring mitochondria, and hence plays an important role in mitochondrial Ca(2+) homeostasis. Although experimental data on the kinetics of Na(+)-Ca(2+) antiporter are available, the structure and composition of its functional unit and kinetic mechanisms associated with the Na(+)-Ca(2+) exchange (including the stoichiometry) remains unclear. To gain a quantitative understanding of mitochondrial Ca(2+) homeostasis, a biophysic ...[more]

PMID: 20338843

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Project description:Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) using NADPH as the reducing cofactor, and thereby maintains a constant GSH level in the system. GSH scavenges superoxide (O2(*-)) and hydroxyl radicals (OH) nonenzymatically or by serving as an electron donor to several enzymes involved in reactive oxygen species (ROS) detoxification. In either case, GSH oxidizes to GSSG and is subsequently regenerated by the catalytic action of GR. Although the GR kinetic mechanism has been extensively studied under various experimental conditions with variable substrates and products, the catalytic mechanism has not been studied in terms of a mechanistic model that accounts for the effects of the substrates and products on the reaction kinetics. The aim of this study is therefore to develop a comprehensive mathematical model for the catalytic mechanism of GR. We use available experimental data on GR kinetics from various species/sources to develop the mathematical model and estimate the associated model parameters. The model simulations are consistent with the experimental observation that GR operates via both ping-pong and sequential branching mechanisms based on relevant concentrations of its reaction substrate GSSG. Furthermore, we show the observed pH-dependent substrate inhibition of GR activity by GSSG and bimodal behavior of GR activity with pH. The model presents a unique opportunity to understand the effects of products on the kinetics of GR. The model simulations show that under physiological conditions, where both substrates and products are present, the flux distribution depends on the concentrations of both GSSG and NADP(+), with ping-pong flux operating at low levels and sequential flux dominating at higher levels. The kinetic model of GR may serve as a key module for the development of integrated models for ROS-scavenging systems to understand protection of cells under normal and oxidative stress conditions.

Dataset Information

A biophysically based mathematical model for the kinetics of mitochondrial Na+-Ca2+ antiporter.

Publications

A biophysically based mathematical model for the kinetics of mitochondrial Na+-Ca2+ antiporter.

Similar Datasets

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