A Computational model of reactive oxygen species and redox balance in cardiac mitochondria

Laura D. Gauthier, Joseph L. Greenstein, Sonia Cortassa, Brian O'Rourke, Raimond L. Winslow

Research output: Contribution to journalArticlepeer-review

Abstract

Elevated levels of reactive oxygen species (ROS) play a critical role in cardiac myocyte signaling in both healthy and diseased cells. Mitochondria represent the predominant cellular source of ROS, specifically the activity of complexes I and III. The model presented here explores the modulation of electron transport chain ROS production for state 3 and state 4 respiration and the role of substrates and respiratory inhibitors. Model simulations show that ROS production from complex III increases exponentially with membrane potential (ΔΨm) when in state 4. Complex I ROS release in the model can occur in the presence of NADH and succinate (reverse electron flow), leading to a highly reduced ubiquinone pool, displaying the highest ROS production flux in state 4. In the presence of ample ROS scavenging, total ROS production is moderate in state 3 and increases substantially under state 4 conditions. The ROS production model was extended by combining it with a minimal model of ROS scavenging. When the mitochondrial redox status was oxidized by increasing the proton permeability of the inner mitochondrial membrane, simulations with the combined model show that ROS levels initially decline as production drops off with decreasing ΔΨm and then increase as scavenging capacity is exhausted. Hence, this mechanistic model of ROS production demonstrates how ROS levels are controlled by mitochondrial redox balance.

Original languageEnglish (US)
Pages (from-to)1045-1056
Number of pages12
JournalBiophysical journal
Volume105
Issue number4
DOIs
StatePublished - Aug 20 2013

ASJC Scopus subject areas

  • Biophysics

Fingerprint

Dive into the research topics of 'A Computational model of reactive oxygen species and redox balance in cardiac mitochondria'. Together they form a unique fingerprint.

Cite this