An integrated mitochondrial ROS production and scavenging model: Implications for heart failure

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

Research output: Contribution to journalArticle

Abstract

It has been observed experimentally that cells from failing hearts exhibit elevated levels of reactive oxygen species (ROS) upon increases in energetic workload. One proposed mechanism for this behavior is mitochondrial Ca 2+ mismanagement that leads to depletion of ROS scavengers. Here, we present a computational model to test this hypothesis. Previously published models of ROS production and scavenging were combined and reparameterized to describe ROS regulation in the cellular environment. Extramitochondrial Ca 2+ pulses were applied to simulate frequency-dependent changes in cytosolic Ca2+. Model results show that decreased mitochondrial Ca2+uptake due to mitochondrial Ca2+ uniporter inhibition (simulating Ru360) or elevated cytosolic Na+, as in heart failure, leads to a decreased supply of NADH and NADPH upon increasing cellular workload. Oxidation of NADPH leads to oxidation of glutathione (GSH) and increased mitochondrial ROS levels, validating the Ca2+ mismanagement hypothesis. The model goes on to predict that the ratio of steady-state [H 2O2]m during 3Hz pacing to [H2O 2]m at rest is highly sensitive to the size of the GSH pool. The largest relative increase in [H2O2]m in response to pacing is shown to occur when the total GSH and GSSG is close to 1 mM, whereas pool sizes below 0.9 mM result in high resting H2O 2 levels, a quantitative prediction only possible with a computational model.

Original languageEnglish (US)
Pages (from-to)2832-2842
Number of pages11
JournalBiophysical journal
Volume105
Issue number12
DOIs
StatePublished - Dec 17 2013

ASJC Scopus subject areas

  • Biophysics

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