A Computational Model of Oxidative Stress in a Human Ventricular Myocyte
- 1University of California, Davis
Abstract
Mitochondrial reactive oxygen species (ROS) are implicated in cardiac dysfunction, but complex dynamic interactions between ROS, intracellular calcium, and electrophysiology make it difficult to resolve mechanisms experimentally. We developed the Zukowski excitation-contraction-mitochondrial-ROS (ECM-ROS) model, a computational model that couples human ventricular electrophysiology with mitochondrial calcium handling, energetics, ROS production, and ROS dependent modulation of the ryanodine receptor, SERCA, L-type calcium current, and late sodium current. Model predictions were evaluated against independent experimental measurements of ROS induced changes in action potential duration and intracellular calcium. We then used the model to characterize ROS calcium feedback across physiological pacing rates and applied it to doxorubicin induced oxidative stress. Increasing cytosolic calcium produced nonlinear amplification of mitochondrial activity and cytosolic ROS, with greater amplification at faster pacing rates. Moderate ROS elevation initially enhanced calcium release, whereas greater oxidative stress depleted sarcoplasmic reticulum calcium stores. During simulated doxorubicin exposure, faster pacing lowered the level of oxidative stress required to produce calcium dysregulation and action potential prolongation. Mitochondrial ROS and calcium accumulation preceded detectable electrophysiological remodeling. In populations incorporating variability in ion channel expression, neither doxorubicin induced oxidative stress nor subtle pharmacological IKr block alone produced early afterdepolarizations. However, early afterdepolarizations were predicted to emerge with combined perturbations. These findings establish a computational framework for investigating bidirectional coupling among mitochondrial function, ROS, calcium handling, and human cardiac electrophysiology. The model generates testable predictions regarding the early detection of oxidative cardiac injury and the physiological conditions that increase susceptibility to arrhythmia.
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BibTeX
@misc{zukowski2026computational,
title = {{A Computational Model of Oxidative Stress in a Human Ventricular Myocyte}},
author = {H. M. Zukowski and G. Hernandez Hernandez and P.-C. Yang and C. E. Clancy},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752441},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752441v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Computational Model of Oxidative Stress in a Human Ventricular Myocyte
AU - H. M. Zukowski
AU - G. Hernandez Hernandez
AU - P.-C. Yang
AU - C. E. Clancy
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752441
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752441v1
AB - Mitochondrial reactive oxygen species (ROS) are implicated in cardiac dysfunction, but complex dynamic interactions between ROS, intracellular calcium, and electrophysiology make it difficult to resolve mechanisms experimentally. We developed the Zukowski excitation-contraction-mitochondrial-ROS (ECM-ROS) model, a computational model that couples human ventricular electrophysiology with mitochondrial calcium handling, energetics, ROS production, and ROS dependent modulation of the ryanodine receptor, SERCA, L-type calcium current, and late sodium current. Model predictions were evaluated against independent experimental measurements of ROS induced changes in action potential duration and intracellular calcium. We then used the model to characterize ROS calcium feedback across physiological pacing rates and applied it to doxorubicin induced oxidative stress. Increasing cytosolic calcium produced nonlinear amplification of mitochondrial activity and cytosolic ROS, with greater amplification at faster pacing rates. Moderate ROS elevation initially enhanced calcium release, whereas greater oxidative stress depleted sarcoplasmic reticulum calcium stores. During simulated doxorubicin exposure, faster pacing lowered the level of oxidative stress required to produce calcium dysregulation and action potential prolongation. Mitochondrial ROS and calcium accumulation preceded detectable electrophysiological remodeling. In populations incorporating variability in ion channel expression, neither doxorubicin induced oxidative stress nor subtle pharmacological IKr block alone produced early afterdepolarizations. However, early afterdepolarizations were predicted to emerge with combined perturbations. These findings establish a computational framework for investigating bidirectional coupling among mitochondrial function, ROS, calcium handling, and human cardiac electrophysiology. The model generates testable predictions regarding the early detection of oxidative cardiac injury and the physiological conditions that increase susceptibility to arrhythmia.
ER -