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Updated: Mar 11, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial
Bernardo L de Oliveira1, Steven Niederer1
1Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
Abstract:
The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which is associated with mitochondrial dysfunction. Redox cycling, mitochondrial DNA damage and electron transport chain inhibition have been identified as potential mechanisms of toxicity. However, the relative roles of each of these proposed mechanisms are still not fully understood. The purpose of this study is to identify which of these pathways independently or in combination are responsible for doxorubicin toxicity. A state of the art mathematical model of the mitochondria including the citric acid cycle, electron transport chain and ROS production and scavenging systems was extended by incorporating a novel representation for mitochondrial DNA damage and repair. In silico experiments were performed to quantify the contributions of each of the toxicity mechanisms to mitochondrial dysfunction during the acute and chronic stages of toxicity. Simulations predict that redox cycling has a minor role in doxorubicin cardiotoxicity. Electron transport chain inhibition is the main pathway for acute toxicity for supratherapeutic doses, being lethal at mitochondrial concentrations higher than 200μM. Direct mitochondrial DNA damage is the principal pathway of chronic cardiotoxicity for therapeutic doses, leading to a progressive and irreversible long term mitochondrial dysfunction.
Insights
Doxorubicin cardiotoxicity stems from mitochondrial dysfunction. While electron transport chain inhibition causes acute toxicity, direct mitochondrial DNA damage is the main driver of chronic toxicity, leading to irreversible damage.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Doxorubicin, an anthracycline, is limited by cardiotoxicity.
- Mitochondrial dysfunction is a key feature of doxorubicin cardiotoxicity.
- Mechanisms like redox cycling, mtDNA damage, and ETC inhibition are proposed but not fully understood.
Purpose of the Study:
- To elucidate the specific roles of redox cycling, mitochondrial DNA (mtDNA) damage, and electron transport chain (ETC) inhibition in doxorubicin-induced cardiotoxicity.
- To differentiate contributions to acute versus chronic toxicity stages.
Main Methods:
- Developed a sophisticated mathematical model of mitochondrial function.
- Integrated novel representations for mtDNA damage and repair into the model.
- Conducted in silico experiments to simulate doxorubicin toxicity under various conditions.
Main Results:
- Redox cycling plays a minor role in doxorubicin cardiotoxicity.
- ETC inhibition is the primary cause of acute cardiotoxicity at supratherapeutic doses.
- Direct mtDNA damage is the principal mechanism of chronic cardiotoxicity at therapeutic doses, causing irreversible dysfunction.
Conclusions:
- Doxorubicin cardiotoxicity involves distinct mechanisms for acute and chronic effects.
- mtDNA damage is critical for long-term, irreversible mitochondrial dysfunction and cardiotoxicity.
- Mathematical modeling provides valuable insights into complex drug toxicity pathways.
