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Updated: Feb 15, 2026
06:05
An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
4.5K
Dronedarone-Induced Cardiac Mitochondrial Dysfunction and Its Mitigation by Epoxyeicosatrienoic Acids
Aneesh Karkhanis1, Jacqueline Wen Hui Leow1, Thilo Hagen2
1Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543.
Summary
Dronedarone causes cardiac mitochondrial injury by disrupting energy production and metabolism, unlike amiodarone. This mitochondrial damage may explain dronedarone
Area of Science:
- Cardiology
- Mitochondrial Biology
- Pharmacology
Background:
- Dronedarone and amiodarone are antiarrhythmic drugs with similar structures but differing cardiac safety profiles.
- Dronedarone is associated with worsening cardiac adverse effects, while amiodarone lacks such cardiac adversity.
- Previous studies indicated dronedarone's potential for liver mitochondrial toxicity.
Purpose of the Study:
- To investigate the comparative potential of dronedarone and amiodarone in inducing mitochondrial injury within cardiomyocytes.
- To elucidate the specific mechanisms by which these drugs impact cardiomyocyte mitochondrial function.
- To assess the role of drug metabolites in mediating mitochondrial toxicity.
Main Methods:
- H9c2 cardiomyocytes were treated with dronedarone, amiodarone, and their metabolites (NDBD, NDEA).
- Assays included intracellular ATP content, mitochondrial membrane potential (Δψm), carnitine palmitoyltransferase I (CPT1) activity, and arachidonic acid (AA) metabolism.
- Isolated rat heart mitochondria were used to study electron transport chain (ETC) activities and uncoupling.
Main Results:
- Both dronedarone and amiodarone, along with their metabolites, significantly decreased intracellular ATP content and dissipated Δψm.
- Dronedarone, NDBD, and NDEA showed weak inhibition of CPT1, while amiodarone had negligible effect.
- Dronedarone potently inhibited AA metabolism, and both drugs inhibited ETC activity; exogenous EETs ameliorated cytotoxicity.
Conclusions:
- Dronedarone induces cardiomyocyte mitochondrial injury by disrupting Δψm, inhibiting mitochondrial complex I, uncoupling ETC, and dysregulating AA-EET metabolism.
- These findings suggest that cardiac mitochondrial injury is a potential contributor to dronedarone-induced cardiac failure exacerbation.
- The study highlights key mechanistic differences in the cardiac mitochondrial toxicity between dronedarone and amiodarone.
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