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Enhanced Cardiomyocyte Ca 2 + Cycling Precedes Terminal AV-Block in Mitochondrial Cardiomyopathy Mterf3 KO Mice

Abstract : Aims: Heart disease is commonly associated with altered mitochondrial function and signs of oxidative stress. This study elucidates whether primary cardiac mitochondrial dysfunction causes changes in cardiomyocyte handling of reactive oxygen species (ROS) and Ca 2+. We used a mouse model with a tissue-specific ablation of the recently discovered mtDNA transcription regulator Mterf3 (Mterf3 KO). These mice display a cardiomy-opathy with severe respiratory chain dysfunction, cardiac hypertrophy, and shortened lifespan. ROS and Ca 2+ handling were measured using fluorescent indicators and confocal microscopy. Results: Mterf3 KO hearts displayed no signs of increased ROS production or oxidative stress. Surprisingly, Mterf3 KO cardiomyocytes showed enlarged Ca 2+ transient amplitudes, faster sarcoplasmic reticulum (SR) Ca 2+ reuptake, and increased SR Ca 2+ load, resembling increased adrenergic stimulation. Furthermore, spontaneous releases of Ca 2+ were frequent in Mterf3 KO cardiomyocytes. Electrocardiography (measured with telemetry in freely moving mice) showed a terminal state in Mterf3 KO mice with gradually developing bradycardia and atrioventricular block. Conclusion: In conclusion, mitochondrial dysfunction induced by Mterf3 KO leads to a cardiomyopathy without signs of oxidative stress but with increased cardiomyocyte Ca 2+ cycling and an arrhythmogenic phenotype. These findings highlight the complex interaction between mitochondrial function, cardiomyocyte contractility, and compensatory mechanisms, such as activation of adrenergic signaling. Antioxid. Redox Signal. 15, 2455-2464.
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Soumis le : mardi 14 avril 2020 - 14:13:57
Dernière modification le : jeudi 16 avril 2020 - 01:42:20

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Daniel Andersson, J. Fauconnier, Chan Park, Shi-Jin Zhang, J Thireau, et al.. Enhanced Cardiomyocyte Ca 2 + Cycling Precedes Terminal AV-Block in Mitochondrial Cardiomyopathy Mterf3 KO Mice. Antioxidants and Redox Signaling, Mary Ann Liebert, 2011, 15 (9), pp.2455-2464. ⟨10.1089/ars.2011.3915⟩. ⟨hal-02542081⟩

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