Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance
Rattachement africain : ca, de, us, fr. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
ABSTRACT BACKGROUND Changes in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model. METHODS AND RESULTS Atrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca 2+ -concentration ([Ca 2+ ] Mito ), reactive oxygen species (mtROS) production, membrane potential (ΔΨ m ), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca 2+ ] Mito and mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca 2+ -current (I CaL )-downregulation in canine and human AF ACMs in vitro . Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca 2+ -overload, mtROS-overproduction, structural damage and abnormalities in ΔΨ m and respiration. Functionally, mitoquinone reduced AF-induced Ca 2+ -current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability. CONCLUSIONS Mitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance
- Date Crossref
- 01/02/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Montreal Heart Institute Department of Medicine and Research Center pays non établi dans la noticeOrganisme public
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Université de Montréal pays non établi dans la noticeUniversité ou école supérieure
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West German Heart and Vascular Center Essen pays non établi dans la noticeÉtablissement de santé
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University of Duisburg-Essen pays non établi dans la noticeUniversité ou école supérieure
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Baylor College of Medicine Department of Integrative Physiology pays non établi dans la noticeUniversité ou école supérieure
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Université de Bordeaux pays non établi dans la noticeUniversité ou école supérieure
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Electrophysiology and Heart Modeling Institute pays non établi dans la noticeStructure de recherche
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University of California Department of Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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University Duisburg-Essen Institute of Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Université Bordeaux IHU LIRYC and Fondation Bordeaux pays non établi dans la noticeUniversité ou école supérieure
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University Bordeaux pays non établi dans la noticeUniversité ou école supérieure
Department of Medicine and Research Center — Montreal Heart Institute, Université de Montréal et West German Heart and Vascular Center Essen, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.