Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance

Nattel, S.; Qi, X.; Xiong, F.; Xiao, J.; Muthukumarasamy, K. M.; Altuntas, Y.; Zhong, Y.; Abu-Taha, I.; Bruns, F.; Tekook, M.; Kamler, M.; Villeneuve, L.; Nozza, A.; Sirois, M.; Karch, J.; Pasdois, P.; Bers, D. M.; Dobrev, D.

doi:10.1101/2025.01.29.635508

bioRxiv · 10.1101/2025.01.29.635508

Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance

Nattel, S.·Qi, X.·Xiong, F.·Xiao, J.·Muthukumarasamy, K. M.·Altuntas, Y.·Zhong, Y.·Abu-Taha, I.·Bruns, F.·Tekook, M.·Kamler, M.·Villeneuve, L.·Nozza, A.·Sirois, M.·Karch, J.·Pasdois, P.·Bers, D. M.·Dobrev, D.

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Abstract

BACKGROUNDChanges 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 RESULTSAtrial 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 Ca2+-concentration ([Ca2+]Mito), reactive oxygen species (mtROS) production, membrane potential ({Delta}{Psi}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. [Ca2+]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 Ca2+-current (ICaL)-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 Ca2+-overload, mtROS-overproduction, structural damage and abnormalities in {Delta}{Psi}m and respiration. Functionally, mitoquinone reduced AF-induced Ca2+-current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability. CONCLUSIONSMitochondria 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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Nattel, S., Qi, X., Xiong, F., Xiao, J., Muthukumarasamy, K. M., Altuntas, Y., Zhong, Y., Abu-Taha, I., Bruns, F., Tekook, M., Kamler, M., Villeneuve, L., Nozza, A., Sirois, M., Karch, J., Pasdois, P., Bers, D. M., Dobrev, D.. 2025-02-01. Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance. https://doi.org/10.1101/2025.01.29.635508

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