Article Impact Level: HIGH Data Quality: STRONG Summary of Circulation Research https://doi.org/10.1161/CIRCRESAHA.124.325658 Dr. Julius Ryan D. Pronto et al.
Points
- Atrial fibrillation involves disrupted calcium signaling between heart muscle cell mitochondria and the sarcoplasmic reticulum, impacting energy production.
- Mitochondrial calcium uptake is reduced in atrial fibrillation, limiting the regeneration of key energy carriers necessary for heart function.
- High-resolution microscopy revealed a loss of spatial proximity between the sarcoplasmic reticulum and mitochondria in diseased atrial fibrillation cells.
- This disrupted coupling contributes to electrical instability and an imbalance in the heart muscle’s energy supply, promoting irregular heartbeats.
- The study suggests that enhancing mitochondrial calcium uptake could be a potential therapeutic strategy for treating atrial fibrillation.
Summary
This study investigated the role of mitochondrial calcium (Ca2+) handling and cellular redox state in atrial fibrillation (AF) using cardiac myocytes isolated from patient-derived right atrial biopsies. The researchers subjected these myocytes to workload transitions and β-adrenergic stimulation while monitoring NAD(P)H/FAD autofluorescence, cytosolic, and mitochondrial [Ca2+]. Findings revealed that mitochondrial Ca2+ accumulation during increased workload was blunted in AF, which was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. This suggests a significant disruption in cardiac energetics during AF.
Nanoscale imaging, including electron microscopy, tomography, and stimulated emission depletion microscopy, demonstrated spatial disorganization of the sarcoplasmic reticulum and mitochondria in AF myocytes. This disorganization was linked to microtubule destabilization. This observation was further corroborated in human induced pluripotent stem cell (hiPSC)–derived cardiac myocytes, where treatment with the microtubule destabilizer nocodazole displaced mitochondria and increased proarrhythmic Ca2+ sparks. These arrhythmogenic events were notably rescued by MitoTEMPO, indicating a potential therapeutic target related to mitochondrial function and structural integrity.
The study further explored the therapeutic potential of ezetimibe, a mitochondrial Ca2+ uptake enhancer. Ezetimibe effectively reduced the occurrence of arrhythmogenic Ca2+ release events in both AF myocytes and nocodazole-treated hiPSC-derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients receiving ezetimibe treatment. These findings strongly suggest that disrupted calcium signaling and spatial coupling between the sarcoplasmic reticulum and mitochondria are critical mechanisms underlying AF, with microtubule integrity and mitochondrial Ca2+ uptake representing promising targets for novel AF therapies.
Link to the article: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.124.325658
References
Pronto, J. R. D., Mason, F. E., Rog-Zielinska, E. A., Fakuade, F. E., Bülow, D., Tóth, M., Machwart, K., Brandes, P., Wiedmann, F., Kohlhaas, M., Nickel, A., Wolf, M., Mustroph, J., Vu, K.-C., Brandenburg, S., Do, T. Q., Siedler, P. J., Ritzenhoff, K., Xue, Z., … Voigt, N. (2025). Impaired atrial mitochondrial calcium handling in patients with atrial fibrillation. Circulation Research, 137(11), 1333–1352. https://doi.org/10.1161/CIRCRESAHA.124.325658
