Resistance to atrial fibrillation domestication and mitochondrial dysfunction in sheep: a potential key role of the TCA cycle and mitochondrial redox state

@article{caluori2026resistance,
  title = {{Resistance to atrial fibrillation domestication and mitochondrial dysfunction in sheep: a potential key role of the TCA cycle and mitochondrial redox state}},
  author = {Guido Caluori and Stanley Nattel and Benoît Pinson and Patrice Naud and Bertrand Beauvoit and Stéphane Claverol and Fanny Vaillant and Sabine Charron and Florent Guilloteau and Virginie Loyer and Marion Constantin and Miruna Popa and Andrei Belykh and Anaïs Rogowsky and Andreas Haeberlin and Sylvain Ploux and Hassan Adam Mahamat and Rémi Dubois and Bastien Guillot and Philipp Krisai and Tsukasa Kamakura and Olivier Bernus and Pierre Jaïs and Pierre Dos Santos and Philippe Pasdois},
  journal = {Redox Biology},
  year = {2026},
  month = oct,
  doi = {10.1016/j.redox.2026.104391},
  url = {https://doi.org/10.1016/j.redox.2026.104391},
  note = {CC BY},
}

TY  - JOUR
TI  - Resistance to atrial fibrillation domestication and mitochondrial dysfunction in sheep: a potential key role of the TCA cycle and mitochondrial redox state
AU  - Guido Caluori
AU  - Stanley Nattel
AU  - Benoît Pinson
AU  - Patrice Naud
AU  - Bertrand Beauvoit
AU  - Stéphane Claverol
AU  - Fanny Vaillant
AU  - Sabine Charron
AU  - Florent Guilloteau
AU  - Virginie Loyer
AU  - Marion Constantin
AU  - Miruna Popa
AU  - Andrei Belykh
AU  - Anaïs Rogowsky
AU  - Andreas Haeberlin
AU  - Sylvain Ploux
AU  - Hassan Adam Mahamat
AU  - Rémi Dubois
AU  - Bastien Guillot
AU  - Philipp Krisai
AU  - Tsukasa Kamakura
AU  - Olivier Bernus
AU  - Pierre Jaïs
AU  - Pierre Dos Santos
AU  - Philippe Pasdois
PY  - 2026
DA  - 2026/10/30
JO  - Redox Biology
DO  - 10.1016/j.redox.2026.104391
UR  - https://doi.org/10.1016/j.redox.2026.104391
AB  - Background: Atrial fibrillation (AF) often progresses from paroxysmal to more stable forms. It is well-recognized that patients vary in their AF progression, but the underlying mechanisms remain unclear. This work, performed in a sheep AF-model, aimed to identify atrial redox and energetic status differences between animals developing stable AF (AF-S) versus those resistant to AF-stabilization (AF-R). Methods: AF was induced with bursts of atrial tachystimulation, maintained whenever sinus rhythm resumed, and monitored with telemetry. Electrophysiological and structural remodeling were assessed via contact mapping, and histology, respectively. Proteomic, metabolomic, enzymatic, and bioenergetic remodeling were evaluated using left atrial appendage (LAA) tissues and isolated LAA mitochondria. Healthy rats were used to investigate whether a metabolic challenge stabilizes electrically induced AF episodes. Results: AF-S (N = 12) sheep developed stable AF after 13 days on average, whereas AF-R (N = 8) sheep failed to develop self-sustained AF despite 120 days of tachypacing. Contact mapping and histological analysis revealed that AF-S animals presented reduced atrial conduction velocity, and increased endomysial fibrosis. Metabolic analysis showed significant differences in tricarboxylic acid cycle (TCA) enzymes activities and a 45% succinate content increase in AF-S LAA versus AF-R. AF-S mitochondria showed abnormal succinate oxidation, decreased ATP synthesis rate, and increased ROS emission. The ratios of ATP/ADP, NAD + /NADH, and Complex I/II activities were disturbed in AF-S compared to AF-R. Calculated mitochondrial NAD + /NADH ratios suggest an oxidized state in AF-S while AF-R showed a reduced state. Exogenous succinate was metabolized when incubated with rat atrial cardiomyocytes, while intravenous succinate injection stabilized atrial arrhythmias electrically-induced in vivo . Conclusions: AF-S sheep showed TCA cycle, energetic and redox adaptations compared to AF-R. In this animal model, TCA cycle remodeling and associated redox and energetic responses determined the resistance to AF domestication, with potential relevance to identify new mechanistic determinants of AF progression in humans.
SN  - 2213-2317
ER  -