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Background <p>Atrial fibrillation (AF) remains a major clinical burden because structural and metabolic remodeling, particularly mitochondrial dysfunction and fibrosis, often persists beyond rhythm control. Human-relevant models that disentangle these axes and connect them to patient data are limited.</p> Methods <p>Human atrial organoids were exposed to two AF-relevant stressors: rapid pacing (FP) and angiotensin II (AngII). We assessed mitochondrial and fibrotic remodeling by transcript/protein analyses, imaging, and contractility readouts, and benchmarked organoid responses against four public AF transcriptomic datasets (GEO: GSE128188, GSE138252, GSE222793, GSE239321). Statistical analyses used predefined contrasts versus matched controls with multiple-testing correction.</p> Results <p>FP predominantly suppressed mitochondrial biogenesis/oxidative programs and increased stress-response features, resembling signatures observed in AF with heart failure (e.g., downregulation of mitochondrial regulators and altered cytochrome c patterns). AngII elicited stronger profibrotic signaling with a mixed mitochondrial response, mirroring profiles more typical of AF without heart failure. Both stressors impaired organoid contractility. Protein and immunostaining corroborated mitochondria–fibrosis crosstalk, with changes in PGC1α and cytochrome c alongside increased extracellular matrix deposition and myofibroblast markers (COL1A1, αSMA), consistent with stimulus-specific but partially overlapping remodeling trajectories.</p> Conclusion <p>Distinct AF-relevant stressors drive divergent mitochondrial and fibrotic remodeling in human atrial organoids that recapitulate key features of patient datasets. These organoid models provide a translational platform to prioritize mitochondria-targeted and antifibrotic interventions and to inform biomarker development for residual dysfunction in AF.</p>

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Divergent mitochondrial and fibrotic signatures in atrial fibrillation: insights from organoids and GEO data

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Jihee Won,
  • Hyocheol Jung,
  • Jin Chul Kim,
  • Ji-Eun Jeong,
  • Young Il Park,
  • Biaggio Uricoli,
  • Sanghee Lee,
  • Young Hoon Son,
  • Gun-Jae Jeong

摘要

Background

Atrial fibrillation (AF) remains a major clinical burden because structural and metabolic remodeling, particularly mitochondrial dysfunction and fibrosis, often persists beyond rhythm control. Human-relevant models that disentangle these axes and connect them to patient data are limited.

Methods

Human atrial organoids were exposed to two AF-relevant stressors: rapid pacing (FP) and angiotensin II (AngII). We assessed mitochondrial and fibrotic remodeling by transcript/protein analyses, imaging, and contractility readouts, and benchmarked organoid responses against four public AF transcriptomic datasets (GEO: GSE128188, GSE138252, GSE222793, GSE239321). Statistical analyses used predefined contrasts versus matched controls with multiple-testing correction.

Results

FP predominantly suppressed mitochondrial biogenesis/oxidative programs and increased stress-response features, resembling signatures observed in AF with heart failure (e.g., downregulation of mitochondrial regulators and altered cytochrome c patterns). AngII elicited stronger profibrotic signaling with a mixed mitochondrial response, mirroring profiles more typical of AF without heart failure. Both stressors impaired organoid contractility. Protein and immunostaining corroborated mitochondria–fibrosis crosstalk, with changes in PGC1α and cytochrome c alongside increased extracellular matrix deposition and myofibroblast markers (COL1A1, αSMA), consistent with stimulus-specific but partially overlapping remodeling trajectories.

Conclusion

Distinct AF-relevant stressors drive divergent mitochondrial and fibrotic remodeling in human atrial organoids that recapitulate key features of patient datasets. These organoid models provide a translational platform to prioritize mitochondria-targeted and antifibrotic interventions and to inform biomarker development for residual dysfunction in AF.