Mitochondrial dysfunction and fibrosis in atrial fibrillation: Molecular signaling in fast-pacing organoid models

Atrial fibrillation (Afib) presents significant public health challenges due to its complex mechanisms and elevated risks of stroke and heart disease. This study employs 3D fast-paced organoid models derived from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to investigate mitochondrial dysfunction and cardiac fibrosis in Afib at the molecular level. Rapid pacing at 3 Hz for 24 h triggered a 50 % decline in peak contraction amplitude and a 55 % reduction in contraction velocity. Multi-omics profiling revealed pronounced mitochondrial injury—succinate dehydrogenase sub-units SDHA–D decreased by 35–60 % and the master regulator PGC-1α fell 48 % together with a 2.3-fold increase in cytosolic cytochrome-c. Profibrotic signalling was activated in parallel (AGTR1 was up-regulated 2.1-fold, TGF-β1 was up-regulated 2.5-fold), driving extracellular-matrix accumulation (collagen-I and α-SMA levels rose 1.9- and 2.2-fold, respectively). Public Gene Expression Omnibus (GEO) datasets further validated the clinical relevance of our model; the organoid transcriptional fingerprint correlated strongly with human atrial-tissue fibrosis signatures (R = 0.71, p < 0.001; GSE128188), highlighting its translational value. Collectively, these quantitative data demonstrate that 3-D fast-paced organoids recapitulate both the functional impairment and synchronous mitochondrial-fibrotic remodeling characteristic of early Afib. Taken together, coupling high-resolution functional metrics with multi-omics read-outs elevates cardiac-disease modelling and can accelerate the development of targeted therapies for atrial fibrillation.