Introduction: Multiple cardiac pathologies have their origin in the dysregulation of intracellular calcium, yet most computational models of cardiomyocyte calcium handling focus primarily on sarcolemmal and sarcoplasmic reticulum fluxes. Emerging evidence highlights that mitochondria and lysosomes actively shape local calcium microdomains and modulate excitation-contraction coupling and metabolic adaptation. However, their joint contribution remains poorly understood. To address this, we aim to integrate mechanistic models of mitochondrial and lysosomal calcium dynamics into established whole-cell and higher-resolution spatial cardiac electrophysiology frameworks to evaluate how these organelles influence beat-to-beat calcium cycling.
Methods: We couple lysosomal and mitochondrial calcium handling formulations to baseline ventricular myocyte models. These include lysosomal two-pore calcium channel release and mitochondrial calcium uniporter, permeability transition pore, and sodium-calcium exchanger, as well as regulation of other channels like SERCA or the sodium-potassium pump via ATP and ROS dynamics mediated by mitochondria. Existing models for lysosomal and mitochondria calcium dynamics for different animal species are adjusted to be integrated into T-World, a state-of-the-art model of human ventricular myocyte.
Results: The integrated cell models reproduce expected coupling between lysosomal, mitochondrial, and cytosolic calcium dynamics, with only a small impact on the intracellular calcium transient during normal pacing conditions. Whole-cell dynamics were comparable between the detailed sub-cellular spatial cell model and the non-spatial cell model.
Conclusions: The integrated framework provides a platform to explore how organelle dysfunction contributes to arrhythmogenesis and metabolic-electrical coupling. Further work incorporating experimental data from studies in human induced pluripotent stem cells could be valuable to refine model parameters for human specificity and to unveil how organelle-organelle interactions underpin dysfunction.