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The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in keeping proper ion homeostasis have pathological consequences. Accordingly, several human diseases are caused by the dysfunction of ion transporters. These include osteopetrosis, caused by the dysfunction of Cl−/H+ exchange by the lysosomal transporter ClC-7. To better understand how chloride transport affects lysosomal ion homeostasis and how its disruption impinges on lysosomal function, we developed a mathematical model of lysosomal ion homeostasis including Ca2+ dynamics. The model recapitulates known biophysical properties of ClC-7 and enables the investigation of its differential activation kinetics on lysosomal ion homeostasis. We show that normal functioning of ClC-7 supports the acidification process, is associated with increased luminal concentrations of sodium, potassium, and chloride, and leads to a higher Ca2+ uptake and release. Our model highlights the role of ClC-7 in lysosomal acidification and shows the existence of differential Ca2+ dynamics upon perturbations of Cl−/H+ exchange and its activation kinetics, with possible pathological consequences.