Calcium transfer from the ER to other organelles for optimal signaling in Toxoplasma gondii

Ca ²⁺ signaling in cells begins with the opening of Ca ²⁺ channels in either the plasma membrane (PM) or endoplasmic reticulum (ER), leading to a sharp increase of the physiologically low (<100 nM) cytosolic Ca ²⁺ level. The temporal and spatial regulation of Ca²⁺ is crucial for the precise activation of key biological processes. In the apicomplexan parasite Toxoplasma gondii , which infects approximately one-third of the global population, Ca²⁺ signaling governs essential aspects of the parasite’s infection cycle. T. gondii relies on Ca²⁺ signals to regulate pathogenic traits, with several Ca²⁺-signaling components playing critical roles. Ca ²⁺ entry from the extracellular environment has been demonstrated in T. gondii for both, extracellular parasites, exposed to high Ca ²⁺ , and intracellular parasites, which acquire Ca²⁺ from host cells during host Ca²⁺ signaling events. Active egress, an essential step of the parasite’s infection cycle, is preceded by a large increase in cytosolic Ca ²⁺ , most likely initiated by release from intracellular stores. However, extracellular Ca ²⁺ is also necessary to reach a cytosolic Ca ²⁺ threshold required for timely egress. In this study, we investigated the mechanism of Ca²⁺ intracellular store replenishment and identified a central role for the SERCA-Ca ²⁺ -ATPase in maintaining Ca²⁺ homeostasis not only within the ER but also in other organelles. We demonstrate mitochondrial Ca ²⁺ uptake, which occurs by transfer of Ca ²⁺ from the ER, likely through membrane contact sites. Our findings suggest that the T. gondii ER plays a key role in sequestering and redistributing Ca²⁺ to intracellular organelles following Ca²⁺ influx at the PM.