Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery

Calcium (Ca²⁺) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca²⁺, resulting in the propagation of Ca²⁺ signals through the activation of processes, such as store-operated Ca²⁺ entry (SOCE). SOCE provides a sustained Ca²⁺ entry into the cytosol; moreover, the uptake of SOCE-mediated Ca²⁺ by mitochondria can shape cytosolic Ca²⁺ signals, function as a feedback signal for the SOCE molecular machinery, and drive numerous mitochondrial processes, including adenosine triphosphate (ATP) production and distinct cell death pathways. In recent years, tremendous progress has been made in identifying the proteins mediating these signaling pathways and elucidating molecular structures, invaluable for understanding the underlying mechanisms of function. Nevertheless, there remains a disconnect between using this accumulating protein structural knowledge and the design of new research tools and therapies. In this review, we provide an overview of the Ca²⁺ signaling pathways that are involved in mediating S/ER stored Ca²⁺ release, SOCE, and mitochondrial Ca²⁺ uptake, as well as pinpoint multiple levels of crosstalk between these pathways. Further, we highlight the significant protein structures elucidated in recent years controlling these Ca²⁺ signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design.