Highlights d L-lactate triggers ER Mg 2+ release that promotes mitochondrial Mg 2+ uptake d Mg 2+ is a second messenger for metabolic circuits d Limiting Mrs2-mediated Mg 2+ uptake enhances mitochondrial bioenergetics d Inflammation-induced lactate contributes to organ failure via m Mg 2+ surge

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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.

Stromal interaction molecule−1 and −2 (STIM1/2) are endoplasmic reticulum (ER) membrane-inserted calcium (Ca 2+) sensing proteins that, together with Orai1-composed Ca 2+ channels on the plasma membrane (PM), regulate intracellular Ca 2+ levels. Recent evidence suggests that S-nitrosylation of the luminal STIM1 Cys residues inhibits store operated Ca 2+ entry (SOCE). However, the effects of thiol modifications on STIM2 during nitrosative stress and their role in regulating basal Ca 2+ levels remain unknown. Here, we demonstrate that the nitric oxide (NO) donor nitrosoglutathione (GSNO) thermodynamically stabilizes the STIM2 Ca 2+ sensing region in a Cys-specific manner. We uncovered a remarkable synergism in this stabilization involving the three luminal Cys of STIM2, which is unique to this paralog. S-nitrosylation causes structural perturbations that converge on the face of the ef-hand and sterile α motif (EF-SAM) domain, implicated in unfolding-coupled activation. In HEK293T cells, enhanced free basal cytosolic ca 2+ and SOCE mediated by STIM2 overexpression could be attenuated by GSNO or mutation of the modifiable Cys located in the luminal domain. Collectively, we identify the Cys residues within the N-terminal region of STIM2 as modifiable targets during nitrosative stress that can profoundly and cooperatively affect basal Ca 2+ and Soce regulation. Stromal-interaction molecules (STIM)s are endoplasmic reticulum (ER) membrane-inserted calcium (Ca 2+) sensors that respond to fluctuations in luminal stored Ca 2+ levels 1,2. In Homo sapiens, two STIM homologs exist: stromal interaction molecule−1 (STIM1) and −2 (STIM2) 3. Upon ER luminal Ca 2+ store depletion, human STIM1 undergoes structural changes that promote oligomerization and translocation to ER-plasma membrane (PM) junctions 4-6. At these junctions, STIM1 interacts with Orai1 proteins, which are the pore-forming subunits of Ca 2+ release activated Ca 2+ (CRAC) channels 7-9. The direct interaction of STIM1 with Orai1 facilitates gating of the CRAC channels to induce the influx of extracellular Ca 2+ into the cytosol 10-12 , otherwise known as store operated Ca 2+ entry (SOCE) 13,14. The human STIM2 paralog similarly regulates SOCE; however, STIM2 is less efficient than STIM1 in this cellular process 15-18. Instead, STIM2 is more intimately involved in the regulation of basal Ca 2+ levels 15. Interestingly, in lower order eukaryotes such as Drosophila melanogaster and Caenorhabditis elegans, only one STIM gene product has been identified 3. The highly conserved EF-hand and sterile α-motif (EF-SAM) domains of STIMs are the core luminal protein machinery that sense ER Ca 2+ changes 17,19,20 , while the cytosolic STIM-Orai1-activating-region (SOAR) coiled-coils are the highly conserved cytosolic domains that couple to and open Orai1 channels 11,12. Compared

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