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The interconnection between the endoplasmic reticulum (ER) and mitochondria to transfer Ca into the mitochondrial matrix constitutes a major part of intracellular Ca signaling. By increasing mitochondrial Ca ([Ca]m) uptake, ER-mitochondrial crosstalk enhances energy production through accelerating mitochondrial respiration, thereby supporting cellular function and survival. ER-mitochondrial associations are established by multiprotein complexes formed, for instance, by ER-bound inositol-1,4,5-trisphosphate receptor (IP3R), mitochondriaresident voltage-dependent anion channel 1 (VDAC1) and the heat shock protein glucose-regulated protein 75 (GRP75). While IP3R and VDAC1 are Ca -permeable ion channels driving Ca flux, GRP75 is essential to maintain the physical contact between the organelles, thereby facilitating the propagation of the Ca signal into the mitochondria. Reduced GRP75 expression in tumor cells derived from bone, breast or colon has been linked to an increased susceptibility to cell death, and small molecule GRP75-inhibitory drugs are exploited as a potential therapeutic intervention. However, the relevance of GRP75 for ER-mitochondrial crosstalk in neurons or brain-derived tumor cells is largely unknown. Under physiological conditions, GRP75 inhibition seemed to activate mitochondrial stress responses such as the mitochondrial unfolded protein response or autophagy in human neuroblastoma SH-SY5Y cells. In contrast, under pathological conditions, GRP75 expression exerted different effects. For instance, in SH-SY5Y cells increased GRP75 expression prevented mitochondrial dysfunction and cell death following proteolytic stress induced by overexpression of mitochondrial ornithine transcarbamylase. In contrast, in human dopaminergic neurons, GRP75 overexpression potentiated the cytotoxic effects of the mitochondrial complex I inhibitor rotenone. Our recent study published in Cell Death & Discovery provided further insights into the role of GRP75 on mitochondrial dysfunction and cell death in a neuronal model of oxidative stress. Using immortalized hippocampal HT22 cells, we investigated the consequences of GRP75 expression on cell survival in a model of glutamate-induced oxytosis. In this study, inhibition and/ or gene silencing of GRP75 via siRNA or CRISPR/Cas9knockout fully prevented the oxidative cell death. In particular, GRP75 depletion exerted protection by preserving the mitochondrial network, preventing mitochondrial membrane depolarization and restoring the mitochondrial redox balance. Furthermore, GRP75 depletion restored Ca homeostasis by preventing [Ca]m overload and late-stage cytosolic Ca 2+ dysregulation mediated by Ca release-activated calcium channel protein 1 (ORAI1). In turn, elevating GRP75 expression increased the sensitivity of neural HT22 cells towards the glutamate challenge. Notably, neither pharmacological inhibition alone nor genetic downregulation of GRP75 had any effect on cell survival or mitochondrial function in control conditions. GRP75 gene silencing neither impaired cell proliferation, nor altered the mitochondrial network, mitochondrial ROS, or the mitochondrial membrane potential. We therefore suggest that the GRP75-dependent ER-mitochondrial coupling is a major determinant of cell fate in conditions of oxidative stress, without affecting

One protein, different cell fate: the differential outcome of depleting GRP75 during oxidative stress in neurons