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Abstract Background Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear. Results Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells. Conclusions Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death.

Background: Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear. Results: Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells. Conclusions: Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, Endoplasmic Reticulum (ER) is an interconnected membranous organelle and plays important roles in protein synthesis and lipid metabolism. We have previously demonstrated that TMCO1 is an ER Ca2+ channel actively preventing ER Ca2+ overloading. Recently, we also found that TMCO1 deficiency in mouse granulosa cells (GCs) caused abnormal Ca2+ signaling, ER stress and enhanced reactive oxygen species (ROS). In this study, we further examined the roles of TMCO1 in lipid metabolism and mitochondrial functions. Intriguingly, we found that TMCO1 deletion reduced the number of lipid droplets (LDs) and the content of triglyceride (TG), which was due to ER stress associated degradation (ERAD) of the important enzyme in catalyzing TG synthesis, diacylglycerol acyltransferase 2 (DGAT2). Hypofunction in transforming non-esterification fatty acid (NEFA) to TG caused NEFA deposit, a potential risk of mitochondrial dysfunction. Furthermore, in TMCO1 deficient cells, mitochondria volume decreased and inefficient oxidative phosphorylation was detected, which underlined enhanced mitophagy and impaired mitochondrial functions. Taken these data together, we for the first time revealed the role of TMCO1 in regulating lipid-metabolism and mitochondrial function. This study may provide new insights into understanding TMCO1 defect syndrome. • Cellular LDs significantly reduced upon TMCO1 deletion. • ER stress caused by TMCO1 deletion resulted in DGAT2 degradation, which led to the reduction of LDs and the increase of FAs. • Mitophagy augmented and mitochondria volume decreased in TMCO1 deficient cells. • Mitochondrial morphology and function were impaired due to the elevated FAs, a potential risk of mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]