Abstract
The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.
Highlights
Could show that this is achieved by an endoplasmic reticulum (ER) Ca leak that is directed towards mitochondria Knock-Down by Sigma-1 Receptor (S1R)
To clarify the mechanism of how S1R is facilitating the increase of mitochondrial bioenergetics during early ER stress, we investigated mitochondria-associated ER membranes (MAMs)
[9,11], we have attempted to clarify the involvement of rodegeneration and cancer [9,11], we have attempted to clarify the involvement of S1R in in mitochondrial bioenergetics during the early phases of
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Metabolites 2021, 11, 422 increased during the early stages of ER stress to exchange Ca2+ more efficiently and to promote mitochondrial ATP production [5]. Using SH-SY5Y neuroblastoma cells, we have been able to demonstrate that is indispensable for increased mitochondrial during early ER stress. Sigma-1 Receptor Is Essential for Increased Mitochondrial ATP Level during Early ER. Sigma-1 Receptor Is Essential for Increased Mitochondrial ATP Level during Early ER Stress. Mitochondrial ATP was maximally increased after 2 h and slightly after 8 h of h of tunicamycin treatment of control cells (Figure 2a). Basal mitochondrial ATP levels tunicamycin treatment of control cells (Figure 2a). Basal mitochondrial ATP levels remained remained unaffected in cells treated with siRNA against S1R (Figure 2a,b). Since the NADH redox index represents NADH/NAD+ ratio, the decline of this ratio, Iscombined increasedHyperpolarisation mitochondrial membrane and
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