CDN1163, an activator of sarco/endoplasmic reticulum Ca2+ ATPase, up-regulates mitochondrial functions and protects against lipotoxicity in pancreatic β-cells

Background and Purpose: High levels of Ca2+ in the endoplasmic reticulum (ER), established by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), are required for protein folding and cell signalling. Excessive ER Ca2+ release or decreased SERCA activity induces unfolded protein accumulation and ER stress in pancreatic ss-cells, leading to defective insulin secretion and diabetes. Here we have investigated the consequences of enhancing ER Ca2+ uptake on ss-cell survival and function. Experimental Approach: The effects of SERCA activator, CDN1163, on Ca2+ homeostasis, protein expression, mitochondrial activities, insulin secretion, and lipotoxicity have been studied in mouse pancreatic ss-cells and MIN6 cells. Key Results: CDN1163, increased insulin synthesis and exocytosis from islets. CDN1163 also increased the sensitivity of the cytosolic Ca2+ oscillation response to glucose and potentiated it in dispersed and sorted ss-cells. CDN1163 augmented the ER and mitochondrial Ca2+ content, the mitochondrial membrane potential, respiration, and ATP synthesis. CDN1163 up-regulated expression of inositol 1,4,5-trisphosphate receptors and antioxidant enzymes, and mitochondrial biogenesis, including peroxisome proliferator-activated receptor. coactivator 1a (PGC1 alpha). Overexpression of SERCA2a or 2b replicated the effects of CDN1163, while knockdown of SERCA2 abolished the stimulatory actions of CDN1163. In palmitatetreated ss-cells, CDN1163 prevented ER Ca2+ depletion, mitochondrial dysfunction, cytosolic and mitochondrial oxidative stress, defective insulin secretion, and apoptotic cell death. Conclusions and Implications: Activation of SERCA enhanced mitochondrial bioenergetics and antioxidant capability, suppressing the cytotoxic effects of palmitate. Our results suggest that targeting SERCA could be a novel therapeutic strategy to protect ss-cells from lipotoxicity and the development of Type 2 diabetes.