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 β-cells, leading to defective insulin secretion and diabetes. Here we have investigated the consequences of enhancing ER Ca²⁺ uptake on β-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 β-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 β-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 γ coactivator 1α (PGC1α). Overexpression of SERCA2a or 2b replicated the effects of CDN1163, while knockdown of SERCA2 abolished the stimulatory actions of CDN1163. In palmitate-treated β-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 β-cells from lipotoxicity and the development of Type 2 diabetes.