Affiliation:
1. Department of Physiology Yonsei University Wonju College of Medicine Wonju South Korea
2. Mitohormesis Research Center Yonsei University Wonju College of Medicine Wonju South Korea
3. Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland
4. Department of Cell Physiology and Metabolism University of Geneva Geneva Switzerland
5. Department of Clinical Sciences Lund University Malmö Sweden
Abstract
Background and PurposeHigh 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 ApproachThe 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 ResultsCDN1163, 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 ImplicationsActivation 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.
Funder
Ministry of Science and ICT, South Korea
Cited by
4 articles.
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