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

Nguyen, Ha Thu ; Noriega Polo, Carlos ; Wiederkehr, Andreas ; Wollheim, Claes B. LU and Park, Kyu Sang (2023) In British Journal of Pharmacology 180(21). p.2762-2776
Abstract

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... (More)

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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CDN1163, lipotoxicity, mitochondria, pancreatic β-cell, sarco/endoplasmic reticulum Ca ATPase
in
British Journal of Pharmacology
volume
180
issue
21
pages
2762 - 2776
publisher
Wiley
external identifiers
  • pmid:37277321
  • scopus:85164746748
ISSN
0007-1188
DOI
10.1111/bph.16160
language
English
LU publication?
yes
id
f40c8e81-55ef-46e5-b26d-75eec92faa9b
date added to LUP
2023-10-04 10:49:00
date last changed
2024-04-19 01:55:14
@article{f40c8e81-55ef-46e5-b26d-75eec92faa9b,
  abstract     = {{<p>Background and Purpose: High levels of Ca<sup>2+</sup> in the endoplasmic reticulum (ER), established by the sarco/endoplasmic reticulum Ca<sup>2+</sup> ATPase (SERCA), are required for protein folding and cell signalling. Excessive ER Ca<sup>2+</sup> 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 Ca<sup>2+</sup> uptake on β-cell survival and function. Experimental Approach: The effects of SERCA activator, CDN1163, on Ca<sup>2+</sup> 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 Ca<sup>2+</sup> oscillation response to glucose and potentiated it in dispersed and sorted β-cells. CDN1163 augmented the ER and mitochondrial Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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.</p>}},
  author       = {{Nguyen, Ha Thu and Noriega Polo, Carlos and Wiederkehr, Andreas and Wollheim, Claes B. and Park, Kyu Sang}},
  issn         = {{0007-1188}},
  keywords     = {{CDN1163; lipotoxicity; mitochondria; pancreatic β-cell; sarco/endoplasmic reticulum Ca ATPase}},
  language     = {{eng}},
  number       = {{21}},
  pages        = {{2762--2776}},
  publisher    = {{Wiley}},
  series       = {{British Journal of Pharmacology}},
  title        = {{CDN1163, an activator of sarco/endoplasmic reticulum Ca<sup>2+</sup> ATPase, up-regulates mitochondrial functions and protects against lipotoxicity in pancreatic β-cells}},
  url          = {{http://dx.doi.org/10.1111/bph.16160}},
  doi          = {{10.1111/bph.16160}},
  volume       = {{180}},
  year         = {{2023}},
}