Calcium efflux from the endoplasmic reticulum leads to β-cell death

T Hara, J Mahadevan, K Kanekura, M Hara, S Lu… - …, 2014 - academic.oup.com
T Hara, J Mahadevan, K Kanekura, M Hara, S Lu, F Urano
Endocrinology, 2014academic.oup.com
It has been established that intracellular calcium homeostasis is critical for survival and
function of pancreatic β-cells. However, the role of endoplasmic reticulum (ER) calcium
homeostasis in β-cell survival and death is not clear. Here we show that ER calcium
depletion plays a critical role in β-cell death. Various pathological conditions associated with
β-cell death, including ER stress, oxidative stress, palmitate, and chronic high glucose,
decreased ER calcium levels and sarcoendoplasmic reticulum Ca2+-ATPase 2b …
It has been established that intracellular calcium homeostasis is critical for survival and function of pancreatic β-cells. However, the role of endoplasmic reticulum (ER) calcium homeostasis in β-cell survival and death is not clear. Here we show that ER calcium depletion plays a critical role in β-cell death. Various pathological conditions associated with β-cell death, including ER stress, oxidative stress, palmitate, and chronic high glucose, decreased ER calcium levels and sarcoendoplasmic reticulum Ca2+-ATPase 2b expression, leading to β-cell death. Ectopic expression of mutant insulin and genetic ablation of WFS1, a causative gene for Wolfram syndrome, also decreased ER calcium levels and induced β-cell death. Hyperactivation of calpain-2, a calcium-dependent proapoptotic protease, was detected in β-cells undergoing ER calcium depletion. Ectopic expression of sarcoendoplasmic reticulum Ca2+-ATPase 2b, as well as pioglitazone and rapamycin treatment, could prevent calcium efflux from the ER and mitigate β-cell death under various stress conditions. Our results reveal a critical role of ER calcium depletion in β-cell death and indicate that identification of pathways and chemical compounds restoring ER calcium levels will lead to novel therapeutic modalities and pharmacological interventions for type 1 and type 2 diabetes and other ER-related diseases including Wolfram syndrome.
Oxford University Press