Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress

Estrogen receptor alpha (ER alpha) action plays an important role in pancreatic beta-cell function and survival; thus, it is considered a potential therapeutic target for the treatment of type 2 diabetes in women. However, the mechanisms underlying the protective effects of ER alpha remain unclear. Because ER alpha regulates mitochondrial metabolism in other cell types, we hypothesized that ER alpha may act to preserve insulin secretion and promote beta-cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ER alpha knockout (PER alpha KO) mice and Min6 beta-cells in culture with Esr1 knockdown (KD). We found that Esr1-KD promoted reactive oxygen species production that associated with reduced fission/fusion dynamics and impaired mitophagy. Electron microscopy showed mitochondrial enlargement and a pro-fusion phenotype. Mitochondrial cristae and endoplasmic reticulum were dilated in Esr1-KD compared with ER alpha replete Min6 beta-cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ER alpha-KD cells. In contrast, ER alpha overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ER alpha binding to consensus estrogen-response element sites in the Oma1 and Chop promoters.