| First Author | Zhou Z | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 13 | Pages | 4735-4751 |
| PubMed ID | 29378845 | Mgi Jnum | J:262855 |
| Mgi Id | MGI:6157586 | Doi | 10.1074/jbc.M117.805069 |
| Citation | Zhou Z, et al. (2018) Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J Biol Chem 293(13):4735-4751 |
| abstractText | Estrogen receptor alpha (ERalpha) 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 ERalpha remain unclear. Because ERalpha regulates mitochondrial metabolism in other cell types, we hypothesized that ERalpha 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 ERalpha knockout (PERalphaKO) 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 ERalpha replete Min6 beta-cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ERalpha-KD cells. In contrast, ERalpha overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ERalpha binding to consensus estrogen-response element sites in the Oma1 and Chop promoters. Together, our findings suggest that ERalpha promotes beta-cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and Chop repression. |
