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

Zhenqi Zhou, Vicent Ribas, Prashant Rajbhandari, Brian G. Drew, Timothy M. Moore, Amy H. Fluitt, Britany R. Reddish, Kate A. Whitney, Senta Georgia, Laurent Vergnes, Karen Reue, Marc Liesa, Orian Shirihai, Alexander M. Van Der Bliek, Nai Wen Chi, Sushil K. Mahata, Joseph P. Tiano, Sylvia C. Hewitt, Peter Tontonoz, Kenneth S. KorachFranck Mauvais-Jarvis, Andrea L. Hevener

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Estrogen receptor (ER) action plays an important role in pancreatic -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 remain unclear. Because ER regulates mitochondrial metabolism in other cell types, we hypothesized that ER may act to preserve insulin secretion and promote -cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ER knockout (PERKO) mice and Min6 -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 replete Min6 -cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ER-KD cells. In contrast, ER overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ER binding to consensus estrogen-response element sites in the Oma1 and Chop promoters. Together, our findings suggest that ER promotes -cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and Chop repression.

Original languageEnglish
Pages (from-to)4735-4751
Number of pages17
JournalJournal of Biological Chemistry
Volume293
Issue number13
DOIs
StatePublished - 30 Mar 2018
Externally publishedYes

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