| First Author | Aharoni-Simon M | Year | 2016 |
| Journal | Endocrinology | Volume | 157 |
| Issue | 6 | Pages | 2270-81 |
| PubMed ID | 27070098 | Mgi Jnum | J:235176 |
| Mgi Id | MGI:5793017 | Doi | 10.1210/en.2015-1964 |
| Citation | Aharoni-Simon M, et al. (2016) Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic beta-Cells. Endocrinology 157(6):2270-81 |
| abstractText | In pancreatic beta-cells, controlling the levels of reactive oxygen species (ROS) is critical to counter oxidative stress, dysfunction and death under nutrient excess. Moreover, the fine-tuning of ROS and redox balance is important in the regulation of normal beta-cell physiology. We recently demonstrated that Bcl-2 and Bcl-xL, in addition to promoting survival, suppress beta-cell glucose metabolism and insulin secretion. Here, we tested the hypothesis that the nonapoptotic roles of endogenous Bcl-2 extend to the regulation of beta-cell ROS and redox balance. We exposed mouse islet cells and MIN6 cells to the Bcl-2/Bcl-xL antagonist Compound 6 and the Bcl-2-specific antagonist ABT-199 and evaluated ROS levels, Ca(2+) responses, respiratory control, superoxide dismutase activity and cell death. Both acute glucose stimulation and the inhibition of endogenous Bcl-2 progressively increased peroxides and stimulated superoxide dismutase activity in mouse islets. Importantly, conditional beta-cell knockout of Bcl-2 amplified glucose-induced formation of peroxides. Bcl-2 antagonism also induced a mitochondrial proton leak that was prevented by the antioxidant N-acetyl-L-cysteine and, therefore, secondary to redox changes. We further established that the proton leak was independent of uncoupling protein 2 but partly mediated by the mitochondrial permeability transition pore. Acutely, inhibitor-induced peroxides promoted Ca(2+) influx, whereas under prolonged Bcl inhibition, the elevated ROS was required for induction of beta-cell apoptosis. In conclusion, our data reveal that endogenous Bcl-2 modulates moment-to-moment ROS signaling and suppresses a redox-regulated mitochondrial proton leak in beta-cells. These noncanonical roles of Bcl-2 may be important for beta-cell function and survival under conditions of high metabolic demand. |
