β-cell-selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake.
| Autor: | Yeo CT; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Kropp EM; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Hansen PA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Pereckas M; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Oleson BJ; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Naatz A; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Stancill JS; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Ross KA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Gundry RL; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Corbett JA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address: jcorbett@mcw.edu. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2023 Mar; Vol. 299 (3), pp. 102994. Date of Electronic Publication: 2023 Feb 10. |
| DOI: | 10.1016/j.jbc.2023.102994 |
| Abstrakt: | Nitric oxide (NO) plays a dual role in regulating DNA damage response (DDR) signaling in pancreatic β-cells. As a genotoxic agent, NO activates two types of DDR signaling; however, when produced at micromolar levels by the inducible isoform of NO synthase, NO inhibits DDR signaling and DDR-induced apoptosis in a β-cell-selective manner. DDR signaling inhibition by NO correlates with mitochondrial oxidative metabolism inhibition and decreases in ATP and NAD + . Unlike most cell types, β-cells do not compensate for impaired mitochondrial oxidation by increasing glycolytic flux, and this metabolic inflexibility leads to a decrease in ATP and NAD + . Here, we used multiple analytical approaches to determine changes in intermediary metabolites in β-cells and non-β-cells treated with NO or complex I inhibitor rotenone. In addition to ATP and NAD + , glycolytic and tricarboxylic acid cycle intermediates as well as NADPH are significantly decreased in β-cells treated with NO or rotenone. Consistent with glucose-6-phosphate residing at the metabolic branchpoint for glycolysis and the pentose phosphate pathway (NADPH), we show that mitochondrial oxidation inhibitors limit glucose uptake in a β-cell-selective manner. Our findings indicate that the β-cell-selective inhibition of DDR signaling by NO is associated with a decrease in ATP to levels that fall significantly below the K Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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