β-cell-selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake.
β-cell-selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake.
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DOI：
10.1016/j.jbc.2023.102994
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发表时间：
2023-03
影响因子：
4.8
通讯作者：
Corbett, John A.
中科院分区：
文献类型：
--
作者：
Yeo, Chay Teng;Kropp, Erin M.;Hansen, Polly A.;Pereckas, Michael;Oleson, Bryndon J.;Naatz, Aaron;Stancill, Jennifer S.;Ross, Kyle A.;Gundry, Rebekah L.;Corbett, John A.
一氧化氮（NO）在调节胰腺β细胞DNA损伤反应（DDR）信号传导中起双重作用。作为一种基因毒性物质，NO激活两种类型的DDR信号；然而，当NO合成酶的诱导异构体以微摩尔水平产生时，NO以β细胞选择性的方式抑制DDR信号传导和DDR诱导的细胞凋亡。NO对DDR信号的抑制与线粒体氧化代谢抑制、ATP和NAD+的减少有关。与大多数细胞类型不同，β细胞不能通过增加糖酵解通量来补偿线粒体氧化受损，这种代谢不灵活性导致ATP和NAD+的减少。在这里，我们使用多种分析方法来确定在NO或复合物I抑制剂鱼藤酮处理下β细胞和非β细胞中中间代谢物的变化。除ATP和NAD+外，NO或鱼藤酮处理的β细胞糖酵解和三羧酸循环中间体以及NADPH均显著降低。与葡萄糖-6-磷酸存在于糖酵解和戊糖磷酸途径（NADPH）的代谢分支点一致，我们表明线粒体氧化抑制剂以β细胞选择性的方式限制葡萄糖摄取。我们的研究结果表明，一氧化氮对β细胞DDR信号的选择性抑制与ATP水平的降低有关，ATP水平明显低于葡萄糖激酶（葡萄糖摄取）的KM水平，并表明这种作用使β细胞处于一种休眠状态，在这种状态下，它处于代谢惰性状态，直到一氧化氮被去除，代谢功能才能恢复。
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 KM for ATP of glucokinase (glucose uptake) and suggest that this action places the β-cell in a state of suspended animation where it is metabolically inert until NO is removed, and metabolic function can be restored.
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