Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Mol Cell Biol. 2019 Aug 27;39(18). doi: 10.1128/MCB.00153-19. Print 2019 Sep 15.
In this report, we show that nitric oxide suppresses DNA damage response (DDR) signaling in the pancreatic β-cell line INS 832/13 and rat islets by inhibiting intermediary metabolism. Nitric oxide is known to inhibit complex IV of the electron transport chain and aconitase of the Krebs cycle. Non-β cells compensate by increasing glycolytic metabolism to maintain ATP levels; however, β cells lack this metabolic flexibility, resulting in a nitric oxide-dependent decrease in ATP and NAD Like nitric oxide, mitochondrial toxins inhibit DDR signaling in β cells by a mechanism that is associated with a decrease in ATP. Non-β cells compensate for the effects of mitochondrial toxins with an adaptive shift to glycolytic ATP generation that allows for DDR signaling. Forcing non-β cells to derive ATP via mitochondrial respiration (replacing glucose with galactose in the medium) and glucose deprivation sensitizes these cells to nitric oxide-mediated inhibition of DDR signaling. These findings indicate that metabolic flexibility is necessary to maintain DDR signaling under conditions in which mitochondrial oxidative metabolism is inhibited and support the inhibition of oxidative metabolism (decreased ATP) as one protective mechanism by which nitric oxide attenuates DDR-dependent β-cell apoptosis.
在本报告中，我们表明一氧化氮通过抑制中间代谢来抑制胰岛β细胞系 INS 832/13 和大鼠胰岛中的 DNA 损伤反应 (DDR) 信号。众所周知，一氧化氮抑制电子传递链的复合物 IV 和三羧酸循环中的顺乌头酸酶。非β细胞通过增加糖酵解代谢来代偿以维持 ATP 水平；然而，β细胞缺乏这种代谢灵活性，导致依赖于一氧化氮的 ATP 和 NAD 减少。与一氧化氮一样，线粒体毒素通过与 ATP 减少相关的机制抑制β细胞中的 DDR 信号。非β细胞通过适应性转向糖酵解 ATP 生成来代偿线粒体毒素的作用，从而允许 DDR 信号。通过迫使非β细胞通过线粒体呼吸（在培养基中用半乳糖代替葡萄糖）产生 ATP 并剥夺葡萄糖，可使这些细胞对一氧化氮介导的 DDR 信号抑制敏感。这些发现表明，代谢灵活性对于在抑制线粒体氧化代谢的情况下维持 DDR 信号是必要的，并支持抑制氧化代谢（减少 ATP）作为一氧化氮减轻 DDR 依赖性β细胞凋亡的一种保护机制。
