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Implication of Mitochondrial NO/cGMP/PKG Signaling System in the Activation and Inhibition of Mitochondrial Respiration by L-Arginine and NO Donors
Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Pub Date : 2019-10-01 , DOI: 10.1134/s1990747819040056
V. V. Dynnik , E. V. Grishina , N. I. Fedotcheva

The involvement of the mitochondrial calcium-dependent NO synthase (mtNOS) in the regulation of mitochondrial respiration has not been sufficiently studied. Moreover, the possible functioning of a mitochondrial signaling system involving mtNOS/guanylate cyclase (GC)/protein kinase G (PKG) and the impact of this system (mtNOS/GC/PKG-SS) on mitochondrial respiration have not yet been analyzed. To investigate this issue, we performed experiments on isolated rat liver using specific inhibitors of NOS, GC, and PKG. The high rate of mitochondrial respiration was supported by pyruvate and glutamate or by succinate in the presence of hexokinase, glucose, and ADP. It was shown that L-arginine and the NO donor sodium nitroprusside (SNP) exert concentration-dependent effects on the mitochondrial respiration rate. At low concentrations, L‑arginine (up to 200 μM) and SNP (up to100 μM) activated mitochondrial respiration. The inhibitors of NOS, GC, and PKG eliminated this effect indicating that mtNOS/GC/PKG-SS is involved in the activation of respiration. At high concentrations, L-arginine and SNP, on the contrary, inhibited respiration. Under these conditions, the inhibitors of GC and PKG enhanced the inhibition of respiration, which indicates an opposite effect of the excess of NO and PKG on the mitochondrial respiration. The results suggest that the functioning of calcium-dependent mtNOS/GC/PKG-SS can ensure the activation of respiration at low concentrations of L-arginine or SNP in the medium.

中文翻译:

线粒体 NO/cGMP/PKG 信号系统在 L-精氨酸和 NO 供体激活和抑制线粒体呼吸中的意义

线粒体钙依赖性 NO 合酶 (mtNOS) 在线粒体呼吸调节中的参与尚未得到充分研究。此外,尚未分析涉及 mtNOS/鸟苷酸环化酶 (GC)/蛋白激酶 G (PKG) 的线粒体信号系统的可能功能以及该系统 (mtNOS/GC/PKG-SS) 对线粒体呼吸的影响。为了研究这个问题,我们使用 NOS、GC 和 PKG 的特异性抑制剂对离体大鼠肝脏进行了实验。在己糖激酶、葡萄糖和 ADP 存在下,丙酮酸和谷氨酸或琥珀酸支持线粒体呼吸的高速率。结果表明,L-精氨酸和 NO 供体硝普钠 (SNP) 对线粒体呼吸速率产生浓度依赖性影响。在低浓度下,L-精氨酸(高达 200 μM)和 SNP(高达 100 μM)激活线粒体呼吸。NOS、GC 和 PKG 的抑制剂消除了这种影响,表明 mtNOS/GC/PKG-SS 参与了呼吸的激活。相反,在高浓度下,L-精氨酸和 SNP 会抑制呼吸。在这些条件下,GC 和 PKG 的抑制剂增强了对呼吸的抑制,这表明过量的 NO 和 PKG 对线粒体呼吸具有相反的作用。结果表明,钙依赖性 mtNOS/GC/PKG-SS 的功能可以确保在培养基中低浓度 L-精氨酸或 SNP 时激活呼吸。PKG 消除了这种影响,表明 mtNOS/GC/PKG-SS 参与了呼吸的激活。相反,在高浓度下,L-精氨酸和 SNP 会抑制呼吸。在这些条件下,GC 和 PKG 的抑制剂增强了对呼吸的抑制,这表明过量的 NO 和 PKG 对线粒体呼吸具有相反的作用。结果表明,钙依赖性 mtNOS/GC/PKG-SS 的功能可以确保在培养基中低浓度 L-精氨酸或 SNP 时激活呼吸。PKG 消除了这种影响,表明 mtNOS/GC/PKG-SS 参与了呼吸的激活。相反,在高浓度下,L-精氨酸和 SNP 会抑制呼吸。在这些条件下,GC 和 PKG 的抑制剂增强了对呼吸的抑制,这表明过量的 NO 和 PKG 对线粒体呼吸具有相反的作用。结果表明,钙依赖性 mtNOS/GC/PKG-SS 的功能可以确保在培养基中低浓度 L-精氨酸或 SNP 时激活呼吸。
更新日期:2019-10-01
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