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Oxidative pentose phosphate pathway and glucose anaplerosis support maintenance of mitochondrial NADPH pool under mitochondrial oxidative stress
Bioengineering & Translational Medicine ( IF 7.4 ) Pub Date : 2020-08-24 , DOI: 10.1002/btm2.10184 Sun Jin Moon 1 , Wentao Dong 1 , Gregory N. Stephanopoulos 1 , Hadley D. Sikes 1
Bioengineering & Translational Medicine ( IF 7.4 ) Pub Date : 2020-08-24 , DOI: 10.1002/btm2.10184 Sun Jin Moon 1 , Wentao Dong 1 , Gregory N. Stephanopoulos 1 , Hadley D. Sikes 1
Affiliation
Mitochondrial NADPH protects cells against mitochondrial oxidative stress by serving as an electron donor to antioxidant defense systems. However, due to technical challenges, it still remains unknown as to the pool size of mitochondrial NADPH, its dynamics, and NADPH/NADP+ ratio. Here, we have systemically modulated production rates of H2O2 in mitochondria and assessed mitochondrial NADPH metabolism using iNap sensors, 13C glucose isotopic tracers, and a mathematical model. Using sensors, we observed decreases in mitochondrial NADPH caused by excessive generation of mitochondrial H2O2, whereas the cytosolic NADPH was maintained upon perturbation. We further quantified the extent of mitochondrial NADPH/NADP+ based on the mathematical analysis. Utilizing 13C glucose isotopic tracers, we found increased activity in the pentose phosphate pathway (PPP) accompanied small decreases in the mitochondrial NADPH pool, whereas larger decreases induced both PPP activity and glucose anaplerosis. Thus, our integrative and quantitative approach provides insight into mitochondrial NADPH metabolism during mitochondrial oxidative stress.
中文翻译:
氧化戊糖磷酸途径和葡萄糖动脉粥样硬化支持线粒体氧化应激下线粒体NADPH池的维持
线粒体NADPH通过充当抗氧化剂防御系统的电子供体,保护细胞免受线粒体氧化应激。但是,由于技术挑战,对于线粒体NADPH的库大小,动力学和NADPH / NADP +比率,仍然未知。在这里,我们已经系统地调节了线粒体中H 2 O 2的生产率,并使用iNap传感器,13 C葡萄糖同位素示踪剂和数学模型评估了线粒体NADPH代谢。使用传感器,我们观察到线粒体H 2 O 2的过量生成导致线粒体NADPH的降低,而细胞质NADPH则在发生干扰时得以维持。基于数学分析,我们进一步量化了线粒体NADPH / NADP +的程度。利用13 C葡萄糖同位素示踪剂,我们发现戊糖磷酸途径(PPP)的活性增加伴随着线粒体NADPH库的小幅下降,而较大的下降既诱导了PPP活性,又引起了葡萄糖的动脉粥样硬化。因此,我们的整合和定量方法提供了线粒体氧化应激过程中线粒体NADPH代谢的见解。
更新日期:2020-09-23
中文翻译:
氧化戊糖磷酸途径和葡萄糖动脉粥样硬化支持线粒体氧化应激下线粒体NADPH池的维持
线粒体NADPH通过充当抗氧化剂防御系统的电子供体,保护细胞免受线粒体氧化应激。但是,由于技术挑战,对于线粒体NADPH的库大小,动力学和NADPH / NADP +比率,仍然未知。在这里,我们已经系统地调节了线粒体中H 2 O 2的生产率,并使用iNap传感器,13 C葡萄糖同位素示踪剂和数学模型评估了线粒体NADPH代谢。使用传感器,我们观察到线粒体H 2 O 2的过量生成导致线粒体NADPH的降低,而细胞质NADPH则在发生干扰时得以维持。基于数学分析,我们进一步量化了线粒体NADPH / NADP +的程度。利用13 C葡萄糖同位素示踪剂,我们发现戊糖磷酸途径(PPP)的活性增加伴随着线粒体NADPH库的小幅下降,而较大的下降既诱导了PPP活性,又引起了葡萄糖的动脉粥样硬化。因此,我们的整合和定量方法提供了线粒体氧化应激过程中线粒体NADPH代谢的见解。