Increased demand for NAD+ relative to ATP drives aerobic glycolysis
Increased demand for NAD+ relative to ATP drives aerobic glycolysis
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DOI：
10.1101/2020.06.08.140558
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发表时间：
2020-06
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通讯作者：
Alba Luengo;Zhaoqi Li;D. Y. Gui;Lucas B. Sullivan;Maria Zagorulya;Brian T. Do;R. Ferreira;Adi Naamati;A. Ali;C. Lewis;Craig J. Thomas;S. Spranger;N. Matheson;M. V. Vander Heiden
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作者：
Alba Luengo;Zhaoqi Li;D. Y. Gui;Lucas B. Sullivan;Maria Zagorulya;Brian T. Do;R. Ferreira;Adi Naamati;A. Ali;C. Lewis;Craig J. Thomas;S. Spranger;N. Matheson;M. V. Vander Heiden
有氧糖酵解或葡萄糖衍生的丙酮酸优先发酵为乳酸，尽管有可用的氧气，是在许多生物体和条件下观察到的增殖代谢的标志。为了更好地理解为什么有氧糖酵解与细胞增殖相关，我们研究了激活丙酮酸脱氢酶复合物（PDH）以增加线粒体丙酮酸氧化而牺牲发酵的代谢结果。我们发现增加PDH活性通过降低烟酰胺腺嘌呤二核苷酸辅因子比率（NAD+/NADH）来损害细胞增殖。NAD+/NADH比率的这种变化是由线粒体膜电位的增加引起的，线粒体膜电位的增加损害了线粒体电子传递和NAD+再生。将线粒体呼吸与ATP合成解偶联或增加ATP水解恢复NAD+/NADH稳态和增殖，即使葡萄糖氧化增加。这些数据表明，当NAD+支持氧化反应的需求超过细胞中ATP消耗的需求时，线粒体呼吸作用的NAD+再生受到限制，尽管有可用的氧气，但仍促进发酵。这表明，当细胞对NAD+的需求超过细胞对ATP的需求时，细胞参与有氧糖酵解。
Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is a hallmark of proliferative metabolism that is observed across many organisms and conditions. To better understand why aerobic glycolysis is associated with cell proliferation, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase mitochondrial pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the nicotinamide adenine dinucleotide cofactor ratio (NAD+/NADH). This change in NAD+/NADH ratio is caused by an increase in mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling mitochondrial respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when the demand for NAD+ to support oxidation reactions exceeds the demand for ATP consumption in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation despite available oxygen. This argues that cells engage in aerobic glycolysis when the cellular demand for NAD+ is in excess of the cellular demand for ATP.