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：
10.1016/j.molcel.2020.12.012
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发表时间：
2021-02-18
期刊：
影响因子：
16
通讯作者：
Vander Heiden MG
中科院分区：
文献类型：
--
作者：
Luengo A;Li Z;Gui DY;Sullivan LB;Zagorulya M;Do BT;Ferreira R;Naamati A;Ali A;Lewis CA;Thomas CJ;Spranger S;Matheson NJ;Vander Heiden MG
有氧糖酵解，或葡萄糖衍生的丙酮酸优先发酵为乳酸，与许多生物体和条件下的增殖有关。为了更好地理解这种关联，我们研究了激活丙酮酸脱氢酶复合物（PDH）以增加丙酮酸氧化而牺牲发酵的代谢后果。我们发现增加PDH活性通过降低NAD+/NADH比值来损害细胞增殖。这种NAD+/NADH的变化是由线粒体膜电位的增加引起的，这会损害线粒体电子传递和NAD+再生。从ATP合成中解耦呼吸或增加ATP水解可以恢复NAD+/NADH稳态和增殖，即使在葡萄糖氧化增加的情况下。这些数据表明，当支持氧化反应的NAD+的需求超过细胞中ATP的周转率时，线粒体呼吸的NAD+再生受到限制，尽管有可用的氧气，但仍促进发酵。这表明，当对NAD+的需求超过对ATP的需求时，细胞就会进行有氧糖酵解。
Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand this association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling 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 demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation despite available oxygen. This argues cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.
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