Study summary · research use only
Increased demand for NAD(+) relative to ATP drives aerobic glycolysis
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this cell study (species not specified), the authors examined the metabolic effect of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation relative to fermentation. They report that increasing PDH activity reduced cell proliferation by lowering the NAD+/NADH ratio, a change attributed to increased mitochondrial membrane potential that impaired mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis, or increasing ATP hydrolysis, restored NAD+/NADH balance and proliferation even when glucose oxidation was increased. The authors conclude that when cellular demand for NAD+ to support oxidation exceeds the rate of ATP turnover, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation despite available oxygen, and that this may explain aerobic glycolysis.
Abstract
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 that 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 that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.
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