Increased demand for NAD+ relative to ATP drives aerobic glycolysis
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1-s2.0-S1097276520309047-main.pdf
Description
Published version
Size
2.7 MB
Format
Adobe PDF
Checksum (MD5)
bf047e3df1295b56f69945a3b4169cb8
Author(s)
Luengo, Alba
Li, Zhaoqi
Gui, Dan Y
Sullivan, Lucas B
Zagorulya, Maria
Do, Brian T
Ferreira, Raphael
Naamati, Adi
Ali, Ahmed
Lewis, Caroline A
Date Issued
2021
Journal
Molecular Cell
Publisher
Elsevier BV
Version
Final published version
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. + + + + + + +
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.molcel.2020.12.012
