Increased demand for NAD+ relative to ATP drives aerobic glycolysis
Journal article, 2021
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. Aerobic glycolysis is associated with proliferation in many biological contexts, yet what drives this phenotype has not been fully explained. Luengo et al. show that cells engage in aerobic glycolysis when the demand for NAD+ exceeds the demand for ATP, which leads to impaired NAD+ regeneration by mitochondrial respiration.
Warburg Effect
Fermentation
NAD+
PDK
Cell Metabolism
Aerobic Glycolysis
Author
Alba Luengo
Massachusetts Institute of Technology (MIT)
Zhaoqi Li
Massachusetts Institute of Technology (MIT)
Dan Y. Gui
Massachusetts Institute of Technology (MIT)
Lucas B. Sullivan
Fred Hutchinson Cancer Center
Massachusetts Institute of Technology (MIT)
Maria Zagorulya
Massachusetts Institute of Technology (MIT)
Brian T. Do
Massachusetts Institute of Technology (MIT)
Harvard Medical School
Raphael Ferreira
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Adi Naamati
University of Cambridge
Ahmed Ali
Massachusetts Institute of Technology (MIT)
Caroline A. Lewis
Whitehead Institute for Biomedical Research
Craig J. Thomas
National Center for Advancing Translational Sciences (NCATS)
Stefani Spranger
Massachusetts Institute of Technology (MIT)
Nicholas J. Matheson
University of Cambridge
Massachusetts Institute of Technology (MIT)
Matthew G. Vander Heiden
Massachusetts Institute of Technology (MIT)
Dana-Farber Cancer Institute
Molecular Cell
1097-2765 (ISSN) 1097-4164 (eISSN)
Vol. 81 4 691-707.e6Subject Categories
Cell Biology
Cell and Molecular Biology
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
DOI
10.1016/j.molcel.2020.12.012
PubMed
33382985