Increased demand for NAD+ relative to ATP drives aerobic glycolysis
Artikel i vetenskaplig tidskrift, 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




Cell Metabolism

Aerobic Glycolysis


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, Biologi och bioteknik, Systembiologi

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.e6



Cell- och molekylärbiologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)





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