TY - JOUR
T1 - Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells
AU - Wang, Yahui
AU - Stancliffe, Ethan
AU - Fowle-Grider, Ronald
AU - Wang, Rencheng
AU - Wang, Cheng
AU - Schwaiger-Haber, Michaela
AU - Shriver, Leah P.
AU - Patti, Gary J.
N1 - Funding Information:
We thank Dr. Cong-Hui Yao for discussion related to experimental design. Financial support was received for this work from NIH awards R35ES028365 (G.J.P.) and R24OD024624 (G.J.P.), as well as the Edward Mallinckrodt Jr. Foundation (G.J.P.) and the Pew Charitable Trusts (G.J.P.). Y.W. E.S. R.F.-G. R.W. L.P.S. and G.J.P. designed the study. E.S. wrote the code for flux analysis. Y.W. and M.S.-H. acquired data for metabolite quantitation. C.W. contributed to data analysis. Y.W. performed and analyzed all other experiments. Y.W. L.P.S. and G.J.P. wrote the manuscript. All authors discussed the results, contributed to data interpretation, and approved the final manuscript. G.J.P. is a scientific advisory board member for Cambridge Isotope Laboratories. The Patti laboratory has a collaborative agreement with Thermo Fisher Scientific and Agilent Technologies.
Funding Information:
We thank Dr. Cong-Hui Yao for discussion related to experimental design. Financial support was received for this work from NIH awards R35ES028365 (G.J.P.) and R24OD024624 (G.J.P.), as well as the Edward Mallinckrodt Jr. Foundation (G.J.P.) and the Pew Charitable Trusts (G.J.P.).
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Proliferating cells exhibit a metabolic phenotype known as “aerobic glycolysis,” which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.
AB - Proliferating cells exhibit a metabolic phenotype known as “aerobic glycolysis,” which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.
KW - aerobic glycolysis
KW - cancer metabolism
KW - glycerol 3-phosphate shuttle
KW - isotope-tracer analysis
KW - malate-aspartate shuttle
KW - metabolic flux
KW - metabolomics
KW - NADH shuttles
KW - the Warburg effect
UR - http://www.scopus.com/inward/record.url?scp=85136588196&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2022.07.007
DO - 10.1016/j.molcel.2022.07.007
M3 - Article
C2 - 35973426
AN - SCOPUS:85136588196
SN - 1097-2765
VL - 82
SP - 3270-3283.e9
JO - Molecular Cell
JF - Molecular Cell
IS - 17
ER -