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 - 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 - NADH shuttles
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 - 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 -