Glutamine-derived NADH fuels lactate production to maximize ATP yield under oxygen consumption constraints in head and neck cancer
- 1Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam
Abstract
Metabolic reprogramming is one of the hallmarks of cancer. A well-known change is the Warburg effect: glucose is consumed at increased rates and fermented to lactate instead of being respired to carbon dioxide, despite the presence of sufficient oxygen (O2). We show that head and neck squamous cell carcinoma (HNSCC) cells excrete more carbon in the form of lactate than is consumed as glucose, indicating the presence of additional carbon sources for lactate. Amino acid uptake and [U-13C]-glutamine labelling data show that glutamine is highly consumed and oxidized in the tricarboxylic acid (TCA) cycle, but remarkably does not contribute to lactate carbon. To explain these observations, we generated a cell-line specific metabolic model to understand the link between lactate production and glutamine metabolism. In the model, we show how low cellular O2 consumption capacity can cause increased lactate production with glutamine as NADH source. The model suggests that ATP production under limited O2 consumption is augmented by increased glutamine oxidation which yields ATP, FADH2 and NADH. FADH2 can only be respired, despite yielding less ATP than NADH respiration. NADH can be exported from the mitochondrion to be reoxidized by lactate dehydrogenase, permitting more cycles of glutamine oxidation, thereby increasing the total ATP yield. By experimentally inhibiting mitochondrial respiration, we confirmed that non-glucose carbon sources are used for lactate production under decreased O2 consumption capacity. This unexpected feature of O2-constrained ATP production provides a credible mechanism for the increased lactate production via a novel redox cycle in HNSCC cells.
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BibTeX
@misc{odendaal2026glutaminederived,
title = {{Glutamine-derived NADH fuels lactate production to maximize ATP yield under oxygen consumption constraints in head and neck cancer}},
author = {C. Odendaal and R. Dalhuisen and M. Hoving and M. Zhang and M. Stigter-van Walsum and D. Botman and A. Gerding and J. B. Poell and B. M. Bakker and B. Teusink and R. H. Brakenhoff and J. R. Haanstra},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.25.761662},
url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761662v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Glutamine-derived NADH fuels lactate production to maximize ATP yield under oxygen consumption constraints in head and neck cancer
AU - C. Odendaal
AU - R. Dalhuisen
AU - M. Hoving
AU - M. Zhang
AU - M. Stigter-van Walsum
AU - D. Botman
AU - A. Gerding
AU - J. B. Poell
AU - B. M. Bakker
AU - B. Teusink
AU - R. H. Brakenhoff
AU - J. R. Haanstra
PY - 2026
DA - 2026/10/25
PB - bioRxiv
DO - 10.64898/2026.10.25.761662
UR - https://www.biorxiv.org/content/10.64898/2026.10.25.761662v1
AB - Metabolic reprogramming is one of the hallmarks of cancer. A well-known change is the Warburg effect: glucose is consumed at increased rates and fermented to lactate instead of being respired to carbon dioxide, despite the presence of sufficient oxygen (O2). We show that head and neck squamous cell carcinoma (HNSCC) cells excrete more carbon in the form of lactate than is consumed as glucose, indicating the presence of additional carbon sources for lactate. Amino acid uptake and [U-13C]-glutamine labelling data show that glutamine is highly consumed and oxidized in the tricarboxylic acid (TCA) cycle, but remarkably does not contribute to lactate carbon. To explain these observations, we generated a cell-line specific metabolic model to understand the link between lactate production and glutamine metabolism. In the model, we show how low cellular O2 consumption capacity can cause increased lactate production with glutamine as NADH source. The model suggests that ATP production under limited O2 consumption is augmented by increased glutamine oxidation which yields ATP, FADH2 and NADH. FADH2 can only be respired, despite yielding less ATP than NADH respiration. NADH can be exported from the mitochondrion to be reoxidized by lactate dehydrogenase, permitting more cycles of glutamine oxidation, thereby increasing the total ATP yield. By experimentally inhibiting mitochondrial respiration, we confirmed that non-glucose carbon sources are used for lactate production under decreased O2 consumption capacity. This unexpected feature of O2-constrained ATP production provides a credible mechanism for the increased lactate production via a novel redox cycle in HNSCC cells.
ER -