Loss of TCA cycle turning promotes stem cell function
- 1UT Southwestern Medical Center, Dallas, TX, USA
Abstract
The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO2, and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo, and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.
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BibTeX
@misc{li2026loss,
title = {{Loss of TCA cycle turning promotes stem cell function}},
author = {Y. Li and J. Rose and E. O. Kwarteng and X. Yang and J. Zielke and L. Li and Z. Zhao and J. H. Jun and M. Agathocleous},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753355},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753355v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Loss of TCA cycle turning promotes stem cell function
AU - Y. Li
AU - J. Rose
AU - E. O. Kwarteng
AU - X. Yang
AU - J. Zielke
AU - L. Li
AU - Z. Zhao
AU - J. H. Jun
AU - M. Agathocleous
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753355
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753355v1
AB - The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO2, and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo, and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.
ER -