A genetically encoded redox bottleneck constrains human developmental rate
- 1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Abstract
The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.
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BibTeX
@misc{valdebenito2026genetically,
title = {{A genetically encoded redox bottleneck constrains human developmental rate}},
author = {G. E. Valdebenito and J. P. Madden and C. Mendez and L. M. Azurdia and X. Zhu and S. Chen and D. Atlas and K. Introcaso and H. Zhang and Y. Wang and F. Dong and R. Sharma and V. K. Mootha and G. J. Patti and M. Diaz-Cuadros},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750701},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750701v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - A genetically encoded redox bottleneck constrains human developmental rate
AU - G. E. Valdebenito
AU - J. P. Madden
AU - C. Mendez
AU - L. M. Azurdia
AU - X. Zhu
AU - S. Chen
AU - D. Atlas
AU - K. Introcaso
AU - H. Zhang
AU - Y. Wang
AU - F. Dong
AU - R. Sharma
AU - V. K. Mootha
AU - G. J. Patti
AU - M. Diaz-Cuadros
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750701
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750701v1
AB - The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.
ER -