Compartmentalized metabolism supports midgestation mammalian development

Ashley Solmonson, Brandon Faubert, Wen Gu, Aparna Rao, Mitzy A. Cowdin, Ivan Menendez-Montes, Sherwin Kelekar, Thomas J. Rogers, Chunxiao Pan, Gerardo Guevara, Amy Tarangelo, Lauren G. Zacharias, Misty S. Martin-Sandoval, Duyen Do, Panayotis Pachnis, Dennis Dumesnil, Thomas P. Mathews, Alpaslan Tasdogan, An Pham, Ling Cai, Zhiyu Zhao, Min Ni, Ondine Cleaver, Hesham A. Sadek, Sean J. Morrison and Ralph J. DeBerardinis ()
Additional contact information
Ashley Solmonson: University of Texas Southwestern Medical Center
Brandon Faubert: University of Texas Southwestern Medical Center
Wen Gu: University of Texas Southwestern Medical Center
Aparna Rao: University of Texas Southwestern Medical Center
Mitzy A. Cowdin: University of Texas Southwestern Medical Center
Ivan Menendez-Montes: University of Texas Southwestern Medical Center
Sherwin Kelekar: University of Texas Southwestern Medical Center
Thomas J. Rogers: University of Texas Southwestern Medical Center
Chunxiao Pan: University of Texas Southwestern Medical Center
Gerardo Guevara: University of Texas Southwestern Medical Center
Amy Tarangelo: University of Texas Southwestern Medical Center
Lauren G. Zacharias: University of Texas Southwestern Medical Center
Misty S. Martin-Sandoval: University of Texas Southwestern Medical Center
Duyen Do: University of Texas Southwestern Medical Center
Panayotis Pachnis: University of Texas Southwestern Medical Center
Dennis Dumesnil: University of Texas Southwestern Medical Center
Thomas P. Mathews: University of Texas Southwestern Medical Center
Alpaslan Tasdogan: University of Texas Southwestern Medical Center
An Pham: University of Texas Southwestern Medical Center
Ling Cai: University of Texas Southwestern Medical Center
Zhiyu Zhao: University of Texas Southwestern Medical Center
Min Ni: University of Texas Southwestern Medical Center
Ondine Cleaver: University of Texas Southwestern Medical Center
Hesham A. Sadek: University of Texas Southwestern Medical Center
Sean J. Morrison: University of Texas Southwestern Medical Center
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center

Nature, 2022, vol. 604, issue 7905, 349-353

Abstract: Abstract Mammalian embryogenesis requires rapid growth and proper metabolic regulation1. Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development2,3. Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5–11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose’s contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle4,5. LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5–GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero.

Date: 2022
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DOI: 10.1038/s41586-022-04557-9

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