Identifying the metabolic requirements for the TCA cycle in embryonic development

Active Project Grant Awarded Last action

Award ID
F31HD119933
Recipient
Awarding agency
Obligated
$149,190

Award facts

Completion date 43% complete
Place of performance
New York, NY 10065, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Embryonic development involves complex changes in cell proliferation, macromolecule synthesis, and nutrient availability, all of which impose different metabolic demands. Accordingly, cells must remodel central metabolic pathways during early development, but the metabolic requirements of early differentiation and how metabolic pathways are reprogrammed during this critical developmental window remain poorly understood. Recently, our lab demonstrated that the tricarboxylic acid (TCA) cycle, a central metabolic hub critical for energy production and provision of biosynthetic intermediates, undergoes dynamic shifts during cell state transitions. Using mouse embryonic stem cells (ESCS) as a model system, we found that naïve pluripotent ESCS, which mimic the pre-implantation epiblast, predominantly rely on the conventional configuration of the TCA cycle, in which citrate is oxidized within the mitochondria. In contrast, more committed ESCS, including those mimicking post-implantation epiblast-like states, preferentially export citrate from the mitochondria, bypassing canonical TCA cycle oxidation. Accordingly, aconitase 2 (ACO2), a key enzyme in the TCA cycle that initiates the catabolism of citrate within the mitochondria, is essential for maintaining the naïve pluripotent state but is dispensable in more differentiated cells. Notably, loss of ACO2 function in humans is linked to severe neurodevelopmental disorders, and mice with heterozygous ACO2 mutations fail to produce viable homozygous null pups. Together, these results indicate that ACO2 plays a context-specific role in early development, but what metabolic outputs of ACO2 support development and the developmental consequences of ACO2 disruption remain unknown. The goal of this project is to determine the role of ACO2 in maintaining naïve pluripotency and supporting early embryonic development. Our preliminary data indicate that ACO2 is dispensable for both energy production and generation of macromolecular precursors; rather, ACO2 is essential to prevent the accumulation of toxic citrate in highly oxidative cellular states. Aim 1 will combine genetic and pharmacologic approaches to determine whether increased citrate production in naïve ESCS induces dependence on ACO2 for citrate clearance and cell fitness. Aim 2 will reveal the developmental consequences of ACO2 loss in vivo using newly generated ACO2+/- mice. We will genotype embryos from ACO2+/- crosses to determine the stage at which ACO2-/-embryos lose viability. Based on these findings, we will isolate ACO2-/- embryos before lethality and investigate the impact of ACO2 loss on cell fate specification, proliferation, and cell death using immunofluorescence techniques. These studies will enhance our understanding of how TCA cycle outputs support early embryonic development. The training plan outlined in this proposal will be completed under the guidance of DR. Lydia finley and DR. Anna-katerina hadjantonakis, experts in metabolism, stem cell biology, and embryology. The excellent environment and comprehensive training proposed will prepare the applicant for future success as an independent academic researcher.

Transactions

Action Obligated Date
Amendment $50,114
Amendment $49,538
Original award $49,538

Quick answers

Who received award F31HD119933?

F31HD119933 was awarded to Weill Medical College Of Cornell University by National Institute of Child Health and Human Development (National Institutes of Health) on July 28, 2025.

How much is award F31HD119933 worth?

$149,190 has been obligated on F31HD119933.

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