Defining the role of the malate aspartate shuttle in embryonic development
Active Project Grant Awarded Last action
- Award ID
- F31HD122367
- Recipient
-
Regents Of The University Of Michigan UEI GNJ7BBP73WE9
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $88,318
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date 0% complete
- Originally
- Place of performance
- Ann Arbor, MI 48109, USA
Award details come from USAspending.gov.
Description
- Abstract
- The malate aspartate shuttle (MAS) is a redox pathway that maintains energy homeostasis between the cytosol and the mitochondria. Energy generated in the cytosol as "nadh" cannot be directly transferred into the mitochondria; thus, the MAS facilitates the net transfer of nadh from the cytosol across the inner mitochondrial membrane. Key enzymes of this pathway include two glutamate-oxaloacetate transaminases (got), cytosolic GOT1 and mitochondrial GOT2. Partial loss-of-function mutations in MAS genes have been reported to cause severe neurological manifestations in affected patients with no curative treatment. Presumably, total loss of got activity is incompatible with life. Our lab has shown that germline deletion of GOT1 and GOT2 in mice leads to early embryonic lethality. However, the mechanisms linking MAS dysfunction to these phenotypes have not been elucidated. While embryos homozygous for GOT1 and GOT2 deletion are embryonic lethal, I found that this occurs at different stages: embryonic day (E) 12.5 for GOT1 mutants and E9.5 for GOT2 mutants. GOT2 mutant embryos exhibit brain, heart, and tail morphological defects that are not observed in GOT1 mutant embryos. In contrast, GOT1 mutant embryos exhibit normal development, as compared to wild-type littermates, except for vasculature abnormalities in the extra-embryonic yolk SAC. This suggests that GOT2 deletion could be impairing metabolic processes necessary during embryogenesis in a manner distinct from GOT1 deletion. This observation is remarkable because prevailing models indicate GOT1 and GOT2 function in a linear pathway, which would imply identical phenotypes upon loss of function. Thus, I hypothesize that the spatial compartmentalization of GOT1 and GOT2 are responsible for distinct metabolic perturbations upon germline deletion, causing variations in embryonic lethality in mice. In aim 1 of this proposal, I will determine the metabolic roles of GOT1 and GOT2 in embryonic development. In aim 2 of this proposal, I will determine the tissue-specific necessity GOT1 and GOT2 in embryogenesis. Together, these aims investigate the roles of GOT1 and GOT2 in normal embryonic development as well as the consequences upon deletion.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $44,159 | |
| Amendment | $44,159 | |
| Original award | $0 |
Quick answers
Who received award F31HD122367?
F31HD122367 was awarded to Regents Of The University Of Michigan by National Institute of Child Health and Human Development (National Institutes of Health) on December 1, 2026.
How much is award F31HD122367 worth?
$88,318 has been obligated on F31HD122367.
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