The necessity of mitochondrial MDH2 for gabaergic neuron metabolism
Active Project Grant Awarded Last action
- Award ID
- F31NS139495
- Recipient
-
Northwestern University UEI KG76WYENL5K1
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $224,216
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 50% complete
- Place of performance
- Chicago, IL 60611, USA
Award details come from USAspending.gov.
Description
- Abstract
- Mitochondrial dysfunction is a well-established cause of neurologic and psychiatric disease. The brain is the body's most energetically demanding tissue and is especially vulnerable to metabolic challenges such as hypoglycemia, ischemia, and mitochondrial disease. One such mitochondrial disease is caused by defects in the mitochondrial enzyme MDH2, which catalyzes the final step in the TCA. Patients with mutations in MDH2 develop infantile encephalopathy and epilepsy. The association between mitochondrial dysfunction and neurologic disease is often attributed to a deficiency in ATP. However, in addition to ATP, the mitochondrial TCA generates biosynthetic intermediates like Α-ketoglutarate (Α-KG) which is used to synthesize the neurotransmitter gamma- aminobutyric acid (GABA). GABA is the brain's primary inhibitory neurotransmitter, and decreased GABA signaling underlies neurologic and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, autism spectrum disorder, and epilepsy. The research proposal aims to elucidate the critical role of mitochondrial MDH2 in ATP and GABA production within gabaergic neurons. The hypothesis predicts that MDH2-deficient gabaergic neurons can produce adequate ATP through glycolysis but fail to synthesize GABA, leading to impaired GABA signaling without neuron death. The proposal tests the hypothesis with two specific aims. The first aim investigates whether MDH2 is essential for ATP production in gabaergic neurons. This involves studying the bioenergetic consequences of MDH2 loss in human ipsc-derived gabaergic neuron cultures and a mouse model with MDH2 selectively knocked out in gabaergic neurons. The second aim explores the necessity of MDH2 for GABA synthesis using techniques such as metabolomics, RNA sequencing, isotope tracing, and spatial metabolomics. Additionally, the proposal examines the potential of Α-ketoglutarate (Α-KG) as a supplementary substrate for GABA synthesis to mitigate MDH2 deficiency. This research seeks to uncover the metabolic requirements for gabaergic signaling, providing insights into the connection between mitochondrial dysfunction and GABA-related diseases, and paving the way for new therapeutic strategies targeting gabaergic neuron metabolism.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $46,008 | |
| Amendment | $564 | |
| Amendment | $44,411 | |
| Amendment | $44,411 | |
| Amendment | $0 | |
| Amendment | $44,411 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $44,411 | |
| Amendment | $0 | |
| Original award | $0 |
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Quick answers
Who received award F31NS139495?
F31NS139495 was awarded to Northwestern University by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 1, 2025.
How much is award F31NS139495 worth?
$224,216 has been obligated on F31NS139495.
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