The necessity of mitochondrial MDH2 for GABAergic neuron metabolism

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

Project Summary 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.