Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease
| Autor: | Simon C. Johnson, Philip G. Morgan, Daniel Raftery, Margaret M. Sedensky, Amanda Pan, Grace X Sun, Matt Kaeberlein, Alessandro Bitto, Rebecca Bornstein, Julia Stokes, Ernst-Bernhard Kayser, Kyung Yeon Park |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Mitochondrial Diseases Endocrinology Diabetes and Metabolism Glutamic Acid 030105 genetics & heredity Mitochondrion Biochemistry Article 03 medical and health sciences Glutamatergic Mice 0302 clinical medicine Endocrinology Genetics medicine Animals Neurotransmitter metabolism Molecular Biology PI3K/AKT/mTOR pathway Mice Knockout Electron Transport Complex I Chemistry TOR Serine-Threonine Kinases Neurodegeneration NDUFS4 Glutamate receptor Brain medicine.disease Cell biology Mice Inbred C57BL Disease Models Animal Knockout mouse Metabolome Ketoglutaric Acids Female Leigh Disease 030217 neurology & neurosurgery |
| Zdroj: | Mol Genet Metab |
| ISSN: | 1096-7206 |
| Popis: | Leigh Syndrome (LS) is a mitochondrial disorder defined by progressive focal neurodegenerative lesions in specific regions of the brain. Defects in NDUFS4, a subunit of complex I of the mitochondrial electron transport chain, cause LS in humans; the Ndufs4 knockout mouse (Ndufs4(KO)) closely resembles the human disease. Here, we probed brain region-specific molecular signatures in pre-symptomatic Ndufs4(KO) to identify factors which underlie focal neurodegeneration. Metabolomics revealed that free amino acid concentrations are broadly different by region, and glucose metabolites are increased in a manner dependent on both region and genotype. We then tested the impact of the mTOR inhibitor rapamycin, which dramatically attenuates LS in Ndufs4(KO), on region specific metabolism. Our data revealed that loss of Ndufs4 drives pathogenic changes to CNS glutamine/glutamate/α-ketoglutarate metabolism which are rescued by mTOR inhibition Finally, restriction of the Ndufs4 deletion to pre-synaptic glutamatergic neurons recapitulated the whole-body knockout. Together, our findings are consistent with mTOR inhibition alleviating disease by increasing availability of α-ketoglutarate, which is both an efficient mitochondrial complex I substrate in Ndufs4(KO) and an important metabolite related to neurotransmitter metabolism in glutamatergic neurons. |
| Databáze: | OpenAIRE |
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