Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease

Simon C Johnson, Ernst-Bernhard Kayser, Rebecca Bornstein, Julia Stokes, Alessandro Bitto, Kyung Yeon Park, Amanda Pan, Grace Sun, Daniel Raftery, Matt Kaeberlein, Margaret M Sedensky, Philip G Morgan

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)118-132
Number of pages15
JournalMolecular Genetics and Metabolism
Volume130
Issue number2
DOIs
Publication statusPublished - Jun 2020
Externally publishedYes

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