ArticleMolecular genetics and metabolism2020
Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease.
Article in Molecular genetics and metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
- The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.iScience · 2026Article
- Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.Cellular and molecular neurobiology · 2026Article
- Ndufs4GeroScience · 2025Review
- Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Evaluating the efficacy of vatiquinone in preclinical models of Leigh syndrome and GPX4 deficiency.Orphanet journal of rare diseases · 2025Article
- Mitochondrial transplants to treat mitochondrial dysfunction.Nature metabolism · 2024Article
- Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease.Research square · 2024Article
- Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.Redox biology · 2023Article
- Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.British journal of anaesthesia · 2023Article
- The functional role of Higd1a in mitochondrial homeostasis and in multiple disease processes.Genes & diseases · 2023Review
- Glutamine metabolism in diseases associated with mitochondrial dysfunction.Molecular and cellular neurosciences · 2023Review
- Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from theInternational journal of molecular sciences · 2023Article
- Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.Nature metabolism · 2023Article
- Article
- Polarization Behavior of Bone Macrophage as Well as Associated Osteoimmunity in Glucocorticoid-Induced Osteonecrosis of the Femoral Head.Journal of inflammation research · 2023Review
- mTOR/α-ketoglutarate signaling: impact on brain cell homeostasis under ischemic conditions.Frontiers in cellular neuroscience · 2023Review
- Article
- Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome.Clinical and translational medicine · 2022Article
- Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.Brain : a journal of neurology · 2022Review
- Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome.JCI insight · 2022Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.