Regional metabolic signatures in the Ndufs4(KO) mouse brain implicate defective glutamate/α-ketoglutarate metabolism in mitochondrial disease.
Animals
Brain
/ metabolism
Disease Models, Animal
Electron Transport Complex I
/ physiology
Female
Glutamic Acid
/ metabolism
Ketoglutaric Acids
/ metabolism
Leigh Disease
/ metabolism
Male
Metabolome
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Diseases
/ metabolism
TOR Serine-Threonine Kinases
/ metabolism
Genetics
Leigh syndrome
Metabolism
Mitochondria
Mouse
Rapamycin
Reactive oxygen species
Journal
Molecular genetics and metabolism
ISSN: 1096-7206
Titre abrégé: Mol Genet Metab
Pays: United States
ID NLM: 9805456
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
28
03
2020
accepted:
29
03
2020
pubmed:
26
4
2020
medline:
7
4
2021
entrez:
26
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32331968
pii: S1096-7192(20)30081-0
doi: 10.1016/j.ymgme.2020.03.007
pmc: PMC7272141
mid: NIHMS1586752
pii:
doi:
Substances chimiques
Ketoglutaric Acids
0
Ndufs4 protein, mouse
0
Glutamic Acid
3KX376GY7L
mTOR protein, mouse
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
118-132Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM118514
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS098329
Pays : United States
Organisme : NIGMS NIH HHS
ID : K99 GM126147
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG001751
Pays : United States
Organisme : NIGMS NIH HHS
ID : R00 GM126147
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000057
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG013280
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM105696
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK017047
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare no competing interests.
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