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- W3201517346 abstract "Abstract The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration, suggesting a mechanistic role in neurodegenerative decline. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the OXPHOS ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons." @default.
- W3201517346 created "2021-09-27" @default.
- W3201517346 creator A5042116489 @default.
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- W3201517346 date "2020-01-09" @default.
- W3201517346 modified "2023-10-16" @default.
- W3201517346 title "Succination of Dihydrolipoyllysine Succinyltransferase (DLST) Exacerbates Mitochondrial ATP Deficiency in a Mouse Model of Leigh Syndrome" @default.
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- W3201517346 doi "https://doi.org/10.1101/2020.01.09.900514" @default.
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