Succination of Dihydrolipoyllysine Succinyltransferase by Fumarate Exacerbates Defective Mitochondrial ATP Production during Complex I Deficiency

Abstract

SummaryThe 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, further aggravating the OXPHOS ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. 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.HighlightsCysteine succination by fumarate is increased in model of Complex I deficiencySuccination of DLST impairs KGDHC activity, limits SLP, and reduces lysine succinylationIrreversible succination drives neuropathology independent of the bioenergetic defect