Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism

Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency. [Display omitted] •Tissue-specific Sucla2 mutagenesis yields mouse model of SCS deficiency•Accumulation of succinyl-CoA in the mutant cortex leads to hypersuccinylation•Hypersuccinylation of ETC complex I is associated with impaired enzymatic activity•Nuclear hypersuccinylation is accompanied by changes in neuronal transcription Lancaster et al. present a mouse model of forebrain-specific succinyl-CoA synthetase deficiency, resulting in accumulation of TCA cycle intermediate succinyl-CoA and causing global protein hypersuccinylation. Hypersuccinylation within the forebrain is associated with changes in neuronal transcriptional networks and mitochondrial respiratory dysfunction, suggesting that hypersuccinylation contributes to pathogenesis of SCS deficiency.