Succinyl-CoA synthetase deficiency in mouse forebrain results in hyper-succinylation with perturbed neuronal transcriptional regulation and metabolism

ABSTRACT: Lysine-succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the TCA cycle. Deficiency of succinyl-CoA synthetase (SCS), the TCA-cycle enzyme catalyzing the reversible conversion of succinyl-CoA to succinate, leads to mitochondrial encephalomyopathy in humans and embryonic lethality in mice. This report presents a conditional forebrain-specific knock-out (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 the accumulation of succinyl-CoA in the absence of SCS leads to hyper-succinylation within the cerebral cortex of adult mice. Using immunoprecipitation (IP) and concomitant mass-spectrometry, a highly enriched succinylated proteome is identified in the Sucla2-deficient forebrain. The Sucla2-deficient changes in the succinylome are largely prevalent in metabolic pathways, including the TCA cycle and the electron transport chain (ETC). Specifically, increased succinylation of Complex I of the ETC correlates with functionally significant deficiency of the enzymatic complex. These results suggest that protein-succinylation plays a role in respiratory chain dysfunction associated with SCS-deficiency in patients.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Brett Graham   Amber L. Mosley  

PROVIDER: MSV000089697 | MassIVE | Tue Jun 21 13:42:00 BST 2022

SECONDARY ACCESSION(S): PXD034802

REPOSITORIES: MassIVE