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.
[doi:10.25345/C5QN5ZG1T]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: post-translational modification ; succinyl-CoA synthetase ; succinylation ; TCA cycle ; electron transport chain ; protein-acylation ; ; chromatin ; metabolism ; neurons ; ATAC-sequencing ; mass spectrometry
Principal Investigators: (in alphabetical order) |
Amber L. Mosley, Indiana University School of Medicine, USA Brett Graham, Indiana University School of Medicine, USA |
Submitting User: | edoud |
Lancaster MS, Kim B, Doud EH, Tate MD, Sharify AD, Gao H, Chen D, Simpson E, Gillespie P, Chu X, Miller MJ, Wang Y, Liu Y, Mosley AL, Kim J, Graham BH.
Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
Cell Rep. 2023 Oct 31;42(10):113241. Epub 2023 Oct 17.
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