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

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 (KO0 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. With previous research identifying succinylation marks on histones, and with proteomic evidence of histone lysine-succinylation within the presented model, global chromatin accessibility was surveyed in Sucla2 mutant and control mice via ATAC-sequencing. Data show wide-scale alterations in chromatin landscape and global gene expression. Computational analysis of combined chromatin-accessibility and gene expression data reveal perturbation of neuronal transcriptional regulatory networks in the mutant forebrain, suggesting SCS-related changes in the protein succinylome and chromatin accessibility play a significant role in the neuronal pathogenesis of SCS-deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE208690 | GEO | 2022/07/27

REPOSITORIES: GEO

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

Project description: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 (KO0 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. With previous research identifying succinylation marks on histones, and with proteomic evidence of histone lysine-succinylation within the presented model, global chromatin accessibility was surveyed in Sucla2 mutant and control mice via ATAC-sequencing. Data show wide-scale alterations in chromatin landscape and global gene expression. Computational analysis of combined chromatin-accessibility and gene expression data reveal perturbation of neuronal transcriptional regulatory networks in the mutant forebrain, suggesting SCS-related changes in the protein succinylome and chromatin accessibility play a significant role in the neuronal pathogenesis of SCS-deficiency.

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

Project description: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.

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

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

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