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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.

2022-07-27 | GSE208691 | GEO

Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation

Project description:Recent studies have shown that lysines can be posttranslationally modified by various types of acylations. However, except for acetylation, very little is known about their scope and cellular distribution. We mapped thousands of succinylation sites in bacteria (E. coli), yeast (S. cerevisiae), human (HeLa) cells, and mouse liver tissue, demonstrating widespread succinylation in diverse organisms. A majority of succinylation sites in bacteria, yeast, and mouse liver were acetylated at the same position. Quantitative analysis of succinylation in yeast showed that succinylation was globally altered by growth conditions and mutations that affected succinyl-coenzyme A (succinyl-CoA) metabolism in the tricarboxylic acid cycle, indicating that succinylation levels are globally affected by succinyl-CoA concentration. We preferentially detected succinylation on abundant proteins, suggesting that succinylation occurs at a low level and that many succinylation sites remain unidentified. These data provide a systems-wide view of succinylation and its dynamic regulation and show its extensive overlap with acetylation.

2015-06-02 | PXD002277 | Pride

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis

Project description:The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

2022-06-23 | MTBLS4307 | MetaboLights

Protein Succinylation resulting from succinyl-coA ligase deficiency

Project description:Protein hyper-succinylation in fibroblasts and myotubes derived from patients with mutations in succinyl-coA ligase.

2018-07-11 | MSV000082599 | MassIVE

Coenzyme A binding sites induce proximal acylation across protein families

Project description:Lysine acylations, such as acetylation, succinylation, or glutarylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic and only a specific subset of the proteome has been identified as acylated. Coenzyme A (CoA), a metabolite required in several metabolic pathways, can act as an acyl group carrier via a thioester bond. However, what controls the acylation of lysine residues in the mitochondria remains poorly understood. Using published datasets, we found that proteins with a CoA-binding site are more likely to be acetylated, succinylated, and glutarylated. Using computational modeling, we discovered that, in CoA-binding proteins, lysine residues near the CoA-binding pocket are more likely to be acylated than those far away from the CoA-binding pocket. We hypothesized that acyl-CoA binding enhances the acylation of nearby lysine residues. To experimentally test this hypothesis, we used enoyl-CoA hydratase short chain 1 (ECHS1), a mitochondrial protein with a CoA-binding pocket, and co-incubated ECHS1 with succinyl-CoA and CoA. Using mass spectrometry, we found that succinyl-CoA induced widespread lysine succinylation and that CoA competitively inhibited ECHS1 succinylation. In addition, CoA-induced inhibition at a particular lysine site was inversely correlated with the distance between this lysine residue and the CoA-binding pocket. This indicated that CoA acts as a competitive inhibitor of ECHS1 succinylation by binding to the CoA-binding pocket. Together, this study suggests proximal acylation at protein CoA-binding sites is a primary mechanism for lysine acylation in the mitochondria.

2022-05-09 | MSV000089448 | MassIVE

Operation of a TCA cycle subnetwork in the mammalian nucleus

Project description:<p>Nucleic acid and histone modifications critically depend on tricarboxylic acid (TCA) cycle for substrates and co-factors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass-spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus warranting a revision of the canonical view on metabolic compartmentalization.</p>

2022-06-15 | MTBLS2235 | MetaboLights

Project description:Transcriptional profiling of Salmonella enterica sv Typhimurium under NO stress and comparison of profiles between wild type and lpdA mutant cultures. We investigated the bacteriostatic nature of NO·. S. Typhmurium 14028s is prototrophic for all amino acids but cannot synthesize Methionine or Lysine during nitrosative stress. This MK auxotrophy results from reduced availability of succinyl-CoA, a consequence of NO· targeting lipoamide-dependent LpdA activity. LpdA is an essential component of the pyruvate and α-ketoglutarate dehydrogenase complexes. Additional effects of NO· on gene regulation prevent compensatory pathways of succinyl-CoA production. By microarray analysis, more than 50% of the transcriptional response of S. Typhimurium to nitrosative stress is attributable to LpdA inhibition. Two separate two-condition experiment: NO treated versus untreated, wild type versus lpdA mutant. Three biological replicates. Dye swaps performed on two of these.

2011-06-04 | E-GEOD-29735 | biostudies-arrayexpress

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis [ATAC-seq]

Project description:The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

2024-01-01 | GSE197830 | GEO

TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis [RNA-Seq]

Project description:The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

2024-01-01 | GSE197597 | GEO

Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters

Project description:Tissue homeostasis and regeneration require activation and subsequent lineage commitment of tissue-resident stem cells (SCs). These state changes are controlled by epigenetic barriers. Using hair follicle stem cells (HFSCs) as paradigm, we studied how aging impacts the chromatin landscape and function of mammalian SCs. Analyses of genome-wide chromatin accessibility revealed that aged HFSCs displayed widespread reduction of chromatin accessibility specifically at key SC self-renewal and differentiation genes that were characterized by bivalent promoters carrying both activating and repressive chromatin marks. Consistently, aged HFSCs showed reduced self-renewing capacity and attenuated ability to activate expression of these bivalent genes upon regeneration. These functional defects were niche-dependent as transplantation of aged HFSCs into young recipients or into ex vivo niches restored SC functions and transcription of poised genes. Mechanistically, aged HFSC niche displayed wide-spread alterations in extracellular matrix composition and mechanics, resulting in compressive forces on SCs and subsequent transcriptional repression, leading to loss of bivalent promoters. Tuning tissue mechanics both in vivo and in vitro recapitulated age-related SC changes, implicating niche mechanics as a central regulator of genome organization and function leading to age-dependent SC exhaustion.

2021-05-07 | PXD018352 | Pride

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