Mitochondrial calcium uniporter links acetyl-CoA metabolism and H3K27 acetylation to maintain glioblastoma stem cells
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ABSTRACT:
PROVIDER: PRJNA1220592 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma stem cells (GSCs) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. However, the mechanisms underlying this plasticity remain incompletely understood. Here, we identify a novel metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC fate and tumor initiation. MCU is preferentially expressed in GSCs, and its knockdown significantly impairs GSC self-renewal and viability. Mechanistically, MCU enhances mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation, which drives histone H3K27 acetylation at the TRIB3 locus to sustain stemness programs. In glioblastoma patients, higher MCU expression is correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced TRIB3 expression, higher tumor grade, and poorer survival. Pharmacological inhibition of MCU with Berberine suppresses GSC growth and extends survival in mice. These findings establish MCU as a critical link between mitochondrial metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.
2025-02-28 | GSE289005 | GEO
Project description:Glioblastoma stem cells (GSCs) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. However, the mechanisms underlying this plasticity remain incompletely understood. Here, we identify a novel metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC fate and tumor initiation. MCU is preferentially expressed in GSCs, and its knockdown significantly impairs GSC self-renewal and viability. Mechanistically, MCU enhances mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation, which drives histone H3K27 acetylation at the TRIB3 locus to sustain stemness programs. In glioblastoma patients, higher MCU expression is correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced TRIB3 expression, higher tumor grade, and poorer survival. Pharmacological inhibition of MCU with Berberine suppresses GSC growth and extends survival in mice. These findings establish MCU as a critical link between mitochondrial metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.
2025-02-28 | GSE289004 | GEO
Project description:Mitochondrial calcium uniporter links acetyl-CoA metabolism and H3K27 acetylation to maintain glioblastoma stem cells [ChIP-Seq]
| PRJNA1220593 | ENA
Project description:Acetyl-Coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27). The increase of H3K27 acetylation (H3K27ac) is dependent on ATP-citrate lyase which cleaves citrate to acetyl-CoA in the cytoplasm, and requires histone acetyltransferase GCN5. A comprehensive analysis of the transcriptome and metabolome in combination with the genome-wide H3K27ac profiles of acc1 mutants, demonstrate the dynamic changes of H3K27ac, gene transcripts and metabolites occurring in the cell by the increased levels of acetyl-CoA. This study suggests that H3K27ac is an important link between cytosolic acetyl-CoA level and gene expression in response to the dynamic metabolic environments in plants.
2017-09-25 | GSE79524 | GEO
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.
2013-11-21 | E-GEOD-47983 | biostudies-arrayexpress
Project description:The mitochondria sirtuin 4 (SIRT4) is well-known as a tumor suppressor by controlling several metabolic pathways, although it is highly expressed in certain cancers including hepatocellular carcinoma (HCC). Here, we reported that SIRT4 was highly expressed in a subset of the voltage-gated calcium channel α2δ1 subunit-positive HCC tumor-initiating cells (TIC), and was upregulated by α2δ1-mediated calcium signaling. Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties and invasiveness of HCC cells by directly deacetylating the leucine catabolism pathway enzyme－3-methylcrotonyl-CoA carboxylase 2 (MCCC2) at K269, leading to the formation of a stable MCCC1/MCCC2 complex with robust MCCC enzymatic activity to produce increased levels of acetyl-CoA, which subsequently resulted in increased levels of H3K27 acetylation and stem cell-like properties at tested doses≤2 µM. Interestingly, the expression of SIRT4 in HCC tissues was predictive of poor prognosis of the patients. These findings identify SIRT4 as an oncogene to promote stemness and invasiveness by controlling the production of acetyl-CoA, linking α2δ1-mediated calcium signaling to SIRT4-mediated epigenetic regulation of the stem cell-like properties which hold significant potential for the development of innovative therapeutic strategies targeting HCC TICs.
2024-12-31 | GSE279886 | GEO
Project description:The mitochondria sirtuin 4 (SIRT4) is well-known as a tumor suppressor by controlling several metabolic pathways, although it is highly expressed in certain cancers including hepatocellular carcinoma (HCC). Here, we reported that SIRT4 was highly expressed in a subset of the voltage-gated calcium channel α2δ1 subunit-positive HCC tumor-initiating cells (TIC), and was upregulated by α2δ1-mediated calcium signaling. Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties and invasiveness of HCC cells by directly deacetylating the leucine catabolism pathway enzyme－3-methylcrotonyl-CoA carboxylase 2 (MCCC2) at K269, leading to the formation of a stable MCCC1/MCCC2 complex with robust MCCC enzymatic activity to produce increased levels of acetyl-CoA, which subsequently resulted in increased levels of H3K27 acetylation and stem cell-like properties at tested doses≤2 µM. Interestingly, the expression of SIRT4 in HCC tissues was predictive of poor prognosis of the patients. These findings identify SIRT4 as an oncogene to promote stemness and invasiveness by controlling the production of acetyl-CoA, linking α2δ1-mediated calcium signaling to SIRT4-mediated epigenetic regulation of the stem cell-like properties which hold significant potential for the development of innovative therapeutic strategies targeting HCC TICs.
2024-12-31 | GSE280121 | GEO
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1Δ acs2Δ S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor.
2013-11-21 | GSE47983 | GEO
Project description:The mitochondrial calcium uniporter has been proposed to coordinate the organelle’s energetics with cytosolic calcium signaling. Previous studies have shown that the uniporter current is extremely high in mitochondria from brown adipose tissue (BAT), yet the contribution of the uniporter to BAT physiology in vivo is not known. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice are born in Mendelian ratios on a C57BL6/J genetic background, without any overt phenotypes. Although uniporter based calcium uptake is selectively ablated in BAT mitochondria, these mice are able to defend their body temperature in response to cold challenge and exhibit a normal body weight trajectory on a high fat diet. BAT transcriptional profiles at baseline and following cold-challenge are intact and not impacted by loss of Mcu. Unexpectedly, we found that cold powerfully activates the ATF4-dependent integrated stress response in BAT, and increases both circulating FGF21 and GDF15 levels, raising the hypothesis that the integrated stress response partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis, and unexpectedly, uncovers a striking activation of the integrated stress response of BAT to cold challenge.
2019-04-30 | GSE119964 | GEO
Project description:In order to identify regions of the genome that display quantitative changes in acetyl-CoA, we utilized an established “spike-in” normalization method that allows the quantitative comparison of histone modifications across cell populations using defined quantities of a reference epigenome. We found that some regions of the genome are more sensitive to changes in acetyl-CoA compared to others.
2018-12-20 | GSE109340 | GEO