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Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE135531 | GEO | 2019/08/22

REPOSITORIES: GEO

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Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.

Project description:Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased ?-ketoglutarate (?KG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of ?KG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation.

| S-EPMC6778142 | biostudies-literature

Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (ATAC-seq)

Project description:Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that inhibition of mCa2+ uptake in fibroblasts enhances myofibroblast formation and this translates to increased fibrosis following injury. Fibrotic signaling alters the gating of the mitochondrial calcium uniporter (mtCU) to reduce mCa2+ uptake and induce specific changes in metabolism. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent demethylases which epigenetically modify promoter regions specific to the myofibroblast gene program resulting in differentiation. Our results uncover an important role for mCa2+ uptake beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation.

2019-08-22 | GSE135530 | GEO

Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (RNA-seq)

Project description:Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that inhibition of mCa2+ uptake in fibroblasts enhances myofibroblast formation and this translates to increased fibrosis following injury. Fibrotic signaling alters the gating of the mitochondrial calcium uniporter (mtCU) to reduce mCa2+ uptake and induce specific changes in metabolism. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent demethylases which epigenetically modify promoter regions specific to the myofibroblast gene program resulting in differentiation. Our results uncover an important role for mCa2+ uptake beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation.

2019-08-22 | GSE135529 | GEO

Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation

Project description:Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation

| PRJNA559172 | ENA

Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (RNA-seq)

Project description:Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (RNA-seq)

| PRJNA559174 | ENA

Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (ATAC-seq)

Project description:Mitochondrial Calcium Exchange links Metabolism with the Epigenome to Control Cellular Differentiation (ATAC-seq)

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The mitochondrial transporter SLC25A25 links ciliary TRPP2 signaling and cellular metabolism.

Project description:Cilia are organelles specialized in movement and signal transduction. The ciliary transient receptor potential ion channel polycystin-2 (TRPP2) controls elementary cilia-mediated physiological functions ranging from male fertility and kidney development to left-right patterning. However, the molecular components translating TRPP2 channel-mediated Ca2+ signals into respective physiological functions are unknown. Here, we show that the Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier 25 A 25 (SLC25A25) acts downstream of TRPP2 in an evolutionarily conserved metabolic signaling pathway. We identify SLC25A25 as an essential component in this cilia-dependent pathway using a genome-wide forward genetic screen in Drosophila melanogaster, followed by a targeted analysis of SLC25A25 function in zebrafish left-right patterning. Our data suggest that TRPP2 ion channels regulate mitochondrial SLC25A25 transporters via Ca2+ establishing an evolutionarily conserved molecular link between ciliary signaling and mitochondrial metabolism.

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ATP-citrate lyase links cellular metabolism to histone acetylation.

Project description:Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.

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IRGM1 links mitochondrial quality control to autoimmunity.

Project description:Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA-dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1-/- tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.

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Short-chain fatty acids propionate and butyrate control growth and differentiation linked to cellular metabolism

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-10 | GSE252653 | GEO