Mitochondrial L-2-hydroxyglutarate is a physiologic signaling metabolite [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE273473 | GEO | 2026/04/02
REPOSITORIES: GEO
Similar Datasets
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals, due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-HG aciduria, a rare childhood neurometabolic disorder. Thus, L-2-HG is classified as a toxic metabolite. Furthermore, L-2-HG is produced in response to hypoxia and electron transport chain (ETC) impairment. We investigated the regulation of L-2-HG levels, its impact on gene expression, and whether it has a physiological role in mice. Here, we report that elevated mitochondrial NADH/NAD+ triggers malate dehydrogenase 2 (MDH2) to produce L-2-HG from 2-OG. By contrast, L2HGDH converts L-2-HG to 2-OG in the mitochondrial matrix without requiring a functional ETC. Nascent mRNA expression analysis in mouse embryonic stem cells (mESCs) demonstrated that most genes were downregulated by elevated L-2-HG levels. To identify proteins involved in L-2-HG-dependent gene regulation, we used proteome integral solubility alteration assays (PISA), which showed that L-2-HG stabilizes the RNA demethylase FTO and H3K9 demethylases KDM4A/B/C in mESC nuclear extracts. The L-2-HG-dependent accumulation of m6A in mRNAs and H3K9me3 at the gene promoters negatively correlated with gene expression. Importantly, mitochondrial L2HGDH overexpression during early embryogenesis lowered basal L-2-HG levels and resulted in viable mice at birth but triggered reduced growth, impaired kidney development, and post-natal mortality. Thus, L-2-HG primarily downregulates gene expression and is a signaling metabolite necessary for mammalian development. These findings suggest that other previously considered toxic metabolites might also play physiological roles.
2026-03-31 | PXD054020 | Pride
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals, due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-HG aciduria, a rare childhood neurometabolic disorder2. Thus, L-2-HG is classified as a toxic metabolite2–5. Furthermore, L-2-HG is produced in response to hypoxia, acidic pH, and electron transport chain (ETC) impairment6–10. We investigated the regulation of L-2-HG levels, its impact on gene expression, and whether it has a physiological role in mice. Here, we report that elevated mitochondrial NADH/NAD+ triggers malate dehydrogenase 2 (MDH2) to produce L-2-HG from 2-OG. By contrast, L2HGDH converts L-2-HG to 2-OG in the mitochondrial matrix without requiring a functional ETC. Nascent gene expression analysis in mouse embryonic stem cells (mESCs) demonstrated that the majority of genes were downregulated by elevated L-2-HG levels. To identify proteins involved in L-2-HG-dependent gene regulation, we used proteome integral solubility alteration assays (PISA), which showed that L-2-HG engages the RNA demethylase FTO and H3K9 demethylases KDM4A/B/C in mESC nuclear extracts. The L-2-HG-dependent accumulation of m6A in mRNAs and H3K9me3 at the gene loci negatively correlated with gene expression. Importantly, mitochondrial L2HGDH overexpression during early embryogenesis lowered basal L-2-HG levels and resulted in viable mice at birth but triggered reduced growth, impaired kidney function, and post-natal mortality. Thus, L-2-HG primarily downregulates gene expression and is a signaling metabolite necessary for post-natal mammalian growth and survival. These findings suggest that other previously considered toxic metabolites might also play physiological roles.
2026-04-02 | GSE273474 | GEO
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-HG aciduria, a rare childhood neurometabolic disorder2. Thus, L-2-HG is often classified as a toxic metabolite2–5. Furthermore, L-2-HG is produced in response to hypoxia, acidic pH, and electron transport chain (ETC) impairment6–10. However, whether L-2-HG has a physiological function is unclear. Here, we investigated whether L-2-HG qualifies as a physiological signaling metabolite by testing three criteria: regulated levels, defined molecular targets, and a measurable physiological function. We report that elevated mitochondrial NADH/NAD⁺ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-oxoglutarate (2-OG) into L-2-HG, while L-2-hydroxyglutarate dehydrogenase (L2HGDH) reversibly oxidizes L-2-HG to 2-OG within the mitochondrial matrix, independently of the ETC. Proteome integral solubility alteration (PISA) assays revealed KDM4 family of H3K9 demethylases as L-2-HG-responsive targets. Consistent with the targets, elevated L-2-HG repressed nascent transcription of specific gene sets and promoted accumulation of the repressive histone mark H3K9me3 at those loci. In vivo, early embryonic L2HGDH overexpression lowered L-2-HG broadly, reduced postnatal growth, and caused postnatal mortality. Despite systemic lowering, kidneys displayed a unique vulnerability, developing fibrosis and functional decline. Mechanistically, L-2-HG depletion in the postnatal kidney resulted in a specific loss of H3K9me3 at L1MdTf retrotransposons, leading to their de-repression and coinciding with activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signaling metabolite that couples mitochondrial redox to chromatin regulation and is essential for postnatal kidney development and survival. These findings suggest that metabolites previously regarded as toxic may also serve critical physiological functions.
2026-04-02 | GSE309886 | GEO
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-hydroxyglutaric aciduria, a rare childhood neurometabolic disorder. Thus, L-2-HG is often classified as a toxic metabolite. Furthermore, L-2-HG is produced in response to hypoxia, acidic pH, and electron transport chain (ETC) impairment. However, whether L-2-HG has a physiological function is unclear. Here, we investigated whether L-2-HG qualifies as a physiologic signaling metabolite by testing three criteria: regulated levels, defined molecular targets, and a measurable physiological function. We report that an elevated mitochondrial NADH/NAD⁺ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG, while L2HGDH oxidizes L-2-HG back to 2-OG within the mitochondrial matrix without requiring a functional ETC. Proteome integral solubility alteration (PISA) assays revealed the KDM4 family of H3K9 demethylases as L-2-HG-responsive targets. Consistent with this, elevated L-2-HG repressed nascent transcription of specific gene sets and promoted accumulation of the repressive histone mark H3K9me3 at those loci. In vivo, ubiquitous early embryonic L2HGDH overexpression lowered L-2-HG, reduced postnatal growth, and caused postnatal mortality. Despite systemic lowering of L-2-HG levels, kidneys exhibited a unique vulnerability, displaying functional impairments and histologic alterations. Mechanistically, L-2-HG depletion in the postnatal kidney resulted in the loss of H3K9me3 specifically at L1MdTf retrotransposons, leading to their derepression and coinciding with activation of the integrated stress response (ISR) and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiologic signaling metabolite that couples mitochondrial redox state to chromatin regulation, which is essential for postnatal kidney function and survival. These findings suggest that metabolites previously regarded as toxic may also serve critical physiological functions.
2026-04-02 | GSE326294 | GEO
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-hydroxyglutaric aciduria, a rare childhood neurometabolic disorder. Thus, L-2-HG is often classified as a toxic metabolite. Furthermore, L-2-HG is produced in response to hypoxia, acidic pH, and electron transport chain (ETC) impairment. However, whether L-2-HG has a physiological function is unclear. Here, we investigated whether L-2-HG qualifies as a physiologic signaling metabolite by testing three criteria: regulated levels, defined molecular targets, and a measurable physiological function. We report that an elevated mitochondrial NADH/NAD⁺ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG, while L2HGDH oxidizes L-2-HG back to 2-OG within the mitochondrial matrix without requiring a functional ETC. Proteome integral solubility alteration (PISA) assays revealed the KDM4 family of H3K9 demethylases as L-2-HG-responsive targets. Consistent with this, elevated L-2-HG repressed nascent transcription of specific gene sets and promoted accumulation of the repressive histone mark H3K9me3 at those loci. In vivo, ubiquitous early embryonic L2HGDH overexpression lowered L-2-HG, reduced postnatal growth, and caused postnatal mortality. Despite systemic lowering of L-2-HG levels, kidneys exhibited a unique vulnerability, displaying functional impairments and histologic alterations. Mechanistically, L-2-HG depletion in the postnatal kidney resulted in the loss of H3K9me3 specifically at L1MdTf retrotransposons, leading to their derepression and coinciding with activation of the integrated stress response (ISR) and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiologic signaling metabolite that couples mitochondrial redox state to chromatin regulation, which is essential for postnatal kidney function and survival. These findings suggest that metabolites previously regarded as toxic may also serve critical physiological functions.
2026-04-02 | GSE326292 | GEO
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-hydroxyglutaric aciduria, a rare childhood neurometabolic disorder. Thus, L-2-HG is often classified as a toxic metabolite. Furthermore, L-2-HG is produced in response to hypoxia, acidic pH, and electron transport chain (ETC) impairment. However, whether L-2-HG has a physiological function is unclear. Here, we investigated whether L-2-HG qualifies as a physiologic signaling metabolite by testing three criteria: regulated levels, defined molecular targets, and a measurable physiological function. We report that an elevated mitochondrial NADH/NAD⁺ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG, while L2HGDH oxidizes L-2-HG back to 2-OG within the mitochondrial matrix without requiring a functional ETC. Proteome integral solubility alteration (PISA) assays revealed the KDM4 family of H3K9 demethylases as L-2-HG-responsive targets. Consistent with this, elevated L-2-HG repressed nascent transcription of specific gene sets and promoted accumulation of the repressive histone mark H3K9me3 at those loci. In vivo, ubiquitous early embryonic L2HGDH overexpression lowered L-2-HG, reduced postnatal growth, and caused postnatal mortality. Despite systemic lowering of L-2-HG levels, kidneys exhibited a unique vulnerability, displaying functional impairments and histologic alterations. Mechanistically, L-2-HG depletion in the postnatal kidney resulted in the loss of H3K9me3 specifically at L1MdTf retrotransposons, leading to their derepression and coinciding with activation of the integrated stress response (ISR) and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiologic signaling metabolite that couples mitochondrial redox state to chromatin regulation, which is essential for postnatal kidney function and survival. These findings suggest that metabolites previously regarded as toxic may also serve critical physiological functions.
2026-04-02 | GSE326291 | GEO
Project description:L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-hydroxyglutaric aciduria, a rare childhood neurometabolic disorder. Thus, L-2-HG is often classified as a toxic metabolite. Furthermore, L-2-HG is produced in response to hypoxia, acidic pH, and electron transport chain (ETC) impairment. However, whether L-2-HG has a physiological function is unclear. Here, we investigated whether L-2-HG qualifies as a physiologic signaling metabolite by testing three criteria: regulated levels, defined molecular targets, and a measurable physiological function. We report that an elevated mitochondrial NADH/NAD⁺ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG, while L2HGDH oxidizes L-2-HG back to 2-OG within the mitochondrial matrix without requiring a functional ETC. Proteome integral solubility alteration (PISA) assays revealed the KDM4 family of H3K9 demethylases as L-2-HG-responsive targets. Consistent with this, elevated L-2-HG repressed nascent transcription of specific gene sets and promoted accumulation of the repressive histone mark H3K9me3 at those loci. In vivo, ubiquitous early embryonic L2HGDH overexpression lowered L-2-HG, reduced postnatal growth, and caused postnatal mortality. Despite systemic lowering of L-2-HG levels, kidneys exhibited a unique vulnerability, displaying functional impairments and histologic alterations. Mechanistically, L-2-HG depletion in the postnatal kidney resulted in the loss of H3K9me3 specifically at L1MdTf retrotransposons, leading to their derepression and coinciding with activation of the integrated stress response (ISR) and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiologic signaling metabolite that couples mitochondrial redox state to chromatin regulation, which is essential for postnatal kidney function and survival. These findings suggest that metabolites previously regarded as toxic may also serve critical physiological functions.
2026-04-02 | GSE326293 | GEO
Project description:During early mammalian embryogenesis, dynamic changes in cell growth and proliferation are tightly linked to the underlying genetic and metabolic regulation. However, our understanding of metabolic reprogramming and its impact on epigenetic regulation in early embryo development remains elusive. We reconstruct their metabolic landscapes from the 2-cell and blastocyst stages, as well as their transition from totipotency to pluripotency. While 2-cell embryos favor methionine, polyamine and glutathione metabolism and stay in a more reductive state, blastocyst embryos have higher mitochondrial metabolites related to the tricarboxylic acid cycle, and present a more oxidative state. Moreover, we identify a reciprocal relationship between α-ketoglutarate (α-KG) and the competitive inhibitor of α-KG-dependent dioxygenases, L-2-hydroxyglutarate (2-HG), where 2-cell embryos inherited from oocytes and 1-cell zygotes display higher L-2-HG, whereas blastocysts show higher α-KG.Supplementing 2-HG or knocking down L2hgdh, a gene encoding the 2-HG consuming enzyme L-2-hydroxyglutarate dehydrogenase impeded erasure of global histone methylation markers . Together, our data demonstrate dynamic and interconnected metabolic, transcriptional and epigenetic network remodeling during murine early embryo development.
2021-10-14 | GSE181648 | GEO
Project description:2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide utagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc) – the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.
2020-07-27 | PXD020128 | Pride
Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.
2022-03-09 | GSE197606 | GEO