ArticlePloS one2014
Intermediary metabolite precursor dimethyl-2-ketoglutarate stabilizes hypoxia-inducible factor-1α by inhibiting prolyl-4-hydroxylase PHD2.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics.World journal of stem cells · 2026Article
- Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway.Cell regeneration (London, England) · 2025Article
- Abnormal changes in metabolites caused by mJournal of advanced research · 2025Review
- αKG-induced oxidative stress and mTOR inhibition as a therapeutic strategy for liver cancer.Medical oncology (Northwood, London, England) · 2025Article
- Identification of robust RT-qPCR reference genes for studying changes in gene expression in response to hypoxia in breast cancer cell lines.BMC genomics · 2025Article
- Hypoxic preconditioning increases mitochondrial respiration and HFrontiers in molecular neuroscience · 2025Article
- Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response.International journal of biological sciences · 2024Article
- The context-dependent role of the NaPflugers Archiv : European journal of physiology · 2023Article
- Targeting BCAT1 Combined with α-Ketoglutarate Triggers Metabolic Synthetic Lethality in Glioblastoma.Cancer research · 2022Article
- Simple Esterification of [1-ACS chemical biology · 2021Article
- Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.Nature communications · 2021Article
- Metabolic control of DNA methylation in naive pluripotent cells.Nature genetics · 2021Article
- Nitrogen Trapping as a Therapeutic Strategy in Tumors with Mitochondrial Dysfunction.Cancer research · 2020Article
- Dimethyloxalyl Glycine Regulates the HIF-1 Signaling Pathway in Mesenchymal Stem Cells.Stem cell reviews and reports · 2020Article
- Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration.EBioMedicine · 2020Article
- α-Ketoglutarate inhibits autophagy.Aging · 2019Article
- Blockage of glutamine-dependent anaplerosis affects mTORC1/2 activity and ultimately leads to cellular senescence-like response.Biology open · 2019Article
- Alpha-ketoglutarate: a "magic" metabolite in early germ cell development.The EMBO journal · 2019Article
- Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism.Oncogene · 2017Article
- Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use.Archivum immunologiae et therapiae experimentalis · 2017Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
Hypoxia-inducible factor 1α (HIF-1α), a major mediator of tumor physiology, is activated during tumor progression, and its abundance is correlated with therapeutic resistance in a broad range of solid tumors. The accumulation of HIF-1α is mainly caused by hypoxia or through the mutated succinate dehydrogenase A (SDHA) or fumarate hydratase (FH) expression to inhibit its degradation. However, its activation under normoxic conditions, termed pseudohypoxia, in cells without mutated SDHA or FH is not well documented. Here, we show that dimethyl-2-ketoglutarate (DKG), a cell membrane-permeable precursor of a key metabolic intermediate, α-ketoglutarate (α-KG), known for its ability to rescue glutamine deficiency, transiently stabilized HIF-1α by inhibiting activity of the HIF prolyl hydroxylase domain-containing protein, PHD2. Consequently, prolonged DKG-treatment under normoxia elevated HIF-1α abundance and up-regulated the expression of its downstream target genes, thereby inducing a pseudohypoxic condition. This HIF-1α stabilization phenotype is similar to that from treatment of cells with desferrioxamine (DFO), an iron chelator, or dimethyloxalyglycine (DMOG), an established PHD inhibitor, but was not recapitulated with other α-KG analogues, such as Octyl-2KG, MPTOM001 and MPTOM002. Our study is the first example of an α-KG precursor to increase HIF-1α abundance and activity. We propose that DKG acts as a potent HIF-1α activator, highlighting the potential use of DKG to investigate the contribution of PHD2-HIF-1α pathway to tumor biology.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.