# OGDH
**OGDH** (oxoglutarate dehydrogenase, also called α-ketoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase, E1k) is a human gene on chromosome 7p13 that encodes the E1 dehydrogenase subunit of the 2-[oxoglutarate dehydrogenase complex](https://www.edgepedia.org/oxoglutarate-dehydrogenase-complex), a rate-limiting enzyme of the tricarboxylic acid (TCA, Krebs) cycle located in the mitochondrial matrix.[1](https://www.ncbi.nlm.nih.gov/gene/4967) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC7647956/) The complex catalyzes the overall conversion of 2-oxoglutarate (α-ketoglutarate) to succinyl-CoA and CO₂, producing NADH that feeds the electron transport chain.[1](https://www.ncbi.nlm.nih.gov/gene/4967) • [3](https://insight.jci.org/articles/view/99922)
| Key fact | Detail |
|---|---|
| Gene and protein | OGDH (HGNC:8124), protein-coding, chromosome 7p13, 29 exons; encodes the E1 subunit of the α-ketoglutarate dehydrogenase complex[1](https://www.ncbi.nlm.nih.gov/gene/4967) |
| Reaction | Converts 2-oxoglutarate to succinyl-CoA and CO₂ in the Krebs cycle, generating NADH[1](https://www.ncbi.nlm.nih.gov/gene/4967) • [3](https://insight.jci.org/articles/view/99922) |
| Cofactor | Thiamine pyrophosphate (TPP); OGDH decarboxylates α-ketoglutarate and transfers the intermediate to the E2 component DLST[1](https://www.ncbi.nlm.nih.gov/gene/4967) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC9905285/) |
| Complex composition | OGDH (E1), dihydrolipoamide succinyltransferase DLST (E2), and lipoamide dehydrogenase DLDH/DLD (E3)[3](https://insight.jci.org/articles/view/99922) |
| Expression | Ubiquitous, highest in heart (RPKM 71.3) and kidney (RPKM 57.5)[1](https://www.ncbi.nlm.nih.gov/gene/4967) |
| Disease | Biallelic loss-of-function variants cause oxoglutarate dehydrogenase deficiency (OMIM 203740), an autosomal recessive mitochondrial disease rated Definitive by ClinGen[5](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_a84dffdc-2fb1-4ccc-9dda-20c1fcee1602-2026-02-19T050000.000Z?page=1&size=25) |
| Homologs | OGDHL and DHTKD1, structurally and functionally related E1-type enzymes acting in distinct steps of 2-oxoglutarate/2-oxoadipate metabolism[3](https://insight.jci.org/articles/view/99922) |
## Enzymatic role in the TCA cycle
In the TCA cycle, isocitrate is decarboxylated to α-ketoglutarate by isocitrate dehydrogenase, and α-ketoglutarate then undergoes decarboxylation to succinyl-CoA via the oxoglutarate dehydrogenase complex, producing NADH and releasing CO₂.[6](https://pubmed.ncbi.nlm.nih.gov/36581208/) The OGDH protein is the E1, or first, component: using thiamine pyrophosphate, it decarboxylates α-ketoglutarate and transfers the intermediate substrate to DLST, the E2 component, during the conversion to succinyl-CoA.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC9905285/) The step is described as rate-limiting for the cycle, and the complex is a major modulator of electron transport chain activity and TCA flux.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC7647956/) • [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC5289018/)
**Allosteric control.** Short-term regulation of the complex works through metabolite effectors. Animal OGDHC is very sensitive to ADP, inorganic phosphate, and Ca²⁺, which increase its affinity for 2-oxoglutarate, while it is inhibited by ATP, NADH, and succinyl-CoA; NADH additionally inhibits the E3 component competitively versus NAD⁺. Bacterial and plant forms are activated by AMP instead of ADP.[8](https://iubmb.onlinelibrary.wiley.com/doi/10.1002/bmb.2005.49403304284) This sensitivity lets the enzyme sense the cell's energy status, through the NAD⁺/NADH ratio, ADP/ATP ratio, and phosphate concentration.[9](https://www.sciencedirect.com/science/article/pii/S0014482719303246)
## Regulation of protein levels
Beyond allosteric control, OGDH abundance itself is regulated. The mitochondrial DNAJC-type co-chaperone TCAIM ([T cell](https://www.edgepedia.org/t-cell) activation inhibitor, mitochondria) specifically binds native OGDH, a interaction resolved by cryo-electron microscopy of the human OGDH-TCAIM complex, and facilitates reduction of functional OGDH protein through a mechanism dependent on the chaperone HSPA9 and the protease LONP1, decreasing OGDH complex activity and altering mitochondrial metabolism.[10](https://www.sciencedirect.com/science/article/pii/S109727652500036X) The sirtuin [SIRT5](https://www.edgepedia.org/sirt5), an NAD⁺-dependent mitochondrial deacylase, was identified as a direct post-translational switch that desuccinylates and inhibits OGDH.[9](https://www.sciencedirect.com/science/article/pii/S0014482719303246) • [11](https://affinage.wi.mit.edu/gene/OGDH) Transcriptionally, the NF-κB subunit RELA binds the OGDH promoter and drives its expression, and in the intestine the lineage-specifying factor HNF4 promotes OGDH expression in absorptive enterocytes, where experimental OGDH depletion impaired mitochondrial respiration, curtailed proliferation, and triggered cell death.[11](https://affinage.wi.mit.edu/gene/OGDH) • [12](https://media.nature.com/original/magazine-assets/d41586-025-01583-1/d41586-025-01583-1.pdf)
## Homologous enzymes
Humans encode two homologs with E1-type dehydrogenase and transketolase domains. OGDHL encodes 2-oxoglutarate dehydrogenase-like, a more recently discovered isoform of OGDH, while DHTKD1 differs mainly at the [N-terminus](https://www.edgepedia.org/n-terminus) and substrate-binding pocket; both are predicted to localize to mitochondria and act in distinct steps of 2-oxoglutarate/2-oxoadipate metabolism.[3](https://insight.jci.org/articles/view/99922) Unlike most Krebs cycle genes, which are single-copy, the genes encoding OGDH activity form this small family.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8715183/) Biallelic variants in OGDHL or DHTKD1 produce broad clinical presentations, and neither Dhtkd1 nor Ogdh knockout mice show severe phenotypes, which has been interpreted as functional compensation among the paralogs; restoring OGDH activity has been proposed as a way to alleviate symptoms of OGDHL or DHTKD1 loss.[14](https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-023-01258-4)
## OGDH deficiency
Congenital deficiency of 2-oxoglutarate dehydrogenase activity is associated with hypotonia, metabolic acidosis, and hyperlactatemia.[1](https://www.ncbi.nlm.nih.gov/gene/4967) The biochemical etiology was reported in papers between 1982 and 2000, but the genetic basis was established only in 2020, when whole-exome sequencing of two siblings of consanguineous parents identified a homozygous missense variant, c.959A>G (p.N320S), in OGDH.[5](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_a84dffdc-2fb1-4ccc-9dda-20c1fcee1602-2026-02-19T050000.000Z?page=1&size=25) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC7647956/) The children presented with global developmental delay, elevated lactate, ataxia, and seizure; patient fibroblasts showed decreased OGDH protein and enzyme activity, and the mutant protein failed to rescue lethality of Ogdh-null Drosophila, establishing a severe loss of protein function.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC7647956/) A larger 2022 series of biallelic OGDH variants described a neurodevelopmental disorder with global developmental delay, movement disorder, and metabolic abnormalities, with elevated urine α-ketoglutarate in tested individuals.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC9905285/) • [15](https://openaccess.sgul.ac.uk/id/eprint/115082/1/1-s2.0-S1098360022010000-main.pdf) ClinGen's Mitochondrial Diseases expert panel rates the OGDH–mitochondrial disease association as Definitive with autosomal recessive inheritance.[5](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_a84dffdc-2fb1-4ccc-9dda-20c1fcee1602-2026-02-19T050000.000Z?page=1&size=25)
## OGDH in cancer metabolism
As a control point of TCA flux and NADH production, the α-ketoglutarate dehydrogenase complex participates in the metabolic reprogramming of cancer cells, and its substrate α-ketoglutarate also feeds epigenetic modification pathways.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC5289018/) Several findings illustrate this. The experimental drug CPI-613, which targets the α-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes, significantly decreased mRNA expression of OGDH, DLST, and DLD in chemoresistant ovarian cancer xenografts and inhibited tumor growth.[16](https://link.springer.com/article/10.1186/s13048-024-01546-6) In gastric cancer, OGDH mediates the tumor-suppressive effects of SIRT5 on cell proliferation and migration.[9](https://www.sciencedirect.com/science/article/pii/S0014482719303246) In melanoma, high HSPA9 expression protects OGDH from glucose-deprivation-induced oxidative inactivation, ensuring OGDH-generated succinyl-CoA for succinylation of the methyltransferase METTL3, which licenses NRF2 translation and helps tumor cells evade disulfidptosis (cell death from disulfide stress during glucose starvation), a cell-death program triggered by disulfide stress under glucose starvation.[17](https://pubmed.ncbi.nlm.nih.gov/42567988/) In IDH-mutated gliomas, OGDH mRNA is significantly downregulated relative to other TCA cycle enzymes, a feature described as a metabolic hallmark of that tumor class.[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC11749698/)
## References
1. [OGDH oxoglutarate dehydrogenase [Homo sapiens] – Gene, NCBI](https://www.ncbi.nlm.nih.gov/gene/4967)
2. [Yap ZY et al. (2020). A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease. J Inherit Metab Dis.](https://pmc.ncbi.nlm.nih.gov/articles/PMC7647956/)
3. [Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis. JCI Insight.](https://insight.jci.org/articles/view/99922)
4. [Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder. Genetics in Medicine (2022).](https://pmc.ncbi.nlm.nih.gov/articles/PMC9905285/)
5. [ClinGen Gene-Disease Validity curation: OGDH – mitochondrial disease](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_a84dffdc-2fb1-4ccc-9dda-20c1fcee1602-2026-02-19T050000.000Z?page=1&size=25)
6. [Regulation and function of the mammalian tricarboxylic acid cycle (2022), PubMed](https://pubmed.ncbi.nlm.nih.gov/36581208/)
7. [The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5289018/)
8. [Strumilo S. (2005). Often ignored facts about the control of the 2-oxoglutarate dehydrogenase complex. Biochem Mol Biol Educ.](https://iubmb.onlinelibrary.wiley.com/doi/10.1002/bmb.2005.49403304284)
9. [OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S0014482719303246)
10. [The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism. Molecular Cell (2025).](https://www.sciencedirect.com/science/article/pii/S109727652500036X)
11. [OGDH – Affinage (Whitehead Institute)](https://affinage.wi.mit.edu/gene/OGDH)
12. [News & views: metabolic adaptations direct cell fate during tissue regeneration, Nature (2025)](https://media.nature.com/original/magazine-assets/d41586-025-01583-1/d41586-025-01583-1.pdf)
13. [Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8715183/)
14. [Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity, Genome Medicine (2023)](https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-023-01258-4)
15. [Biallelic variants in OGDH... Genetics in Medicine (2022), full text via SGUL](https://openaccess.sgul.ac.uk/id/eprint/115082/1/1-s2.0-S1098360022010000-main.pdf)
16. [Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors, Journal of Ovarian Research (2024)](https://link.springer.com/article/10.1186/s13048-024-01546-6)
17. [The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation, PubMed (2026)](https://pubmed.ncbi.nlm.nih.gov/42567988/)
18. [IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11749698/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Carbohydrate and energy metabolism › Citric acid cycle › Isocitrate and alpha-ketoglutarate dehydrogenation*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license