Role of dichloroacetate in the treatment of genetic mitochondrial diseases
Open accessAbstract
Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is metabolized by and inhibits the bifunctional zeta-1 family isoform of glutathione transferase/maleylacetoacetate isomerase. Polymorphic variants of this enzyme differ in their kinetic properties toward DCA, thereby influencing its biotransformation and toxicity, both of which are also influenced by subject age. Results from open label studies and controlled clinical trials suggest chronic oral DCA is generally well-tolerated by young children and may be particularly effective in patients with PDH deficiency. Recent in vitro data indicate that a combined DCA and gene therapy approach may also hold promise for the treatment of this devastating condition.
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Dichloroacetate increases PDC activity by decreasing E1α phosphorylation and turnover.
“which stimulates PDC activity by reducing the phosphorylation and turnover of E1α (Morten et al., 1999; Stacpoole et al., 2008).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Stacpoole et al., 2008
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- Authors
- Stacpoole, P. W., Kurtz, T. L., Han, Z., & Langaee, T.
- Affiliations
- University of Florida Health (US)
- University of Florida (US)
- Corresponding author
- Stacpoole, Peter W.
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 60
- Issue
- 13-14
- Pages
- 1478-1487
- ISSN
- 0169-409X (ISSN-L)
- PMC
- PMC3746325
- OpenAlex
- W2040632966
- Cited by
- 145
- References
- 44
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 12 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 4 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 5 · 2012: 5
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
- Funders
- National Institutes of Health (5r01es014617-05)
- National Institute of Environmental Health Sciences (R01-ES014617, ES007355, R01ES007355, ES-014617)
- National Center for Research Resources (M01RR000032, M01RR000082)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- dichloroacetate, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase complex, enzyme polymorphism, drug metabolism, drug toxicity, age-related drug response, gene therapy, oral administration
- MeSH terms
- Adult, Aging, Child, Dichloroacetic Acid, Glutathione Transferase, Haplotypes, Humans, Isoenzymes, Pyruvate Dehydrogenase Complex, Pyruvate Dehydrogenase Complex Deficiency Disease, Randomized Controlled Trials as Topic, cis-trans-Isomerases, Polymorphism, Single Nucleotide, Mitochondrial Diseases
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