Dichloroacetate Improves Animal Survival, Growth, Neuromuscular Activity, Mitochondrial Stress and Physiology, and Elevated Lactate in C. elegans pdha-1 and dld-1 RNAi Models of Pyruvate Dehydrogenase Complex Deficiency (PDCD).
4 affiliations
- 1Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.
- 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
- 3Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
- 4Department of Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
Pyruvate dehydrogenase complex (PDHc) deficiency (PDCD) is a primary mitochondrial disorder characterized by neurodevelopmental disability, altered intermediary metabolism, and early mortality. Dichloroacetate (DCA), a pyruvate analog, activates PDHc and remains under clinical investigation for treatment of PDCD. Here, we studied the in vivo efficacy of a five-point log concentration range of DCA on animal health and metabolism in C. elegans with feeding RNA interference (RNAi) expression knockdown of either PDHA-1 or DLD-1 homologs at graded degrees to model variable disease severity. These worm models recapitulate phenotypic features of PDCD observed in human patients, including reduced survival, delayed growth, locomotor impairment, and elevated lactate and/or pyruvate tissue levels. DCA treatment appeared well-tolerated, with no gross morphologic toxicity seen at doses up to 25 mM. Significantly improved health, survival, tissue lactate levels, and mitochondrial physiology were observed at 25 mM in pdha-1(RNAi) knockdown animals. DCA treatment in dld-1(RNAi) C. elegans models (undiluted, 1:20 dilution, and 1:100 dilution) significantly improved survival, neuromuscular function, and metabolic phenotypes primarily in the moderate (1:20) and/or mild (1:100) dld-1(RNAi) deficiency strains, but not in full-dose dld-1(RNAi). Importantly, linear growth, neuromuscular activity, and mitochondrial physiology were significantly improved with DCA treatment even in the most severe dld-1(RNAi) undiluted model. Overall, preclinical modeling provides objective evidence of DCA therapeutic efficacy in C. elegans knockdown strains for two well-conserved homologs of PDHA1 and DLD representing distinct genetic etiologies of PDCD, with demonstrated beneficial effects on survival, healthspan, tissue lactate, and mitochondrial physiology. These data further confirm that DCA's therapeutic effect correlates with PDHc disease phenotype severity in dld-1(RNAi) animals.
Related
- N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity
- SH3BP2 deficiency in skeletal muscle leads to neuromuscular junction abnormalities and decreased muscle strength.
- SWI/SNF subunit SMARCD1 deficiency promotes clear cell renal cell carcinoma progression via mitochondrial reprogramming
- A respiratory microdomain links ubiquinone biosynthesis to succinate dehydrogenase in an apicomplexan mitochondrion lacking Complex I
- Rational design of L-Pantolactone dehydrogenase to enhance the activity of whole-cell biocatalyst
BibTeX
@article{remes2026dichloroacetate,
title = {{Dichloroacetate Improves Animal Survival, Growth, Neuromuscular Activity, Mitochondrial Stress and Physiology, and Elevated Lactate in C. elegans pdha-1 and dld-1 RNAi Models of Pyruvate Dehydrogenase Complex Deficiency (PDCD).}},
author = {Cristina Remes and Neal D Mathew and Victoria Miranda and Suraiya Haroon and Tyler O'Hara and Vernon E Anderson and Manuela Lavorato and Kelsey Keith and Rui Xiao and Eiko Nakamaru-Ogiso and Marni J Falk},
journal = {Journal of inherited metabolic disease},
year = {2026},
month = oct,
doi = {10.1002/jimd.70257},
url = {https://europepmc.org/article/MED/42844987},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dichloroacetate Improves Animal Survival, Growth, Neuromuscular Activity, Mitochondrial Stress and Physiology, and Elevated Lactate in C. elegans pdha-1 and dld-1 RNAi Models of Pyruvate Dehydrogenase Complex Deficiency (PDCD).
AU - Cristina Remes
AU - Neal D Mathew
AU - Victoria Miranda
AU - Suraiya Haroon
AU - Tyler O'Hara
AU - Vernon E Anderson
AU - Manuela Lavorato
AU - Kelsey Keith
AU - Rui Xiao
AU - Eiko Nakamaru-Ogiso
AU - Marni J Falk
PY - 2026
DA - 2026/10/30
JO - Journal of inherited metabolic disease
DO - 10.1002/jimd.70257
UR - https://europepmc.org/article/MED/42844987
AB - Pyruvate dehydrogenase complex (PDHc) deficiency (PDCD) is a primary mitochondrial disorder characterized by neurodevelopmental disability, altered intermediary metabolism, and early mortality. Dichloroacetate (DCA), a pyruvate analog, activates PDHc and remains under clinical investigation for treatment of PDCD. Here, we studied the in vivo efficacy of a five-point log concentration range of DCA on animal health and metabolism in C. elegans with feeding RNA interference (RNAi) expression knockdown of either PDHA-1 or DLD-1 homologs at graded degrees to model variable disease severity. These worm models recapitulate phenotypic features of PDCD observed in human patients, including reduced survival, delayed growth, locomotor impairment, and elevated lactate and/or pyruvate tissue levels. DCA treatment appeared well-tolerated, with no gross morphologic toxicity seen at doses up to 25 mM. Significantly improved health, survival, tissue lactate levels, and mitochondrial physiology were observed at 25 mM in pdha-1(RNAi) knockdown animals. DCA treatment in dld-1(RNAi) C. elegans models (undiluted, 1:20 dilution, and 1:100 dilution) significantly improved survival, neuromuscular function, and metabolic phenotypes primarily in the moderate (1:20) and/or mild (1:100) dld-1(RNAi) deficiency strains, but not in full-dose dld-1(RNAi). Importantly, linear growth, neuromuscular activity, and mitochondrial physiology were significantly improved with DCA treatment even in the most severe dld-1(RNAi) undiluted model. Overall, preclinical modeling provides objective evidence of DCA therapeutic efficacy in C. elegans knockdown strains for two well-conserved homologs of PDHA1 and DLD representing distinct genetic etiologies of PDCD, with demonstrated beneficial effects on survival, healthspan, tissue lactate, and mitochondrial physiology. These data further confirm that DCA's therapeutic effect correlates with PDHc disease phenotype severity in dld-1(RNAi) animals.
SN - 0141-8955
SN - 1573-2665
ER -