PUBLICATION
Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models
- Authors
- Lavorato, M., Nakamaru-Ogiso, E., Mathew, N.D., Herman, E., Shah, N.K., Haroon, S., Xiao, R., Seiler, C., Falk, M.J.
- ID
- ZDB-PUB-220727-8
- Date
- 2022
- Source
- JCI insight 7(16): (Journal)
- Registered Authors
- Seiler, Christoph
- Keywords
- Drug therapy, Genetic diseases, Genetics, Metabolism, Mitochondria
- MeSH Terms
-
- Animals
- Caenorhabditis elegans/genetics
- Caenorhabditis elegans/metabolism
- Dichloroacetic Acid*
- F-Box Proteins*/genetics
- F-Box Proteins*/metabolism
- Humans
- Mitochondria/metabolism
- Mitochondrial Diseases*/drug therapy
- Mitochondrial Diseases*/genetics
- Ubiquitin-Protein Ligases/metabolism
- Zebrafish
- PubMed
- 35881484 Full text @ JCI Insight
Citation
Lavorato, M., Nakamaru-Ogiso, E., Mathew, N.D., Herman, E., Shah, N.K., Haroon, S., Xiao, R., Seiler, C., Falk, M.J. (2022) Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models. JCI insight. 7(16).
Abstract
Pathogenic variants in the human F Box and Leucine Rich Repeat Protein 4 (FBXL4) gene result in an autosomal recessive, multi-systemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain (RC) complex deficiencies with lactic acidemia. As no FDA-approved effective therapies exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a pyruvate dehydrogenase complex activator, dichloroacetate (DCA) in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts, which showed DCA efficacy in preventing brain damage, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1 (ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Further, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in human subjects with FBXL4-/- disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping