PUBLICATION
dldhcri3 zebrafish exhibited altered mitochondrial ultrastructure, morphology and dysfunction partially rescued by probucol or thiamine
- Authors
- Lavorato, M., Iadarola, D., Remes, C., Kaur, P., Broxton, C., Mathew, N.D., Xiao, R., Seiler, C., Nakamaru-Ogiso, E., Anderson, V.E., Falk, M.J.
- ID
- ZDB-PUB-240821-5
- Date
- 2024
- Source
- JCI insight 9(18): (Journal)
- Registered Authors
- Falk, Marni, Seiler, Christoph
- Keywords
- Drug therapy, Genetics, Intermediary metabolism, Metabolism, Mitochondria
- MeSH Terms
-
- Amino Acids, Branched-Chain/metabolism
- Animals
- Dihydrolipoamide Dehydrogenase/genetics
- Dihydrolipoamide Dehydrogenase/metabolism
- Disease Models, Animal*
- Mitochondria*/drug effects
- Mitochondria*/metabolism
- Mitochondria*/pathology
- Mitochondria*/ultrastructure
- Mitochondrial Diseases/drug therapy
- Mitochondrial Diseases/metabolism
- Mitochondrial Diseases/pathology
- Probucol*/pharmacology
- Zebrafish*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 39163131 Full text @ JCI Insight
Citation
Lavorato, M., Iadarola, D., Remes, C., Kaur, P., Broxton, C., Mathew, N.D., Xiao, R., Seiler, C., Nakamaru-Ogiso, E., Anderson, V.E., Falk, M.J. (2024) dldhcri3 zebrafish exhibited altered mitochondrial ultrastructure, morphology and dysfunction partially rescued by probucol or thiamine. JCI insight. 9(18):.
Abstract
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in DLD, the E3 subunit of mitochondrial α-keto acid dehydrogenase complexes. DLD disease symptoms are multi-systemic, variably manifesting as Leigh syndrome, neurodevelopmental disability, seizures, cardiomyopathy, liver disease, fatigue and lactic acidemia. While most DLD disease symptoms are attributed to dysfunction of the pyruvate dehydrogenase complex, understanding the effects of other α-keto acid dehydrogenase deficiencies remain unclear. Current therapies for DLD deficiency are ineffective, with no vertebrate animal model available for preclinical study. We created a viable Danio rerio (zebrafish) KO model of DLD deficiency, dldhcri3. Detailed phenotypic characterization revealed shortened larval survival, uninflated swim bladder, hepatomegaly and fatty liver, and reduced swim activity. These animals displayed increased pyruvate and lactate levels, with severe disruption of branched-chain amino acid catabolism manifest as increased valine, leucine, isoleucine, α-ketoisovalerate, and α-ketoglutarate levels. Evaluation of mitochondrial ultrastructure revealed gross enlargement, severe cristae disruption and reduction in matrix electron density in liver, intestines, and muscle. Therapeutic modeling of candidate therapies demonstrated probucol or thiamine improved larval swim activity. Overall, this vertebrate model demonstrated characteristic phenotypic and metabolic alterations of DLD disease, offering a robust platform to screen and characterize candidate therapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping