ArticleJCI insight2024
dldhcri3 zebrafish exhibit altered mitochondrial ultrastructure, morphology, and dysfunction partially rescued by probucol or thiamine.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- 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).Journal of inherited metabolic disease · 2026Article
- Aerobic Exercise Attenuates High-Fat Diet-Induced Skeletal Muscle Atrophy by Suppressing Oxidative Stress, Inflammation, and Drp1-Associated Mitochondrial Fission.Antioxidants (Basel, Switzerland) · 2026Article
- A Framework for Selecting Zebrafish Models of Metabolic Diseases: Modeling Strategies, Phenotypic Validation, Mechanistic Investigation, and Efficacy Evaluation.Biomedicines · 2026Review
- Animal models of pyruvate dehydrogenase complex deficiency: insight into mechanisms of cerebral abnormalities and tissue-specific role in metabolism.Frontiers in medicine · 2026Review
- Hepatic Form of Dihydrolipoamide Dehydrogenase Deficiency (DLDD): Phenotypic Spectrum, Laboratory Findings, and Therapeutic Approaches in 52 Patients.Journal of inherited metabolic disease · 2025Article
- Flavor, Lipid, and Transcriptomic Profiles of Chinese Wagyu Beef Cuts: Insights into Meat Quality Differences.Foods (Basel, Switzerland) · 2025Article
- An easily overlooked cause of pulmonary arterial hypertension-thiamine deficiency.Frontiers in nutrition · 2025Review
- Evaluation of the safety and efficacy ofFrontiers in immunology · 2025Article
- Machine learning-based prediction of nasopharyngeal carcinoma risk: a clinical approach.Frontiers in immunology · 2025Article
- Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.Frontiers in pharmacology · 2025Article
- Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders.Therapeutic advances in rare diseaseArticle
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in DLD, the E3 subunit of mitochondrial α-keto (or 2-oxo) acid dehydrogenase complexes. DLD disease symptoms are multisystemic, 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, 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 that 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.
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