Lavorato 2024 JCI Insight
| Lavorato M, Iadarola D, Remes C, Kaur P, Broxton C, Mathew ND, Xiao R, Seiler C, Nakamaru-Ogiso E, Anderson VE, Falk MJ (2024) dldhcri3 zebrafish exhibited altered mitochondrial ultrastructure, morphology and dysfunction partially rescued by probucol or thiamine. JCI Insight [Epub ahead of print]. https://doi.org/10.1172/jci.insight.178973 |
Lavorato Manuela, Iadarola Donna, Remes Cristina, Kaur Prabhjot, Broxton Chynna, Mathew Neal D, Xiao Rui, Seiler Christoph, Nakamaru-Ogiso Eiko, Anderson Vernon E, Falk Marni J (2024) JCI Insight
Abstract: Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in DLD, the E3 subunit of mitochondrial Ξ±-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 Ξ±-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, Ξ±-ketoisovalerate, and Ξ±-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. β’ Keywords: Drug therapy, Genetics, Intermediary metabolism, Metabolism, Mitochondria β’ Bioblast editor: Plangger M β’ O2k-Network Lab: US PA Philadelphia Falk MJ
Oroboros Publications on Zebrafish
- Β» Zebrafish
Labels: MiParea: Respiration, Genetic knockout;overexpression
Stress:Mitochondrial disease Organism: Zebrafish, Fishes
Preparation: Homogenate
Coupling state: ET, LEAK, ROUTINE, OXPHOS
Pathway: N, S, CIV, NS, ROX
HRR: Oxygraph-2k
2024-09
