How mitochondrial dysfunction affects zebrafish development and cardiovascular function: an in vivo model for testing...

Area of Science:

• Mitochondrial biology
• Pharmacology
• Developmental biology

Background:

• Mitochondria are key drug targets for diseases and antiparasitic treatments.
• Zebrafish are an emerging biomedical model with unexplored potential in mitochondrial research.

Purpose of the Study:

• To systematically analyze the effects of mitochondrial respiratory chain inhibitors on zebrafish development and cardiovascular function.
• To evaluate quinones, including ubiquinone mimetics (idebenone, decylubiquinone) and atovaquone, in zebrafish.

Main Methods:

• Chronic and acute exposure of zebrafish embryos to mitochondrial inhibitors and quinone analogues.
• Concentration-response curves, developmental and cardiovascular phenotyping.
• Sequence analysis of inhibitor-binding sites and phenotype rescue assays.

Main Results:

• Complex I/II inhibitors caused developmental abnormalities; toxicity was not additive, indicating alternative pathways.
• Complex III inhibitors induced rapid mortality; ATP synthase inhibition arrested gastrulation.
• Atovaquone showed low toxicity in zebrafish compared to Plasmodium falciparum; idebenone and decylubiquinone modulated cardiac dysfunction.

Conclusions:

• Characterized pharmacologically induced mitochondrial dysfunction phenotypes in zebrafish, providing a basis for future studies.
• Demonstrated zebrafish's utility for in vivo screening of drugs targeting mitochondrial function.
• Implications for interpreting zebrafish models of mitochondrial disease and for antiparasitic drug development.