Please use this identifier to cite or link to this item: https://hdl.handle.net/10216/104697
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dc.creatorBrigida Pinho
dc.creatorMiguel M Santos
dc.creatorAnabela Fonseca Silva
dc.creatorPatricia Valentao
dc.creatorPaula B Andrade
dc.creatorJorge M A Oliveira
dc.date.accessioned2019-01-31T15:08:26Z-
dc.date.available2019-01-31T15:08:26Z-
dc.date.issued2013
dc.identifier.issn0007-1188
dc.identifier.othersigarra:102383
dc.identifier.urihttps://repositorio-aberto.up.pt/handle/10216/104697-
dc.description.abstractBackground and Purpose Mitochondria are a drug target in mitochondrial dysfunction diseases and in antiparasitic chemotherapy. While zebrafish is increasingly used as a biomedical model, its potential for mitochondrial research remains relatively unexplored. Here, we perform the first systematic analysis of how mitochondrial respiratory chain inhibitors affect zebrafish development and cardiovascular function, and assess multiple quinones, including ubiquinone mimetics idebenone and decylubiquinone, and the antimalarial atovaquone. Experimental Approach Zebrafish (Danio rerio) embryos were chronically and acutely exposed to mitochondrial inhibitors and quinone analogues. Concentration-response curves, developmental and cardiovascular phenotyping were performed together with sequence analysis of inhibitor-binding mitochondrial subunits in zebrafish versus mouse, human and parasites. Phenotype rescuing was assessed in co-exposure assays. Key Results Complex I and II inhibitors induced developmental abnormalities, but their submaximal toxicity was not additive, suggesting active alternative pathways for complex III feeding. Complex III inhibitors evoked a direct normal-to-dead transition. ATP synthase inhibition arrested gastrulation. Menadione induced hypochromic anaemia when transiently present following primitive erythropoiesis. Atovaquone was over 1000-fold less lethal in zebrafish than reported for Plasmodium falciparum, and its toxicity partly rescued by the ubiquinone precursor 4-hydroxybenzoate. Idebenone and decylubiquinone delayed rotenone- but not myxothiazol- or antimycin-evoked cardiac dysfunction. Conclusion and Implications This study characterizes pharmacologically induced mitochondrial dysfunction phenotypes in zebrafish, laying the foundation for comparison with future studies addressing mitochondrial dysfunction in this model organism. It has relevant implications for interpreting zebrafish disease models linked to complex I/II inhibition. Further, it evidences zebrafish's potential for in vivo efficacy or toxicity screening of ubiquinone analogues or antiparasitic mitochondria-targeted drugs.
dc.language.isoeng
dc.relationinfo:eu-repo/grantAgreement/Reitoria Universidade do Porto/Reitoria Universidade do Porto/PPII_ZEBRA/Targeting mitochondrial dysfunction with epigenetic modulatory drugs: an integrated in vitro (neurons) and in vivo (zebrafish) approach/PPII_ZEBRA
dc.relationinfo:eu-repo/grantAgreement/Reitoria Universidade do Porto/Reitoria Universidade do Porto/PPII_CARDIAC/Comparative analysis of teratogenic potential and cardiac abnormalities induced by histone deacetylase inhibitors:Predicting human health risk and environmental hazard in the zebrafish model/PPII_CARDIAC
dc.relationinfo:eu-repo/grantAgreement/FCT - Fundação para a Ciência e Tecnologia/Operacional Factores de Competitividade/PTDC/NEU-NMC/0237/2012/Inibição de KDACs e dinâmica intracelular: impacto no desenvolvimento, sobrevivência e transmissão NEUROnal /KDAC´S
dc.rightsopenAccess
dc.subjectMedicina básica
dc.subjectBasic medicine
dc.titleHow mitochondrial dysfunction affects zebrafish development and cardiovascular function: an in vivo model for testing mitochondria-targeted drugs
dc.typeArtigo em Revista Científica Internacional
dc.contributor.uportoFaculdade de Farmácia
dc.contributor.uportoFaculdade de Ciências
dc.identifier.doi10.1111/bph.12186
dc.identifier.authenticusP-006-9R8
dc.subject.fosCiências médicas e da saúde::Medicina básica
dc.subject.fosMedical and Health sciences::Basic medicine
Appears in Collections:FCUP - Artigo em Revista Científica Internacional
FFUP - Artigo em Revista Científica Internacional

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