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While Cox17 functions importantly in copper metalation of cytochrome c oxidase and integral mitochondrial architecture in vertebrates, rare studies have been performed regarding the developmental and physiological characters of vertebrate cox17 mutants. In this study, normal-like developmental phenotype was observed in both cox17Δ6 −/− and cox17Δ4 −/− homozygous zebrafish mutants, while gene ontology term and pathway analysis of the differentially expressed genes in both mutants showed enrichment in oxidoreductase activity, ion transport, histone methylation, MICOS complex, Wnt signaling, etc. This implied the occurrence of damage to the integral function of Cox17 and change of transcriptomes in the two mutants. Further qRT-PCR and WISH assays revealed the down-regulated expression of Wnt signaling and reduced expression of swim bladder marker genes in the two mutants. Moreover, copper stimulation induced no obvious increase in reactive oxygen species (ROS) or in the expression of hemoglobin marker genes, but further reduced the expression of swim bladder marker genes in the mutants. The integral data in this study suggest that: (1) cox17 mutants cannot activate the response of oxidoreductase to copper stimulation; (2) copper depends on the integral function of Cox17 to induce developmental defects in hemoglobin rather than swim bladder and (3) Wnt signaling but not ROS might mediate copper-induced swim bladder developmental defects in fish. Image 1 • The zebrafish cox17 mutant line was established and the function of cox17 in vertebrate was explored for the first time. • Cox17 mutants cannot activate the response of oxidoreductase to copper stimulation. • Copper depends on the integral function of Cox17 to induce developmental defects in hemoglobin. • Wnt signaling rather than ROS might mediate copper-induced swim bladder developmental defects in fish. [ABSTRACT FROM AUTHOR]

Highlights • Cu2+ and CuNPs significantly suppressed hatching in a dosage-dependent manner. • ROS scavengers and Wnt signaling agonist significantly alleviated the suppression effects of Cu2+ and CuNPs on hatching. • Cu2+ and CuNPs delayed hatching via suppressing embryonic motility rather than stimulating hatching enzyme secretion. Abstract The copper ion (Cu2+) has been reported to suppress the hatching of fish. However, little is known about the underlying mechanism. In this study, copper nanoparticles (CuNPs) and Cu2+ were shown to significantly suppress hatching of zebrafish in a dosage-dependent manner, and reactive oxygen species (ROS) scavengers NAC (N -acetylcysteine) & GSH (reduced glutathione) and Wnt signaling agonist BIO (6-bromoindirubin-3′-oxime) significantly alleviated the suppressing effects of Cu2+ and CuNPs on egg hatching. Mechanistically, NAC, GSH, and BIO recovered the egg hatching in copper-treated group via increasing the embryonic motility rather than stimulating the expression and secretion of hatching enzymes before hatching. Additionally, no significant difference in egg hatching was observed between the control and Cu2+-treated group at 72 hpf (hours post fertilization) in cox17 mutant embryos, in which little ROS was producd after copper stimulation. This may be the first report that Cu2+ and CuNPs suppress embryonic motility and the subsequent hatching via inducing ROS and at the same time down-regulating Wnt signaling in fish embryos. [ABSTRACT FROM AUTHOR]