![]() ![]() This is the first report on the novel linkage of cox17 deficiency with defective primitive erythropoiesis and reduced hypoxia tolerance. Moreover, cox17 −/− mutants exhibited significantly downregulated WNT signaling and upregulated ER stress, with a significant reduction of beta-Catenin in gata1a + cells and of binding enrichment in both scl and lmo2 promoters of the WNT transcriptional factor TCF4. Additionally, disrupting mitochondrial metabolism in wild type (WT) larvae treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could mimic the primitive erythropoiesis defects observed in cox17 −/− mutants. Mechanistically, cox17 −/− mutants showed impaired mitochondrial metabolism, coupled with a significant decrease in the mitochondrial membrane potential, ATP and SAM content, and the ratio of SAM and SAH. ![]() Meanwhile, cox17 −/− mutants showed a significant reduction in the expression of pivotal transcriptional regulators in erythropoiesis, such as scl, lmo2, and gata1a at 14 h post fertilization (hpf), with expression remaining downregulated for scl but upregulated for lmo2 and gata1a at 24 hpf. Cox17 −/− larvae were sensitive to hypoxia stress, with reduced primitive erythropoiesis. Here, we report the effects of zebrafish cox17 deficiency on primitive erythropoiesis, mitochondrial metabolism, and hypoxia tolerance. Cox deficiency is associated with hematopoietic diseases such as tubulopathy and leukodystrophy, but whether and how cox17 functions in hematopoiesis are still unknown. Cox17 is required in the assembly of mitochondrial intermembrane space (IMS) and Cu metallization of cytochrome C oxidase (CcO) in mitochondria as well as Cu homeostasis in cells. ![]()
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