PUBLICATION
Zebrafish cox17 modulates primitive erythropoiesis via regulation of mitochondrial metabolism to facilitate hypoxia tolerance
- Authors
- Li, L., Chen, M., Liu, W., Tai, P., Liu, X., Liu, J.X.
- ID
- ZDB-PUB-221009-4
- Date
- 2022
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36: e22596 (Journal)
- Registered Authors
- Keywords
- cox17 −/−, scl/lmo2, WNT, erythrogenesis, mitochondrial metabolism
- MeSH Terms
-
- Adenosine Triphosphate/metabolism
- Animals
- Carbonyl Cyanide m-Chlorophenyl Hydrazone
- Cytochrome-c Oxidase Deficiency*/metabolism
- Electron Transport Complex IV/genetics
- Electron Transport Complex IV/metabolism
- Erythropoiesis
- Hypoxia/metabolism
- LIM Domain Proteins/metabolism
- Mitochondria/metabolism
- Transcription Factors/metabolism
- Zebrafish*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- beta Catenin/metabolism
- PubMed
- 36208295 Full text @ FASEB J.
Citation
Li, L., Chen, M., Liu, W., Tai, P., Liu, X., Liu, J.X. (2022) Zebrafish cox17 modulates primitive erythropoiesis via regulation of mitochondrial metabolism to facilitate hypoxia tolerance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 36:e22596.
Abstract
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. Cox deficiency is associated with hematopoietic diseases such as tubulopathy and leukodystrophy, but whether and how cox17 functions in hematopoiesis are still unknown. Here, we report the effects of zebrafish cox17 deficiency on primitive erythropoiesis, mitochondrial metabolism, and hypoxia tolerance. Cox17-/- larvae were sensitive to hypoxia stress, with reduced primitive erythropoiesis. 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. 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. 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. 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. This is the first report on the novel linkage of cox17 deficiency with defective primitive erythropoiesis and reduced hypoxia tolerance. This study has shed light on the potential mechanism by which Cox deficiency, especially cox17 deficiency, induces Cu homeostasis imbalance, leading to hematopoietic diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping