PUBLICATION
Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio)
- Authors
- Zhao, R., Zhao, J., Xia, W., Yu, W., Zhou, H., Wang, X., Mai, K., He, G., Liu, C.
- ID
- ZDB-PUB-260513-4
- Date
- 2026
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40: e71812e71812 (Journal)
- Registered Authors
- Keywords
- ATF4, ISR, hypoxia, mitophagy, parkin
- MeSH Terms
- none
- PubMed
- 42118049 Full text @ FASEB J.
Citation
Zhao, R., Zhao, J., Xia, W., Yu, W., Zhou, H., Wang, X., Mai, K., He, G., Liu, C. (2026) Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio). FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 40:e71812e71812.
Abstract
The Integrated Stress Response (ISR) is a vital cellular mechanism that regulates cell survival during various stress conditions, including hypoxia. Activating transcription factor 4 (ATF4) is recognized as a key regulator of ISR, however, its role in hypoxic stress responses remain underexplored. In the present study, we generated an Atf4a-deficient zebrafish model to investigate the role of Atf4a in hypoxia tolerance, mitochondrial homeostasis, and cellular stress adaptation. The results showed that atf4a knockout led to significant growth impairment, endoplasmic reticulum and mitochondrial dysfunction, and disrupted energy metabolism, particularly under hypoxic conditions. We observed an increase in mitochondrial DNA and impaired mitochondrial morphology in Atf4a-deficient zebrafish. Metabolomic analysis revealed significant alterations in the pentose phosphate pathway and TCA cycle following atf4a knockout. Additionally, we observed increased mitochondrial oxidative stress and reduced antioxidant capacity in atf4a mutants. Atf4a-deficiency also led to decreased expression of the mitophagy-related gene p62 and parkin. Atf4a transcriptionally regulates the expression of parkin, suggesting that Atf4a regulates mitochondrial homeostasis through parkin-mediated mitophagy in zebrafish. These results underscore the critical role of Atf4a in maintaining cellular homeostasis, mitochondrial integrity, and metabolic adaptation during hypoxic stress, highlighting its potential as a therapeutic target for stress-related diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping