PUBLICATION
Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation
- Authors
- Wei, J., Wang, S., Zhu, H., Cui, W., Gao, J., Gao, C., Yu, B., Liu, B., Chen, J., Peng, J.
- ID
- ZDB-PUB-230717-43
- Date
- 2023
- Source
- iScience 26: 107220107220 (Journal)
- Registered Authors
- Chen, Jun, Peng, Jinrong
- Keywords
- Biological sciences, Cell biology, Hepatology, Molecular biology, Sequence analysis
- MeSH Terms
- none
- PubMed
- 37456842 Full text @ iScience
Citation
Wei, J., Wang, S., Zhu, H., Cui, W., Gao, J., Gao, C., Yu, B., Liu, B., Chen, J., Peng, J. (2023) Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation. iScience. 26:107220107220.
Abstract
Copper is an essential component in the mitochondrial respiratory chain complex IV (cytochrome c oxidases). However, whether any nucleolar factor(s) is(are) involved in regulating the mitochondrial copper homeostasis remains unclear. The nucleolar localized Def-Capn3 protein degradation pathway cleaves target proteins, including p53, in both zebrafish and human nucleoli. Here, we report that hepatic depletion of mDEF in mice causes an excessive copper accumulation in the mitochondria. We find that mDEF-depleted hepatocytes show an exclusion of CAPN3 from the nucleoli and accumulate p53 and NRF1 proteins in the nucleoli. Furthermore, we find that NRF1 is a CAPN3 substrate. Elevated p53 and NRF1 enhances the expression of Sco2 and Cox genes, respectively, to allow more copper acquirement in the mDefloxp/loxp, Alb:Cre mitochondria. Our findings reveal that the mDEF-CAPN3 pathway serves as a novel mechanism for regulating the mitochondrial copper homeostasis through targeting its substrates p53 and NRF1.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping