Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation

Jinsong Wei; Shuai Wang; Haozhe Zhu; Wei Cui; Jianan Gao; Ce Gao; Bo Yu; Bojing Liu; Jun Chen; Jinrong Peng

doi:10.1016/j.isci.2023.107220

Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation

iScience. 2023 Jun 26;26(7):107220. doi: 10.1016/j.isci.2023.107220. eCollection 2023 Jul 21.

Authors

Jinsong Wei¹, Shuai Wang¹, Haozhe Zhu¹, Wei Cui¹, Jianan Gao¹, Ce Gao¹, Bo Yu², Bojing Liu¹, Jun Chen², Jinrong Peng¹

Affiliations

¹ MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
² College of Life Sciences, Zhejiang University, Hangzhou 310058, China.

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 mDef^loxp/lox^p, 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.

Keywords: Biological sciences; Cell biology; Hepatology; Molecular biology; Sequence analysis.