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Abstract: SU-OR14

COX17-Mediated Abnormal Mitochondrial Copper Metabolism Promotes Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Zhu, Saiya, Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China
  • Yu, Chen, Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China
Background

Copper is a trace element essential for almost all living organisms. Previously, we found that elevated intracellular copper contributes a unique role to kidney fibrosis. Furthermore, copper ions in cells were mainly accumulated in mitochondria, which damage the structure and function of mitochondria. However, the mechanisms of the accumulation of copper ions in the mitochondria and how a disturbed copper balance induces mitochondrial dysfunction remain to be identified. Copper chaperone COX17, a protein required for cytochrome c oxidase (COX) assembly, was previously hypothesized to shuttle copper between the cytosol and mitochondria based on its dual localization. We found that in the fibrosis model COX17 was highly expressed and COX activity decreased. Therefore, we speculated that COX17 might be involved in mitochondrial copper overload and renal fibrosis.

Methods

Expression level and pattern of COX17 were examined in ischemia-reperfusion injury (IRI) AKI mice. The regulatory mechanisms of COX17 was investigated in renal tubule epithelium cell line (NRK-52E) and rat fibroblast(NRK-49F)by treating with copper or copper chelator tetrathiomolybdate (copper-chelating agent) .ICP-MS,mitoSOX,electron microscopy,realtime-PCR and western blot analysis were applied in the current study.

Results

Firstly, the expressions of COX 17,Col1 in the kidney of IRI group were extremely upregulated compared with the sham group. Unexpected, we found dysfunction of mitochondria in IRI kidneys evidenced by it’s appearing swollen and ruptured. Secondly, stimulated by TGF-β1, COX activity was declined, and mitochondrial copper content, mitochondrial reactive oxygen species and the expression of cox17, Col1 were significantly upregulated. More importantly, mitochondrial copper content and col1,fibronectin expression were reduced and mitochondrial function was improved after transfecting with COX17 shRNA.Meanwhile, treatment with copper chelator tetrathiomolybdate also alleviated renal fibrosis both in vivo and in vitro.

Conclusion

COX17 was significantly increased in renal fibrosis and transported excessive intracellular copper ions into the mitochondria. Copper overload inhibits the activity of COX and impairs mitochondria, subsequently leading to renal fibrosis.