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Abstract: FR-PO1078

Excessive Mitochondrial Copper Load Driven by Upregulated Copper Transporter 1 Contributes to Mitochondrial Dysfunction and Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Zhu, Saiya, Tongji University, Shanghai, Shanghai, China

Copper is an essential trace element in living organisms and serves as a crucial cofactor for various enzymes. Our previous research has revealed that intracellular copper overload promotes renal fibrosis. However, the underlying mechanisms remain largely unknown. In this study, we found that copper ions mainly accumulate in mitochondria, leading to oligomerization of the DLAT protein involved in the tricarboxylic acid cycle, mitochondrial dysfunction, cellular apoptosis and renal fibrosis. Additionally, copper transporter 1 (CTR1), responsible for transporting copper ions into cells, was significantly upregulated in the renal fibrosis models. Therefore, we propose that CTR1 may drive mitochondrial copper overload, resulting in mitochondrial dysfunction and renal fibrosis.


We assessed the expression levels of CTR1 in fibrotic renal biopsy samples, 28-day fibrosis model of ischemia-reperfusion injury, and NRK-52E cell treated with TGF-β1.We used lentiviral vectors to overexpress and downregulate of CTR1 in NRK-52E and used CTR1 knockdown transgenic mice. Molecular dynamics simulations were conducted to explore the effect of copper ions on the lipoylated DLAT protein. ICP-MS was used to study the regulatory role of CTR1 on mitochondrial copper content. Non-reducing gel electrophoresis was performed to detect DLAT oligomer level. DLAT enzyme activity was evaluated. We used mitoSOX staining and electron microscopy to investigate mitochondrial function. We also use WB, QPCR and Masson to explore the role of CTR1 in renal fibrosis.


Compared to the sham-operated group, mitochondrial copper was overload in IRI 28d fibrotic model and led to mitochondrial swelling and mitochondrial dysfunction. Furthermore, mitochondrial copper overload targeted lipoylated modification sites of DLAT, leading to DLAT oligomerization, enzyme activity inhibition and increased mitochondrial reactive oxygen species. Additionally, CTR1 was increased in fibrotic renal biopsy samples, IRI 28d fibrosis model and TGF-β1 treated cells. Downregulation of CTR1 decreased mitochondrial copper level and improved mitochondrial function.


In renal fibrosis, high expression of CTR1 drives mitochondrial copper overload, leading to abnormal aggregation of lipoylated DLAT protein, enzyme activity inhibition, mitochondrial dysfunction and renal fibrosis.