Abstract: FR-PO1190
COMMD1 Disrupts SOD1 Homodimerization and Activity to Drive Intracellular Copper Overload-Mediated Renal Senescence and Fibrosis
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Author
- Liu, Yuqing, Tongji Hospital Affiliated to Tongji University, Shanghai, China
Background
Renal senescence and fibrosis involve complex molecular and metabolic dysregulations. Cu/Zn superoxide dismutase (SOD1), a copper-dependent antioxidant enzyme, is essential for redox balance. SOD1 deficiency leads to accelerated renal aging and a shortened lifespan due to the accumulation of reactive oxygen species (ROS). Our previous research has demonstrated that intracellular copper overload contributes to renal senescence and fibrosis. However, the mechanistic role of intracellular copper accumulation in regulating SOD1 activity within this context remains unknown.
Methods
To assess the impact of intracellular copper levels on SOD1 dimerization and activity, we generated renal TEC-specific copper transporter 1 (CTR1) knockout mice and lentivirus-mediated CTR1 knockdown cells in vitro to reduce intracellular copper levels. The role of COMMD1 in regulating SOD1 activity, as well as its involvement in renal senescence and fibrosis, was examined by depleting COMMD1 in mice using AAV9-shCOMMD1, and employing lentivirus-mediated COMMD1 knockdown or overexpression in cells in vitro. The role of copper overload in the COMMD1-SOD1 regulatory axis and underlying mechanisms were elucidated through molecular dynamics (MD) simulations and Co-IP analysis.
Results
Reducing copper levels via CTR1 knockdown restored SOD1 activity, decreased ROS production, and alleviated renal senescence and fibrosis. Intracellular copper overload impaired SOD1 activity by decreasing SOD1 homodimers in fibrotic models. Our findings identified COMMD1 as a copper-sensitive regulator of SOD1 activity in renal fibrosis. COMMD1 was upregulated in renal fibrosis and interacted with SOD1, inhibiting its homodimer formation and enzymatic activity. COMMD1 knockdown reversed SOD1 inactivation and suppressed ROS-driven renal senescence and fibrosis, while overexpression worsened these effects. Mechanistically, intracellular copper overload enhanced COMMD1-SOD1 interaction, inhibiting SOD1 homodimer formation and its enzymatic activity.
Conclusion
Our study established a copper-COMMD1-SOD1 axis as a key driver of renal fibrosis. Pathological intracellular copper accumulation enhanced COMMD1-SOD1 interaction, promoting COMMD1-mediated suppression of SOD1 homodimerization, leading to enzymatic inactivation, ROS overproduction, and subsequent progression of renal senescence and fibrosis.
Funding
- Government Support – Non-U.S.