Copper-instigated modulatory cell mortality mechanisms and progress in kidney diseases

Abstract

Copper is a vital cofactor in various enzymes, plays a pivotal role in maintaining cell homeostasis. When copper metabolism is disordered and mitochondrial dysfunction is impaired, programmed cell death such as apoptosis, paraptosis, pyroptosis, ferroptosis, cuproptosis, autophagy and necroptosis can be induced. In this review, we focus on the metabolic mechanisms of copper. In addition, we discuss the mechanism by which copper induces various programmed cell deaths. Finally, this review examines copper's involvement in prevalent kidney diseases such as acute kidney injury and chronic kidney disease. The findings indicate that the use of copper chelators or plant extracts can mitigate kidney damage by reducing copper accumulation, offering novel insights into the pathogenesis and treatment strategies for kidney diseases.

Keywords: Copper homeostasis; cell death; copper chelator; kidney diseases; therapy.

Figure 1.

Copper metabolism. Cu²⁺ is reduced to Cu⁺ by the STEAP, Cu⁺ primarily enters cells through CTR1, while Cu²⁺ can directly enter cells through DMT1. Once inside the cell, Cu⁺ can bind with MT and GSH; it can cause DNA damage by binding to DNA; after binding with CuL, it enters the mitochondrial matrix through SLC25A3 to perform function; binding with ATOX, it transports copper to ATP7A and ATP7B on the trans-Golgi network or plasma membrane, pumping copper outside the cell.

Figure 2.

Copper in mitochondrion. After entering the mitochondrial matrix, some copper can be transferred via CCS to SOD1. Some copper is inserted by SCO1/SCO2 into Cu_A site in COX2 and can be moved to COX11, which then delivers the copper to Cu_B site in COX1 for utilization by CcO.

Figure 3.

Copper and programmed cell death.