Mechanisms and therapeutic strategies of copper homeostasis in the pathogenesis of sepsis-induced cardiomyopathy

Figures

• 

  FIGURE 1. Copper plays a critical role in cellular processes and disease pathogenesis. Following uptake into the body, Cu2+ is reduced to Cu+ by epithelial antigen of the prostate (STEAP) and duodenal cytochrome b (DCYBT), and subsequently imported into hepatocytes via the copper transporter 1 (CTR1). The intracellular copper is then exported into bile for elimination by the transporters copper-transporting ATPase alpha/beta (ATP7A/B). Excess copper disrupts mitochondrial function, leading to the loss of Fe-S cluster proteins and the aggregation of lipoylated proteins, which ultimately triggers cuproptosis, a novel form of regulated cell death. In the context of sepsis-induced cardiomyopathy, excessive copper promotes mitochondrial damage, inflammatory infiltration, and disruption of calcium homeostasis in cardiomyocytes, culminating in cuproptosis and the development of cardiac dysfunction.

• 

  FIGURE 2. Copper metabolism at the cellular level. Extracellular Cu2+ is reduced by the reductase six-transmembrane epithelial antigen of the prostate (STEAP) and duodenal cytochrome b (DCYBT) to Cu+, which is transported into the cell by the Cu transporter copper transporter 1 (CTR1), where it is delivered to cytosolic Cu chaperones such as copper chaperone for superoxide dismutase (CCS) and superoxide dismutase 1 (SOD1) and then delivered to specific subcellular compartments such as the mitochondria, trans Golgi network (TGN), and nucleus. Antioxidant-1 (ATOX1) transports Cu+ to the nucleus, where it binds to transcription factors and drives gene expression, In the nucleus, Cu can bind to transcription factors and drive gene expression, In the TGN, copper-transporting ATPase alpha (ATP7A) and copper-transporting ATPase beta (ATP7B), which are Cu+-ATPase transporters, transfer Cu to its lumen, When intracellular Cu + increases, these Cu+-ATPase fuse with the plasma membrane to export Cu+. In the basolateral membrane of enterocytes, ATP7A facilitates the pumping of copper into the portal circulation, where it subsequently enters the liver, the primary organ responsible for copper storage.…

• 

  FIGURE 3. Copper in Septic-induced Cardiomyopathy. Excessive copper promote the production of inflammatory factors (e.g., IL-1β and TNF-α) and reactive oxygen species (ROS), thereby activating the nuclear factor-κB (NF-κB) signaling pathway. The influx of excess copper into cells via copper transporter 1 (CTR1) induces mitochondrial damage. Within cardiomyocytes, elevated copper levels inhibit superoxide dismutase (SOD) activity and exacerbate ROS accumulation. Concurrently, copper suppresses the expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), thereby reducing calcium uptake by the sarcoplasmic reticulum and leading to disruption of calcium homeostasis. Furthermore, this calcium dysregulation triggers aberrant opening of the mitochondrial permeability transition pore (MPTP), which exacerbates mitochondrial injury. Collectively, these cascade events ultimately contribute to the pathogenesis of septic cardiomyopathy.