Potential relationship between cuproptosis and sepsis-acquired weakness: an intermediate role for mitochondria

Abstract

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Skeletal muscle atrophy due to critical illness is a common phenomenon in the intensive care unit (ICU) and is referred to as ICU-acquired weakness (ICU-AW). The occurrence of ICU-AW in patients with sepsis is known as sepsis-acquired weakness (SAW). Furthermore, it is well known that maintaining normal muscle function closely relates to mitochondrial homeostasis. Once mitochondrial function is impaired, both muscle quality and function are affected. Copper plays a key role in mitochondrial homeostasis as a transition metal that regulates the function and stability of various enzymes. Copper is also involved in oxidation-reduction reactions, and intracellular copper overload causes oxidative stress and induces cell death. Previous studies have shown that excess intracellular copper induces cell death by targeting lipid-acylated proteins that regulate the mitochondrial tricarboxylic acid (TCA) cycle, which differs from the known canonical mechanisms of regulated cell death. Furthermore, inhibitors of cell death, such as apoptosis, necroptosis, pyroptosis and ferroptosis, are not effective in preventing copper-induced cell death. This new form of cell death has been termed "Cuproptosis"; however, the mechanism by which copper-induced cell death is involved in SAW remains unclear. In this paper, we review the possible relationship between cuproptosis and SAW. Cuproptosis may be involved in regulating the pathological mechanisms of SAW through mitochondria-related signaling pathways, mitochondria-related ferroptosis mechanisms, and mitochondria-related genes, and to provide new ideas for further investigations into the mechanism of SAW.

Keywords: cell death; copper; cuproptosis; mitochondria; sepsis-acquired weakness.

FIGURE 1

Mechanism of cuproptosis. Excess intracellular copper targets lipoylated proteins that regulate the mitochondrial tricarboxylic acid (TCA) cycle to induce cell death. Excess copper enters the cell, and ferredoxin 1 (FDX1) reduces copper to toxic monovalent copper ions, which results in the lipoylation and oligomerization of proteins involved in the TCA cycle, as well as iron-sulfur cluster protein loss. Together, these factors lead to proteotoxic stress and induce cuproptosis.

FIGURE 2

Mechanism of copper overload leading to SAW. Intracellular copper overload induces mitochondrial dysfunction and thus regulates SAW through multiple signaling pathways.

FIGURE 3

Mechanisms of cuproptosis and ferroptosis in the SAW. Ferroptosis and cuproptosis may crosstalk with each other and induce SAW by impairing mitochondrial function. Ferroptosis inducers (FINs), Sorafenib (Sora) and Erastin (Era) promote cuproptosis induced by copper ion carriers (CINS) by stabilizing the ferredoxin 1 (FDX1) protein and depleting the intracellular glutathione (GSH) level. Mechanistically, FIN stabilizes FDX1 by inhibiting mitochondrial proteases. Stabilized FDX1 enhances protein-lipid acylation and facilitates the transfer of the reduced copper ion, Cu⁺. In addition, FINs inhibit cystine input by inhibiting the Xc-system, which leads to a lower GSH level and thus a higher copper ion concentration. Together, these factors enhance the aggregation of lipoylated proteins, thereby promoting cellular cuproptosis. Elesclomol decreases the expression of ATP7A, resulting in intracellular retention of copper, which in turn leads to ROS accumulation. This effect promotes the degradation of SLC7A11, which further enhance oxidative stress and ultimately lead to ferroptosis. This suggests that ferroptosis and cuproptosis may crosstalk with each other and induce SAW by impairing mitochondrial function.