Metal ions overloading and cell death

Abstract

Cell death maintains cell morphology and homeostasis during development by removing damaged or obsolete cells. The concentration of metal ions whithin cells is regulated by various intracellular transporters and repositories to maintain dynamic balance. External or internal stimuli might increase the concentration of metal ions, which results in ions overloading. Abnormal accumulation of large amounts of metal ions can lead to disruption of various signaling in the cell, which in turn can produce toxic effects and lead to the occurrence of different types of cell deaths. In order to further study the occurrence and development of metal ions overloading induced cell death, this paper reviewed the regulation of Ca²⁺, Fe³⁺, Cu²⁺ and Zn²⁺ metal ions, and the internal mechanism of cell death induced by overloading. Furthermore, we found that different metal ions possess a synergistic and competitive relationship in the regulation of cell death. And the enhanced level of oxidative stress was present in all the processes of cell death due to metal ions overloading, which possibly due to the combination of factors. Therefore, this review offers a theoretical foundation for the investigation of the toxic effects of metal ions, and presents innovative insights for targeted regulation and therapeutic intervention. HIGHLIGHTS: • Metal ions overloading disrupts homeostasis, which in turn affects the regulation of cell death. • Metal ions overloading can cause cell death via reactive oxygen species (ROS). • Different metal ions have synergistic and competitive relationships for regulating cell death.

Keywords: Apoptosis; Autophagy; Cuprotosis; Ferroptosis; Ions overloading; Necrosis.

Fig. 1

Mechanism of Ca²⁺ overload-induced cell death. Cytoplasmic calcium overload causes a burst of intracellular ROS, which, on the one hand, acts directly on the cell membrane, causing membrane lipid peroxidation, resulting in cell membrane rupture and causing death, and on the other hand, stimulates the activation of mitochondria and endoplasmic reticulum to activate downstream factors that regulate cell death to induce various kinds of death

Fig. 2

Mechanism of Fe³⁺ overload-induced cell death. Cytoplasmic iron overload activates ROS and initiates oxidative stress, causing cellular ferroptosis, apoptosis and autophagy

Fig. 3

Mechanism of Cu²⁺ overload-induced cell death. Cytoplasmic occurrence of copper overload combined with esteroylated protein aggregation can induce cuprotosis, and oxidizing Cu⁺ can induce a burst of ROS, causing ferroptosis, autophagy, and apoptosis

Fig. 4

Mechanism of Zn²⁺ overload-induced cell death. Cytoplasmic zinc overload can stimulate mitochondria, lysosomes, and the nucleus to activate downstream autophagy- and apoptosis-related cytokines thereby causing cell death

Fig. 5

Mechanism of Ca²⁺\Fe³⁺\Cu²⁺\Zn²⁺ overload-induced cell death. The four metal ions have mutually promoting or inhibiting effects on each other, and ROS act as an integral part in the process of ion overload-induced death of different cells