Iron and copper: critical executioners of ferroptosis, cuproptosis and other forms of cell death

Abstract

Regulated cell death (RCD) is a regulable cell death that involves well-organized signaling cascades and molecular mechanisms. RCD is implicated in fundamental processes such as organ production and tissue remodeling, removing superfluous structures or cells, and regulating cell numbers. Previous studies have not been able to reveal the complete mechanisms, and novel methods of RCD are constantly being proposed. Two metal ions, iron (Fe) and copper (Cu) are essential factors leading to RCDs that not only induce ferroptosis and cuproptosis, respectively but also lead to cell impairment and eventually diverse cell death. This review summarizes the direct and indirect mechanisms by which Fe and Cu impede cell growth and the various forms of RCD mediated by these two metals. Moreover, we aimed to delineate the interrelationships between these RCDs with the distinct pathways of ferroptosis and cuproptosis, shedding light on the complex and intricate mechanisms that govern cellular survival and death. Finally, the prospects outlined in this review suggest a novel approach for investigating cell death, which may involve integrating current therapeutic strategies and offer a promising solution to overcome drug resistance in certain diseases. Video Abstract.

Keywords: Copper; Cuproptosis; Ferroptosis; Iron; Proteasome inhibition; RCD; ROS.

Fig. 1

Overview of modes of iron and copper to impart significant cell damage and types of RCDs are mediated by iron and copper

Fig. 2

Iron and copper lead to ferroptosis. Iron induces ferroptosis through iron reduction, the Fenton reaction, lipid peroxidation and GSH deficiency. Elesclomol‐induced copper also triggers the Fenton reaction, produces many ROS and triggers ferroptosis. The red arrow indicates Cu, and the blue arrow indicates Fe

Fig. 3

Process of cuproptosis. Copper induces cuproptosis through copper accumulation and the TCA cycle, and FDX1 promotes lipoylation of DLAT. Excessive copper led to loss of Fe-S cluster proteins under the regulation of FDX1. The red arrow indicates Cu, and the blue arrow indicates Fe

Fig. 4

Iron and copper induce diverse types of cell death. A Iron and copper trigger external and internal apoptosis. In the internal pathway, they lead to mitochondrial dysfunction, regulate BCL−2 family proteins, and release cytochrome c through ROS and proteasome inhibition. Cytochrome c is dependent on BCL−2 family proteins that bind and activate apoptotic protease-activating factor 1 (APAF-1) as well as procaspase 9, forming an apoptosome. B Iron and copper lead to autophagy. Ferritin is degraded by autolysosomes, leading to abnormal iron accumulation and eventually triggering cell death. Copper binds to ULK1 and ULK2 directly, relieving ULK1/ULK2 inhibition and promoting autophagy. Copper also binds to GPX1 to induce autophagy. C Iron overload accelerates ROS accumulation and the RIPK1/RIPK3/MLKL pathway, opens the mitochondrial permeability transition pore (mPTP), eliminates mitochondrial membrane potential, and releases cytochrome c outside mitochondria and DAMPs to the extracellular space, resulting in definitive necroptosis. D Iron stimulates the production of ROS, which induces pyroptosis via the classical caspase-1-mediated pyroptotic pathway and caspase-3-dependent pathway. In the first pathway, iron-elevated ROS cause the oxidation and oligomerization of Tom20, which recruits Bax and facilitates cytochrome c release into the cytosol. Then, cytochrome c activates caspase-9, which activates caspase-3. Finally, caspase-3 aggravates GSDME cleavage and triggers pyroptosis. In the second pathway, iron accelerates ROS accumulation, which activates the NLRP3/ASC/Caspase1 complex and hence induces pyroptosis. Copper also stimulates the production of ROS, induces ER stress and triggers the classical Caspase-1-mediated pyroptotic pathway through the IRE1α-XBP1 axis. The red arrow indicates Cu, and the blue arrow indicates Fe