Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria

Figure 2

Potential mitochondrial targets for ferroptosis manipulation. Mitochondrial oxidative phosphorylation (OXPHOS) is the main cellular source of reactive oxygen species (ROS). In the presence of ferrous ions (Fe²⁺), ROS can induce the production of lipid peroxides (LOOH) in the membrane compartment of the mitochondria (Fenton reaction), thereby compromising the structure and function of the cellular powerhouse and leading to further propagation of oxidative damage within the cell. The transport of iron ions into mitochondria is achieved by mitoferrin-1/2 (MFRN), a member of the mitochondrial solute carrier family of proteins. Once inside the mitochondria, ferrous ions are used for many different purposes, such as the synthesis of heme or iron-sulphur clusters (ISCs) and key prosthetic groups of a variety of enzymes, including the TC complexes. From the standpoint of ferroptosis, the NFS1 and ABCB7 transporters, respectively, responsible for the synthesis and export of ISCs from the mitochondria to the cytosol appear to be important (see text). The excess of free iron is sequestered in mitochondrial ferritin to prevent potentially harmful effects of iron-induced oxidative damage. One possibility which remains to be examined is the potential antioxidant role of ubiquinol and ferroptosis-suppressor protein 1 (FSP1) against accumulated LOOH in the mitochondrial membrane compartment (the question mark in the scheme). The presence and protective role of glutathione peroxidase 4 (GPX4) at the side of cytochrome c release have been shown. Aside from the classical redox active species, mitochondrial metabolic intermediates appear to be involved in cell destiny, pushing it towards ferroptosis. The mitochondria-localized tricarboxylic acid (TCA) cycle is a central hub regulating fatty acid breakdown and synthesis, as well as the flux through OXPHOS. Thus, the TCA cycle could be seen as the major regulating point of ferroptosis through (i) the regulation of ROS production, (ii) the regulation of ATP production, and (iii) the regulation of the production of the precursors (acetyl-CoA units) for the synthesis of ferroptosis executors—polyunsaturated fatty acids (PUFA; #NB: the regulation of acetyl-CoA incorporation into fatty acids is regulated by cytoplasmic enzymes). The voltage-dependent anion channel (VDAC), as one of the central players in the import/export of many different ions/metabolites (X/Y), energy regulation, and ion and intermediate balance across two sides of the mitochondrial membrane, also appears to be involved in the regulation of ferroptosis (see text). ACSF2: mitochondrial medium-chain acyl-CoA ligase; Glu: glutamate; Gln: glutamine. This figure was created using Servier Medical Art templates, which are licensed under the Creative Commons Attribution 3.0 Unported License (https://smart.servier.com).