Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria

Abstract

Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.

Figure 1

The main cellular pathways related to ferroptosis and potential targets for its manipulation (induction or inhibition). The main regulatory pathway of ferroptosis involves the cysteine-GSH-GPX4-lipid peroxide axis. Cysteine is transported into the cell via xCT in its oxidized form (cystine). One of the main roles of cysteine is the synthesis of glutathione (GSH), a process in which the key-limiting step is catalysed by glutamate-cysteine ligase (GCL). GSH serves as a cofactor of glutathione peroxidase 4 (GPX4), which reduces lipid peroxides to their alcohol form. Alternatively, lipid peroxides can be reduced by ubiquinol residing in the membrane compartments of the cell. In this way, produced ubiquinone is reduced back to its alcohol form by the action of ferroptosis-suppressor protein 1 (FSP1). The central event in the lipid peroxide production pathway is the Fenton reaction, a reaction between Fe²⁺ and H₂O₂. The iron is imported into the cell as an iron-loaded transferrin-transferrin receptor 1 (TFR1) complex via receptor-mediated endocytosis. In the endosome (an acidic environment), free Fe³⁺ is converted to Fe²⁺ by the transmembrane metalloreductase STEAP3 and released into the cytoplasm via the divalent metal transporter 1 (DMT1). Red arrows represent potential activators of ferroptosis: (i) inhibitors of xCT (erastin, sulfasalazine), (ii) the inhibitor of GSH biosynthesis and GCL (buthionine sulfoximine (BSO)), and (iii) the inhibitor of GPX (Ras-selective lethal 3 (RSL3)). Green arrows represent potential ferroptosis inhibitors: (i) alternative source of cysteine (N-acetylcysteine (NAC)) and (ii) lipid peroxide scavengers (vitamin E, ferrostatin-1). 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).

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).