The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

Abstract

The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia-reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets.

Fig. 1. Metabolic pathways implicated in ferroptosis.

At the cellular level, ferroptosis is driven primarily by iron-dependent lipid peroxidation. Many aspects of iron metabolism such as the absorption, storage and utilization of iron have important roles in regulating ferroptosis. In addition, the activation of long-chain fatty-acid CoA ligase 4 (LACS4), lysophospholipid acyltransferase 5 (LPLAT5), lipoxygenase (LOX) or NADPH oxidase (NOX) in the lipid metabolic pathway promotes lipid peroxidation and ferroptosis. The canonical ferroptosis-suppressing pathway involves the uptake of cystine (Cys) via the cystine–glutamate antiporter (system x_c⁻), which results in glutathione (GSH) biosynthesis. Using GSH as a cofactor, the glutathione peroxidase 4 (GPX4) reduces phospholipid hydroperoxides to their corresponding alcohols. The peroxidation of phospholipids is also kept in check by the ferroptosis suppressor protein 1 (FSP1)–coenzyme Q₁₀ (CoQ₁₀) system. Ferroptosis is also regulated by the iron metabolism pathway that involves iron absorption, transport, storage and utilization. At the cellular level, non-haem iron is transported into cells by either transferrin receptor protein 1 (TFR1)-mediated, transferrin (TF)-bound iron uptake or metal transporter solute carrier family 39 member 14 (SLC39A14; also known as metal cation symporter ZIP14)-mediated, non-TF-bound iron uptake. In addition, haem degradation and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy can increase the labile iron pool (LIP), thereby sensitizing cells to ferroptosis via the Fenton reaction. FPN, ferroportin; Glu, glutamate; GSSG, glutathione disulfide; HO1, haem oxygenase 1; KEAP1, Kelch-like ECH-associated protein 1; ML1, mucolipin 1; NRAMP2, natural resistance-associated macrophage protein 2; NRF2, nuclear factor-erythroid 2-related factor 2; PUFA, polyunsaturated fatty acid; PUFA–CoA, coenzyme A-activated polyunsaturated fatty acid; PUFA–PL, polyunsaturated fatty acid-containing phospholipid; RNF217, E3 ubiquitin protein ligase RNF217; STEAP3, metalloreductase STEAP3.

Fig. 2. The metabolism of cardiac iron and haem regulates ferroptosis.

a | Iron uptake in cardiomyocytes is dependent on the endocytosis of diferric transferrin (TF) bound to its receptor transferrin receptor protein 1 (TFR1). To maintain the levels of iron in the cytoplasm, iron can be released from TF in endolysosomes and exported to the cytoplasm by natural resistance-associated macrophage protein 2 (NRAMP2) after a metalloreductase STEAP3-mediated reduction. Excess iron is either bound to ferritin heavy chain (FTH) or exported by ferroportin (FPN), the only iron exporter. In addition, iron can be released from FTH via nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation of ferritin, a process known as ferritinophagy. b | Mitoferrin 1 (also known as SLC25A37) and mitoferrin 2 (also known as SLC25A28) mediate the transport of iron across the mitochondrial membrane. Iron is primarily used to synthesize iron–sulfur (Fe–S) clusters and haem in the mitochondria. Excess iron can be stored in the mitochondria-specific form of ferritin (FTMT). FLVCR1B (feline leukaemia virus subgroup C receptor-related protein 1B) promotes haem efflux into the cytoplasm, whereas the export of Fe–S clusters into the cytoplasm might require iron–sulfur clusters transporter ABCB7, mitochondrial (ABCB7) and ABCB8 (also known as mitochondrial potassium channel ATP-binding subunit). Ala, 5-aminolevulinate; ALAS, aminolevulinic acid synthase; Apo-TF, apo-transferrin; CO, carbon monoxide; Cys, cysteine; ETC, electron transport chain; HO1, haem oxygenase 1; Holo-TF, holo-transferrin; LIP, labile iron pool; ML1, mucolipin 1; NFS1, cysteine desulfurase, mitochondrial; OXPHOS, oxidative phosphorylation; RNF217, E3 ubiquitin protein ligase RNF217; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Fig. 3. The regulatory role of mitochondria in ferroptosis.

Mitochondria host a wide range of key metabolic processes (such as the tricarboxylic acid (TCA) cycle) and are a major source of reactive oxygen species (ROS). Separate mitochondria-localized defence systems have evolved to prevent mitochondrial lipid peroxidation and ferroptosis. For example, either the mitochondrial version of phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) or dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) can specifically detoxify mitochondrial lipid peroxides. Moreover, the mitochondria-specific form of ferritin (FTMT) protects mitochondria from iron overload-induced oxidative injury, and mitoNEET (also known as CISD1) suppresses ferroptosis by limiting mitochondrial iron uptake. CoQ₁₀, coenzyme Q₁₀; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1; GSH, glutathione; GSSG, glutathione disulfide; HO1, haem oxygenase 1; LIP, labile iron pool; PL-PUFA-OOH, polyunsaturated fatty acid-containing phospholipid hydroperoxides; PLOO·, phospholipid peroxyl radical; RNF217, E3 ubiquitin protein ligase RNF217; SLC25A39, probable mitochondrial glutathione transporter SLC25A39; SLC39A14, solute carrier family 39 member 14; TF, transferrin; TFR1, transferrin receptor protein 1.