Lipid Quality Control and Ferroptosis: From Concept to Mechanism

Abstract

Cellular quality control systems sense and mediate homeostatic responses to prevent the buildup of aberrant macromolecules, which arise from errors during biosynthesis, damage by environmental insults, or imbalances in enzymatic and metabolic activity. Lipids are structurally diverse macromolecules that have many important cellular functions, ranging from structural roles in membranes to functions as signaling and energy-storage molecules. As with other macromolecules, lipids can be damaged (e.g., oxidized), and cells require quality control systems to ensure that nonfunctional and potentially toxic lipids do not accumulate. Ferroptosis is a form of cell death that results from the failure of lipid quality control and the consequent accumulation of oxidatively damaged phospholipids. In this review, we describe a framework for lipid quality control, using ferroptosis as an illustrative example to highlight concepts related to lipid damage, membrane remodeling, and suppression or detoxification of lipid damage via preemptive and damage-repair lipid quality control pathways.

Keywords: cell death; ferroptosis; lipid peroxidation; membrane; quality control; reactive oxygen species.

Figure 1

A general framework for cellular quality control systems. Quality control systems mediate responses to ensure that aberrant macromolecules (e.g., nucleotides, proteins, lipids) do not accumulate in cells. Conceptually, quality control systems share several general properties that allow them to be represented with a common framework in which preemptive quality control systems prevent damage and damage-repair quality control systems mediate degradation of damaged macromolecules, their conversion to a benign product, or repair to an undamaged product.

Figure 2

Mechanisms of lipid quality control in ferroptosis. The quality of lipids can be regulated by preemptive quality control and damage-repair quality control. The former includes mechanisms such as lipid remodeling, damage prevention, and propagation suppression to protect lipids from damage. Following damage, cells eliminate damaged lipids through either multi-step repair or conversion of toxic lipid species into benign ones. Failure of these quality control processes can lead to the catastrophic accumulation of toxic lipids and cell death. Abbreviations: 7-DHC, 7-dehydrocholesterol; ABHD12, α/β-hydrolase domain containing 12; ACSL, acyl-CoA synthetase long-chain family member; AGPAT3, 1-acylglycerol-3-phosphate O-acyltransferase 3; AKR, aldo-keto reductase; ALOX, arachidonate lipoxygenase; BH₄, tetrahydrobiopterin; CoA, coenzyme A; CoQ, coenzyme Q; CYB5R1, cytochrome B5 reductase 1; DHFR, dihydrofolate reductase; DHODH, dihydroorotate dehydrogenase; DMT1, divalent metal transporter 1; FSP1, ferroptosis suppressor protein 1; GPX4, glutathione peroxidase 4; GR, glutathione reductase; GSH, glutathione; Lipid•, lipid radical; Lipid–O•, lipid alkoxyl acyltransferase 3; MBOAT1/2, membrane-bound O-acyltransferase domain containing 1/2; NO, nitric oxide; NOS, nitric oxideradical; Lipid–OO•, lipid peroxyl radical; L=O, lipid aldehyde; L–OOH, lipid hydroperoxide; LPCAT3, lysophosphatidylcholine synthase; PEBP1, phosphatidylethanolamine binding protein 1; PLA2G6, phospholipase A2 group VI; POR, cytochrome P450 oxidoreductase; PRDX6, peroxiredoxin 6; SCD1, stearoyl-CoA desaturase 1; Tf, transferrin; TFR1, transferrin receptor 1; Vit, vitamin.

Figure 3

Mechanisms of lipid peroxidation and propagation. Lipid peroxidation is driven by nonenzymatic and enzymatic reactions. Iron plays a major role in nonenzymatic lipid peroxidation. Multiple sources contribute to the free iron pool in cells, such as direct transport through DMT1, uptake in the form of transferrin via TFR1, release from heme catabolism by HMOX1, or ferritin degradation by ferritinophagy. Through Fenton’s reaction, iron facilitates the generation of ROS, which subsequently abstracts a labile hydrogen atom from fatty acyl chains of PUFA-containing phospholipids, resulting in the formation of lipid radicals. Lipid radicals can also be generated during enzymatic lipid peroxidation, mediated by CYB5R1/POR or ALOX enzymes. The intermediate radicals are not stable and can undergo chain reaction–style propagation reactions and produce more radicals. Abbreviations: ALOX, arachidonate lipoxygenase; CYB5R1, cytochrome B5 reductase 1; DMT1, divalent metal transporter 1; Fe²+, ferrous iron; Fe³+, ferric ion; HMOX1, heme oxygenase 1; H₂O₂, hydrogen peroxide; HO•, hydroxyl radical; NCOA4, nuclear receptor coactivator 4; OH⁻, hydroxide; PEBP1, phosphatidylethanolamine binding protein 1; PL, phospholipid; POR, cytochrome P450 oxidoreductase; PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; STEAP3, STEAP3 metalloreductase; Tf, transferrin; TFR1, transferrin receptor 1.

Figure 4

Membrane remodeling: promoting and suppressing ferroptosis. PUFAs are highly prone to oxidative damage and PUFA content in phospholipids is a major determinant of membrane sensitivity to peroxidation. MUFAs compete with PUFAs for incorporation into phospholipids, and the incorporation of MUFAs into phospholipids makes membranes more resistant to ferroptosis. Enzymes such as SCD1, ACSL3, and MBOAT1/2, which promote the formation of MUFA-containing phospholipids, inhibit ferroptosis. In contrast, ACSL4, LPCAT3, and AGPAT3 mediate PUFA-containing phospholipid generation and enhance ferroptosis sensitivity. Abbreviations: ACSL, acyl-CoA synthetase long-chain family member; AGPAT3, 1-acylglycerol-3-phosphate O-acyltransferase 3; CoA, coenzyme A; LPCAT3, lysophosphatidylcholine acyltransferase 3; MBOAT, membrane-bound O-acyltransferase domain containing; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; SCD1, stearoyl-CoA desaturase 1; SFA, saturated fatty acid; TAG, triacylglyceride.

Figure 5

Preemptive lipid quality control: damage suppression in ferroptosis. Multiple strategies are employed to preemptively suppress lipid damage and its propagation. (a) The elimination of lipid radicals and the termination of propagation via the recycling of antioxidants, such as the reduced forms of CoQ and VitK by FSP1, BH₄ by DHFR or GCH1, GSSH by GR, NO by NOS, and the reduced form of VitE by reactions with lipophilic antioxidants. (b) The restriction of lipid radicals to local cellular compartments to prevent damage transfer, such as by the generation of reduced CoQ by DHODH in mitochondria. (c) The competition for ROS-induced damage with other lipid species, such as 7-DHC, and plasmalogens, and alteration of aggregate membrane properties such as phospholipid packing by cholesterol and sphingomyelin [i.e., biophysical antioxidants (see inset box)]. Abbreviations: 7-DHC, 7-dehydrocholesterol; AX, antioxidant; BH₂, dihydrobiopterin; BH₄, tetrahydrobiopterin; CoQ, coenzyme Q; DHFR, dihydrofolate reductase; DHO, dihydroorotate; DHODH, dihydroorotate dehydrogenase; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclohydrolase 1; GR, glutathione reductase; GSSH, glutathione persulfide; GSSSSG, glutathione tetrasulfide; Lipid•, lipid radical; Lipid–O•, lipid alkoxyl radical; Lipid–OO•, lipid peroxyl radical; NAD(P)H, nicotinamide adenine dinucleotide (phosphate); NO, nitric oxide; NOS, nitric oxide synthase; ROS, reactive oxygen species; Vit, vitamin.

Figure 6

Damage-repair lipid quality control. When oxidative stress exceeds the capacity of preemptive lipid quality control pathways, lipid damage accumulates. The toxic lipid substrates, such as lipid peroxides, can be converted to benign products through various repair pathways. For instance, GPX4 and PRDX6 function as lipid hydroperoxidases and reduce lipid peroxides into lipid alcohols. AKR catalyzes the reduction of lipid aldehydes to lipid alcohols. Alternatively, lipid peroxides can be detoxified through phospholipid remodeling, mediated by enzymes with phospholipase A2 activities such as PRDX6 and PLA2G6, which cleave oxidized fatty acids from phospholipids and generate lysophospholipids. Subsequently, a new fatty acid can be incorporated into the lysophospholipid by acyltransferase to create new phospholipids, achieving the goal of lipid damage correction. Abbreviations: AKR, aldo-keto reductase; FA, fatty acid; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; L=O, lipid aldehyde; L–OH, lipid alcohol; L–OOH, lipid hydroperoxide; PLA2G6, phospholipase A2 group VI; PRDX6, peroxiredoxin 6.