Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis

Abstract

Ferroptosis is a type of nonapoptotic cell death that is characteristically caused by phospholipid peroxidation promoted by radical reactions involving iron. Researchers have identified many of the protein factors that are encoded by genes that promote ferroptosis. Glutathione peroxidase 4 (GPX4) is a key enzyme that protects phospholipids from peroxidation and suppresses ferroptosis in a glutathione-dependent manner. Thus, the dysregulation of genes involved in cysteine and/or glutathione metabolism is closely associated with ferroptosis. From the perspective of cell dynamics, actively proliferating cells are more prone to ferroptosis than quiescent cells, which suggests that radical species generated during oxygen-involved metabolism are responsible for lipid peroxidation. Herein, we discuss the initial events involved in ferroptosis that dominantly occur in the process of energy metabolism, in association with cysteine deficiency. Accordingly, dysregulation of the tricarboxylic acid cycle coupled with the respiratory chain in mitochondria are the main subjects here, and this suggests that mitochondria are the likely source of both radical electrons and free iron. Since not only carbohydrates, but also amino acids, especially glutamate, are major substrates for central metabolism, dealing with nitrogen derived from amino groups also contributes to lipid peroxidation and is a subject of this discussion.

Keywords: glycolysis; metabolic remodeling; tricarboxylic acid cycle; urea cycle.

Figure 1

Principle pathways for induction of and protection from ferroptosis. Free iron mainly comes from either ferritinophagy or mitochondrial iron, but also originates from iron-containing enzymes. These components may also become the source for radical electrons to initiate lipid peroxidation. Cys availability determines the cellular levels of glutathione, which supports GPX4 in the protection against lipid peroxidation. Part of the central metabolic pathways discussed in the text are also depicted. AA, amino acid; γ-Glu-AA, γ-glutamyl amino acid; CssC, cystine; PepT2, dipeptide transporter; PPP, pentose phosphate pathway; 5-OP, 5-hydroxy proline; Slc6a, 5-oxoproline transporter; TCA, tricarboxylic acid cycle; ETC, electron transport chain; GSR, glutathione reductase; GLS, glutaminase; FSP1, ferroptosis-suppressor protein 1; POR, cytochrome P450 reductase; ALOX, arachidonate-specific lipoxygenase.

Figure 2

Relationship between cell cycle, energy metabolism, and polymer synthesis. This diagram schematically shows the relationship between events that occur in each phase of the cell cycle and the metabolism that synthesizes biopolymers. Darker colored areas mean more active in terms of metabolism.

Figure 3

Radical production pathway involved in ferroptosis centered on the TCA cycle. This diagram shows the process in which carbon derived from glucose and carbon backbones of amino acids are metabolized during the TCA cycle, and how the electrons generated during this process are involved in ferroptosis. Only a few key enzymes that play important roles in metabolism are shown. PPP, pentose phosphate pathway; P-L•, phospholipid radical; PDH, pyruvate dehydrogenase.

Figure 4

A potential role of the polyamine pathway in ferroptosis. Polyamine synthesis that occurs in conjunction with an incomplete urea cycle associates with the production of ROS responsible for ferroptosis. OTC deficiency activates polyamine synthesis by accumulating ornithine. The metabolic process of polyamines generates hydrogen peroxide, which may promote lipid peroxidation and induce ferroptosis.