Emerging Mechanisms and Disease Relevance of Ferroptosis

Abstract

Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers. Understanding the mechanisms governing cell death is critical for addressing its role in disease. Similarly, metabolism is essential for normal energy and biomolecule production, and goes awry in many diseases. Metabolism and cell death are tightly linked in the phenomenon of ferroptosis, a form of regulated cell death driven by peroxidation of phospholipids. Glutathione peroxidase 4 (GPX4) uses glutathione to protect cells from ferroptosis by eliminating phospholipid peroxides. Recent data have revealed glutathione/GPX4-independent axes for suppressing ferroptosis, and insight into the regulation of iron and mitochondria in ferroptosis. Ferroptosis has recently been implicated in multiple diseases, and functions as a tumor suppression mechanism. Ferroptosis induction is a promising approach in treating several conditions, including neoplastic diseases. Here, we summarize these recent advances.

Keywords: ferroptosis; iron; lipid peroxidation; metabolism; ubiquinone, cancer.

Figure 1.. Key regulators of ferroptosis.

Three distinct processes can drive resistance to ferroptosis. Depletion of polyunsaturated fatty acyl phospholipids (PUFA-PLs, purple, lower left) depletes the key substrates needed for lethal lipid peroxidation. Depletion of iron by storage in ferritin or export driven by prominin2 blocks the iron-dependent peroxidation of PUFA-PLs. (blue, lower right). Finally, three parallel pathways act to suppress lipid peroxidation by intercepting intermediates in the process: the glutathione pathway (left), the ubiquinone pathway (middle, NADPH-FSP1-CoQ₁₀), and the tetrahydrobiopterin (GCH1/BH4) pathway (right). These are further regulated by upstream genes and proteins as indicated.

Figure 2.. A schematic model for tumor suppressors regulating ferroptosis.

The expression of SLC7A11 is a key mechanism by which numerous tumor suppressor genes activate ferroptosis to prevent tumor formation. BAP1 and p53 repress SLC7A11, whereas KEAP1 and ARF prevent NRF1 from activating SLC7A11. Downstream of SLC7A11, ALOX12 and GPX4 act in parallel pathways to regulate lipid peroxidation.

Figure 3.. The role of mitochondria in ferroptosis.

Mitochondria, through the citric acid cycle and electron transport chain activity, are the major source of cellular energy production. A side effect accompanying this oxidative process is the generation of reactive oxygen species, including ferroptosis-inducing lipid peroxides. Such a role for mitochondria in ferroptosis can explain the tumor-suppressive function of the citric acid cycle enzyme fumarase. The blue arrows indicate the flow of reactions in metabolism, with glucose providing intermediates that enter the citric acid (TCA) cycle, glutamine (Gln) providing alpha-ketoglutarate (αKG) via glutaminolysis, and then ATP and reactive oxygen species (ROS) flowing out of the TCA cycle.