Regulation of lipid peroxidation and ferroptosis in diverse species

Abstract

Lipid peroxidation is the process by which oxygen combines with lipids to generate lipid hydroperoxides via intermediate formation of peroxyl radicals. Vitamin E and coenzyme Q₁₀ react with peroxyl radicals to yield peroxides, and then these oxidized lipid species can be detoxified by glutathione and glutathione peroxidase 4 (GPX4) and other components of the cellular antioxidant defense network. Ferroptosis is a form of regulated nonapoptotic cell death involving overwhelming iron-dependent lipid peroxidation. Here, we review the functions and regulation of lipid peroxidation, ferroptosis, and the antioxidant network in diverse species, including humans, other mammals and vertebrates, plants, invertebrates, yeast, bacteria, and archaea. We also discuss the potential evolutionary roles of lipid peroxidation and ferroptosis.

Keywords: ROS; cell death; ferroptosis; iron; lipid peroxidation; vitamin E.

Figure 1.

Comparison of ferroptosis pathway components in diverse species. Several key genes, metabolites, and processes relevant to ferroptosis and lipid peroxidation are shown as well as a summary of their role in each species shown.

Figure 2.

Transgenic studies of GPX4 in mice reveal which tissues are, in principle, sensitive to undergoing ferroptosis. A myriad of transgenic studies performed in mice have pinpointed which cells and tissues depend on a functional glutathione/GPX4 system and thus in general are susceptible to ferroptotic cell death. A number of knockout studies with systemic deletion of the Gpx4 gene showed that loss of GPX4 causes early embryonic lethality around the gastrulation stage (i.e., embryonic day 7.5 [E7.5]). Beyond its requirement in early embryogenesis, several conditional deletion approaches of Gpx4 in different neuronal subpopulations revealed its necessity for a number of different neurons, such as pyramidal cells in the hippocampus, glutamatergic neurons in the cerebral cortex, cerebellar Purkinje cells, and motor neurons. Tamoxifen-inducible whole-body deletion of Gpx4 showed that kidney epithelial tubular cells are the limiting factor for survival of adult mice. Loss of GPX4 in hepatocytes and endothelial cells showed that in some tissues, Gpx4 deficiency can be compensated for by dietary vitamin E supplementation. Additional tissue-specific knockout studies for Gpx4 pinpointed that reticulocytes, certain T cells, photoreceptor cells, and male germ cells do depend on a functional GSH/GPX4 system. For further details, see the text.

Figure 3.

Current understanding of the molecular mechanisms leading to ferroptosis-like cell death in plants. Cell death triggered by heat shock (HS) can be prevented by the canonical ferroptosis inhibitors ciclopirox (Cpx) or ferrostatin-1 and is characterized by glutathione depletion and accumulation of ROS and lipid hydroperoxides. Dying cells exhibit retracted cytoplasm and shrunken mitochondria by electron microscopy as well as the presence of lytic vacuoles, while no obvious changes are noticeable in the nucleus.