Little is known about the regulation of nonapoptotic cell death. Using massive insertional mutagenesis of haploid KBM7 cells we identified nine genes involved in small-molecule-induced nonapoptotic ...cell death, including mediators of fatty acid metabolism (ACSL4) and lipid remodeling (LPCAT3) in ferroptosis. One novel compound, CIL56, triggered cell death dependent upon the rate-limiting de novo lipid synthetic enzyme ACC1. These results provide insight into the genetic regulation of cell death and highlight the central role of lipid metabolism in nonapoptotic cell death.
The cell biology of ferroptosis Dixon, Scott J; Olzmann, James A
Nature reviews. Molecular cell biology,
06/2024, Letnik:
25, Številka:
6
Journal Article
Recenzirano
Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution ...and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), ...periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.
Cell death can be a highly regulated process. A large and growing number of mammalian cell death mechanisms have been described over the past few decades. Major pathways with established roles in ...normal or disease biology include apoptosis, necroptosis, pyroptosis and ferroptosis. However, additional non-apoptotic cell death mechanisms with unique morphological, genetic, and biochemical features have also been described. These mechanisms may play highly specialized physiological roles or only become activated in response to specific lethal stimuli or conditions. Understanding the nature of these emerging and understudied mechanisms may provide new insight into cell death biology and suggest new treatments for diseases such as cancer and neurodegeneration.
•Mammalian cells can be killed by several distinct cell death mechanisms.•Some non-apoptotic cell death mechanisms correspond to cell sabotage.•Crosstalk between non-apoptotic cell death mechanisms is common.•The complete set of cell death mechanisms that can be activated is unclear.
Ferroptosis is a mechanism of regulated necrotic cell death characterized by iron-dependent, lipid peroxidation-driven membrane destruction that can be inhibited by glutathione peroxidase 4. ...Morphologically, it is characterized by cellular, organelle and cytoplasmic swelling and the loss of plasma membrane integrity, with the release of intracellular components. Ferroptosis is triggered in cells with dysregulated iron and thiol redox metabolism, whereby the initial robust but selective accumulation of hydroperoxy polyunsaturated fatty acid-containing phospholipids is further propagated through enzymatic and non-enzymatic secondary mechanisms, leading to formation of oxidatively truncated electrophilic species and their adducts with proteins. Thus, ferroptosis is dependent on the convergence of iron, thiol and lipid metabolic pathways. The kidney is particularly susceptible to redox imbalance. A growing body of evidence has linked ferroptosis to acute kidney injury in the context of diverse stimuli, such as ischaemia-reperfusion, sepsis or toxins, and to chronic kidney disease, suggesting that ferroptosis may represent a novel therapeutic target for kidney disease. However, further work is needed to address gaps in our understanding of the triggers, execution and spreading mechanisms of ferroptosis.
The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that ...exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.
Exchange of extracellular cystine for intracellular glutamate by the antiporter system xc (-) is implicated in numerous pathologies. Pharmacological agents that inhibit system xc (-) activity with ...high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system xc (-). RNA sequencing revealed that inhibition of cystine-glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1, providing a pharmacodynamic marker for system xc (-) inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system xc (-) function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis.DOI: http://dx.doi.org/10.7554/eLife.02523.001.
Ferroptosis is an iron-dependent form of cell death implicated in cancer and neurodegenerative diseases. In this issue of Cell Chemical Biology, Shao et al. (2022) and Wang et al. (2022) describe ...imaging techniques to monitor ferrous iron levels and iron-dependent lipid peroxidation, two key determinants of ferroptosis sensitivity.
Ferroptosis is an iron-dependent form of cell death implicated in cancer and neurodegenerative diseases. In this issue of Cell Chemical Biology, Shao et al. (2022) and Wang et al. (2022) describe imaging techniques to monitor ferrous iron levels and iron-dependent lipid peroxidation, two key determinants of ferroptosis sensitivity.
PDF
