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Iron Stories

Ironing Out Mechanisms of Ferroptosis

Karin Finberg

An intriguing, emerging area of iron biology is the process of ferroptosis, an iron-dependent form of cell death driven by oxidative damage to phospholipids. Ferroptosis has been linked to neurogenerative diseases, and in several cancer types, ferroptosis appears to represent a cellular vulnerability that might be exploited for cancer therapy. Precisely how ferroptosis is regulated is not yet well understood. In a recent article (Zou Y, et al. Nature. 2020;585:603-608), the groups of Robert Weinberg at Massachusetts Institute of Technology and Stuart Schreiber at Harvard University reveal a novel role for peroxisomes, membrane-bound cytoplasmic organelles, in ferroptosis susceptibility.

To discover factors that promote susceptibility to ferroptosis, the authors performed genome-wide CRISPR-Cas9 suppressor screens in two ferroptosis-susceptible renal and ovarian carcinoma lines. In addition to genes already implicated as ferroptosis regulators, top hits from the screen included genes involved in peroxisome biogenesis. By overexpressing or depleting genes involved in peroxisome biogenesis, the authors showed a positive correlation between peroxisome number and susceptibility to ferroptosis.

Peroxisomes perform multiple key cellular functions, including detoxification of reactive oxygen species and the degradation of very-long-chain and branched-chain fatty acids. They also participate in the biosynthesis of ether-linked glycerolipids, in which an ether linkage is present at the glycerol sn-1 position. Interestingly, hits in the above-mentioned ferroptosis suppressor screen also included genes encoding peroxisome-associated enzymes that catalyze the biosynthesis of ether lipids. Through lipidomic profiling, the authors found that peroxisomes affect sensitivity to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which serve as substrates for the lipid peroxidation that induces ferroptosis.

The authors next examined whether peroxisomes also promote sensitivity to ferroptosis in neoplastic and non-neoplastic settings. In murine tumor xenografts, carcinoma cells initially sensitive to ferroptosis became ferroptosis-resistant in vivo, a switch that was associated with marked downregulation of PUFA-ePLs. Additionally, selective upregulation of PUFA-ePLs was shown to be associated with a ferroptosis-susceptible state in neurons and cardiomyocytes. In sum, the study of Zou et al. uncovers a role for the peroxisome–ether-phospholipid axis in promoting susceptibility to, as well as evasion, from ferroptosis. These findings raise the possibility that perturbation of this axis may have therapeutic relevance in ferroptosis-related diseases. Additionally, they raise the question as to whether altered susceptibility to ferroptosis contributes to the diverse clinical features observed in patients with certain inborn errors of metabolism that impair peroxisome function (peroxisome biogenesis disorders).

While iron is essential for ferroptosis, the role of iron in ferroptosis requires further clarification. Interestingly, in the ferroptosis suppressor screen described above, one of the identified genes encoding peroxisome-associated enzymes was GNPAT (glyceronephosphate O-acyltransferase). A polymorphism in GNPAT (p.D519G) has been identified as a genetic modifier of iron overload in individuals with HFE-hemochromatosis in a population drawn from Australia, Canada, and the United States (McLaren CE, et al. Hepatology. 2015;62:429-39), although the association has not replicated in cohorts drawn from other geographic regions. The contribution of ferroptosis to liver injury in patients with genetic and acquired forms of hemochromatosis requires further elucidation. Nevertheless, the finding of GNPAT as a modifier of ferroptosis in in vitro raises the curious possibility that genetic variation in susceptibility to ferroptosis might contribute to the variable clinical penetrance of HFE-hemochromatosis.

posted: February 2, 2021