FSP1 is a glutathione-independent ferroptosis suppressor

Abstract

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids 1,2. To date, ferroptosis has been believed to be restrained only by the phospholipid hydroperoxide (PLOOH)-reducing enzyme glutathione peroxidase 4 (GPX4) 3,4 and radicaltrapping antioxidants (RTAs) 5,6. The factors which underlie a given cell type's sensitivity to ferroptosis 7 is, however, critical to understand the pathophysiological role of ferroptosis and how it may be exploited for cancer treatment. Although metabolic constraints 8 and phospholipid composition 9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been yet been identified that account for ferroptosis resistance. We undertook an expression cloning approach to identify genes able to complement GPX4 loss. These efforts uncovered the flavoprotein "apoptosis inducing factor mitochondria-associated 2 (AIFM2)" as a previously unrecognized anti-ferroptotic gene. AIFM2, hereafter renamed "ferroptosis-suppressor-protein 1" (FSP1), initially described as a pro-apoptotic gene 11 , confers an unprecedented protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that ferroptosis suppression by FSP1 is mediated via ubiquinone (CoQ10): its reduced form ubiquinol traps lipid peroxyl radicals that mediate lipid peroxidation, while FSP1 catalyses its regeneration by using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. Conclusively, FSP1/CoQ10/NAD(P)H exists as a standalone parallel system, which cooperates with GPX4 and glutathione (GSH) to suppress phospholipid peroxidation (pLPO) and ferroptosis. program NEUROPROTEKT (03VP04260), as well as the m4 Award provided by the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi) to M.C., the Cancer Research UK

“Induction of pancreatic tumor-selective ferroptosis through modulation of cystine import”

“…While additional work will be necessary to illuminate precisely how CoAdependent processes contribute to suppression of ferroptosis, one potential model is that inhibition of GSH elevates the amount of cysteine available for the production of CoA, and by extension downstream metabolites that regulate detoxification of lipid ROS species. This model is strongly supported by the previous discovery of the ferroptosis inducer FIN56 (37), which inhibits synthesis of mevalonate-derive products such as CoQ 10 , and the recent identification of a glutathione-independent suppressor of ferroptosis, FSP1, which catalyzes the reduction CoQ 10 to directly quench lipid peroxyl radicals (38,39).…”

Ferroptosis: Final destination for cancer?

“…iFSP1 was identified as a potent FSP1 inhibitor and can trigger ferroptosis in GPX4 knockout cells that overexpress FSP1 (Figure 1). 63…”

Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

“…In addition to the canonical glutathione-based GPX4 pathway, a recent study showed that the ferroptosis supresor protein 1 (FSP1) targets ubiquinone in the plasma membrane and reduces it to ubiquinol in order to protect cells from lipid peroxidation and ferroptotic cell death (Bersuker, Hendricks et al, 2019, Doll, Freitas et al, 2019 A key step in ferroptosis execution is the final disruption of the plasma membrane, which mediates the release of intracellular factors acting as DAMPs. However, the molecular mechanism causing the loss of plasma membrane integrity during ferroptosis remains completely unsettled and the nature and size of the membrane injury in ferroptosis has remained unexplored.…”