Publications

• FSP1 is a glutathione-independent ferroptosis suppressor.

  Doll S., Freitas F.P., Shah R., Aldrovandi M., da Silva M.C., Ingold I., Grocin A.G., Xavier da Silva T.N., Panzilius E., Scheel C., Mourao A., Buday K., Sato M., Wanninger J., Vignane T., Mohana V., Rehberg M., Flatley A., Schepers A., Kurz A., White D., Sauer M., Sattler M., Tate E.W., Schmitz W., Schulze A., O'Donnel V., Proneth B., Popowicz G.M., Pratt D., Angeli J.P.F., Conrad M.

  Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids^1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)^3,4 and radical-trapping a ... >> More

  Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids^1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)^3,4 and radical-trapping antioxidants^5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis⁷ is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints⁸ and phospholipid composition^9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene¹¹, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q₁₀, CoQ₁₀): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ₁₀ using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1-CoQ₁₀-NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis. << Less

  Nature 575:693-698(2019) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.

  Bersuker K., Hendricks J., Li Z., Magtanong L., Ford B., Tang P.H., Roberts M.A., Tong B., Maimone T.J., Zoncu R., Bassik M.C., Nomura D.K., Dixon S.J., Olzmann J.A.

  Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids^1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols<sup>3,4</su ... >> More

  Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids^1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols^3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions², and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death⁵. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines⁶, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q₁₀ (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents. << Less

  Nature 575:688-692(2019) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.