The Antioxidant Role of Non-mitochondrial CoQ10: Mystery Solved!

Although confirmed as the primary lipophilic antioxidant molecule endogenously produced by cells, the non-mitochondrial pool of CoQ10’s functional role is still well debated. Recently, both Bersuker et al., 2019Bersuker K. Hendricks J.M. Li Z. Magtanong L. Ford B. Tang P.H. Roberts M.A. Tong B. Maimone T.J. Zoncu R. et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref PubMed Scopus (958) Google Scholar and Doll et al., 2019Doll 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.H. et al.FSP1 is a glutathione-independent ferroptosis suppressor.Nature. 2019; 575: 693-698Crossref PubMed Scopus (920) Google Scholar have identified FSP1 as a novel CoQ10 plasma membrane oxidoreductase, protecting cells from glutathione-independent ferroptosis. Although confirmed as the primary lipophilic antioxidant molecule endogenously produced by cells, the non-mitochondrial pool of CoQ10’s functional role is still well debated. Recently, both Bersuker et al., 2019Bersuker K. Hendricks J.M. Li Z. Magtanong L. Ford B. Tang P.H. Roberts M.A. Tong B. Maimone T.J. Zoncu R. et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref PubMed Scopus (958) Google Scholar and Doll et al., 2019Doll 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.H. et al.FSP1 is a glutathione-independent ferroptosis suppressor.Nature. 2019; 575: 693-698Crossref PubMed Scopus (920) Google Scholar have identified FSP1 as a novel CoQ10 plasma membrane oxidoreductase, protecting cells from glutathione-independent ferroptosis. Ferroptosis is a form of regulated cell death. It is characterized by the iron-dependent incorporation of lipid hydroperoxides leading to lethal levels into the cellular membrane. Cells have exploited complex systems to defend themselves against this vulnerability. The most recognized of these ferroptosis suppressive mechanisms involves peroxidase 4 (GPX4), a glutathione-dependent lipid that is able to convert lipid hydroperoxides into non-toxic lipid alcohols (Stockwell et al., 2017Stockwell B.R. Friedmann Angeli J.P. Bayir H. Bush A.I. Conrad M. Dixon S.J. Fulda S. Gascón S. Hatzios S.K. Kagan V.E. et al.Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.Cell. 2017; 171: 273-285Abstract Full Text Full Text PDF PubMed Scopus (2668) Google Scholar). Remarkably, when GPX4 is inhibited, some cancer cell lines are unresponsive to ferroptosis. This suggests that an alternative ferroptosis resistance mechanism may have yet to be discovered (Viswanathan et al., 2017Viswanathan V.S. Ryan M.J. Dhruv H.D. Gill S. Eichhoff O.M. Seashore-Ludlow B. Kaffenberger S.D. Eaton J.K. Shimada K. Aguirre A.J. et al.Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.Nature. 2017; 547: 453-457Crossref PubMed Scopus (753) Google Scholar). Using unbiased genetic screens, Doll et al. and Bersuker et al. independently identified FSP1 as a novel ferroptosis resistance gene capable of complementing the loss (GPX4KO) or inhibition (RLS3-treated) of GPX4 (Bersuker et al., 2019Bersuker K. Hendricks J.M. Li Z. Magtanong L. Ford B. Tang P.H. Roberts M.A. Tong B. Maimone T.J. Zoncu R. et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref PubMed Scopus (958) Google Scholar, Doll et al., 2019Doll 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.H. et al.FSP1 is a glutathione-independent ferroptosis suppressor.Nature. 2019; 575: 693-698Crossref PubMed Scopus (920) Google Scholar). FSP1 contains both an N-myristoylation signal and a flavoprotein oxidoreductase domain, which are mandatory for its function in suppressing ferroptosis. N-myristoylation is needed in order to recruit FSP1 to the plasma membrane-enriched organelles, such as the endoplasmic reticulum (ER) and the Golgi apparatus. Once recruited, FSP1 functions as an NADH-dependent coenzyme Q10 (also known as CoQ10 or ubiquinone) oxidoreductase. CoQ10 is a mobile lipophilic electron carrier and the only of its kind to endogenously synthesize lipid-soluble antioxidant (Crane, 2007Crane F.L. Discovery of ubiquinone (coenzyme Q) and an overview of function.Mitochondrion. 2007; 7: S2-S7Crossref PubMed Scopus (109) Google Scholar). CoQ10 is critical for electron transfer, both for the respiratory chain activity in the mitochondrial membrane as well as for the protection of lipids from oxidation in the Golgi and plasma membranes (Kalén et al., 1987Kalén A. Norling B. Appelkvist E.L. Dallner G. Ubiquinone biosynthesis by the microsomal fraction from rat liver.Biochim. Biophys. Acta. 1987; 926: 70-78Crossref PubMed Scopus (186) Google Scholar, Turunen et al., 2004Turunen M. Olsson J. Dallner G. Metabolism and function of coenzyme Q.Biochim. Biophys. Acta. 2004; 1660: 171-199Crossref PubMed Scopus (809) Google Scholar). In cells, CoQ10 undergoes a redox cycle (fully oxidized ubiquinone versus fully reduced ubiquinol) that is central to its role in the electron transport chain in mitochondria. CoQ10 also acts as a lipophilic free-radical-scavenging antioxidant in the plasma membrane (Bentinger et al., 2007Bentinger M. Brismar K. Dallner G. The antioxidant role of coenzyme Q.Mitochondrion. 2007; 7: S41-S50Crossref PubMed Scopus (371) Google Scholar). While the function of the mitochondrial redox cycle in mitochondria is well characterized, the process that regulates the redox cycle of the non-mitochondrial (e.g., plasma membrane) pool of CoQ10 is less clear. This publication proposes that FSP1 is the oxidoreductase that reduces CoQ10 at plasma membrane. This FSP1/CoQ10/NADH system alone is then sufficient to suppress lipid peroxidation and ferroptosis. These findings represent the first clear indication that CoQ10 plays a protective role in the plasma membrane of cells. To demonstrate the functional role of CoQ10 in protecting ferroptosis, Bersuker et al., 2019Bersuker K. Hendricks J.M. Li Z. Magtanong L. Ford B. Tang P.H. Roberts M.A. Tong B. Maimone T.J. Zoncu R. et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref PubMed Scopus (958) Google Scholar exploited the removal of CoQ10 from cells by blocking the mitochondrial CoQ10 producing enzyme, COQ2. Once blocked, COQ2 inhibition leads to increased basal and RLS3-mediated lipid oxidation. This indicates that CoQ10 synthesis functions in suppressing ferroptosis. COQ2 loss is generally associated with primary CoQ10 deficiency, which is the loss of mitochondrial bioenergetics (decreased ATP generation). It is also associated with increased mitochondrial ROS production and cell death. To this end, inhibition of the UBIAD1 enzyme, which is a Golgi/ER-located prenyltransferase associated with the synthesis of the non-mitochondrial pool of CoQ10, would be more exclusive in making cells sensitive to ferroptosis (Mugoni et al., 2013Mugoni V. Postel R. Catanzaro V. De Luca E. Turco E. Digilio G. Silengo L. Murphy M.P. Medana C. Stainier D.Y. et al.Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis.Cell. 2013; 152: 504-518Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Considering that CoQ10 is highly hydrophilic and that it stably resides in the cell membrane, this discovery may also shed light on many interesting and unresolved enigmas: do cells contain two independent pools of CoQ10, or do they share a common biosynthetic pathway? Although the biosynthesis of CoQ10 in mitochondria has been studied in detail, only a limited amount of data is available with regard to the synthesis of cellular membrane CoQ10. Several in vivo experiments suggest that CoQ10 synthesis may also occur in the Golgi and ER membranes, providing the cellular membrane CoQ10 pool (Kalén et al., 1990Kalén A. Appelkvist E.L. Chojnacki T. Dallner G. Nonaprenyl-4-hydroxybenzoate transferase, an enzyme involved in ubiquinone biosynthesis, in the endoplasmic reticulum-Golgi system of rat liver.J. Biol. Chem. 1990; 265: 1158-1164PubMed Google Scholar). As a lipophilic radical-trapping antioxidant (RTA) guard, CoQ10 alone is not sufficient unless cells keep it in a reduced state to stop the propagation of lipid peroxides. Bersuker et al. provide evidence that FSP1 is able to directly reduce oxidized CoQ10 by using NADH as cofactor. Also, it has been shown that NQO1, a well-known NAD(P)H-dependent dehydrogenase (quinone) reductase, may play a role in ferroptosis protection by synergizing with FSP1 and regulating the reduction of ubiquinone to ubiquinol. To this end, we must ask whether the supplementation of reduced CoQ10 (ubiquinol) is beneficial in the protection from ferroptosis. Ferroptosis-mediated cell death is involved in neurodegenerative disorders, mainly related to brain or kidney diseases. On the other hand, ferroptosis resistance has been associated with cancer progression (Viswanathan et al., 2017Viswanathan V.S. Ryan M.J. Dhruv H.D. Gill S. Eichhoff O.M. Seashore-Ludlow B. Kaffenberger S.D. Eaton J.K. Shimada K. Aguirre A.J. et al.Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.Nature. 2017; 547: 453-457Crossref PubMed Scopus (753) Google Scholar). Therefore, alternative ways to suppress or promote ferroptosis may benefit several pathological conditions. Using bioinformatic tools and experimental data, Doll et al., 2019Doll 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.H. et al.FSP1 is a glutathione-independent ferroptosis suppressor.Nature. 2019; 575: 693-698Crossref PubMed Scopus (920) Google Scholar and Bersuker et al., 2019Bersuker K. Hendricks J.M. Li Z. Magtanong L. Ford B. Tang P.H. Roberts M.A. Tong B. Maimone T.J. Zoncu R. et al.The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref PubMed Scopus (958) Google Scholar show that FSP1 can be used as a biomarker of ferroptosis resistance in many types of cancer cell lines. Using preclinical in vivo experiments, Bersuker et al. demonstrated that human xenografts having both GPX4KD and FSP1KD show a reduction in tumor growth compared to those bearing only GPX4 KD. These data show that FSP1 is required to maintain the growth of human tumors in vivo when GPX4 is inactivated. To this purpose, Doll et al. identified an FSP inhibitor (iFSP) that selectively induced ferroptosis in GPX4KO and FSP1-overexpressing tumor cell lines, and it may sensitize cells to ferroptosis inducers. Given the critical role of the mevalonate pathway in providing metabolic intermediates for both CoQ10 and selenoprotein GPX4 synthesis, it would be fascinating to investigate statins or other mevalonate-blocking drugs as players in ferroptosis-mediated diseases, such as cancer progression (Figure 1). To this end, we also must investigate whether the overexpression of FSP1 would benefit in protecting neurons from ferroptotic cell death in neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. Bersuker et al. used an analog of CoQ10 called Idebenone or Raxone, a drug that was initially developed for the treatment of Alzheimer’s disease and other neurodegenerative disease. Although clinical trials were inconclusive, this drug is still available in some countries and could be reconsidered for ferroptosis-related diseases. Overall, these two studies uncover a key mechanism behind the regulation of “enigmatic” ferroptosis in normal and pathological settings and put ubiquinone under proper scrutiny. These data suggest that the FSP1/CoQ10 protection branch is somehow secondary to GPX4 but could become primary in particular conditions related to the metabolic needs of cells or tissues. Many questions still need to be addressed and put in the context of human disease to generate important therapeutic insights for this discovery. We thank Ellen Jane Corcoran for editorial and language assistance. Research in the lab of M.M.S. is founded by the European Research Council (ERC) (grant agreement no. 647057) and Associazione Italiana Ricerca sul Cancro (AIRC) as Investigator grant no. 20119.