Marcus Conrad

Doctor
Helmholtz Munich German Research Center for Environmental Health, Germany
Institute of Metabolism and Cell Death Ingolstädter Landstr. 1 85764 Neuherberg, Germany
 

Topic: Modulating Ferroptosis for Disease Prevention

ABSTRACT
Ferroptosis is a metabolic form of regulated cell death characterized by an iron-dependent oxidative destruction of cellular membranes. Ferroptosis emerges as the underlying cause of several degenerative diseases and presents a pharmacologically tractable vulnerability to eradicate difficult-to-treat cancers. Years before the term “ferroptosis” was coined, we had shown that glutathione peroxidase 4 (GPX4), by preventing unrestrained phospholipid peroxidation in cells and mice, controls a new type of non-apoptotic cell death, now known as ferroptosis. Using genetic suppressor screens, we further introduced ferroptosis suppressor protein-1 (FSP1) as the second ferroptosis surveillance system. The anti-ferroptotic role of FSP1 is based on the NAD(P)H dependent reduction of extra-mitochondrial coenzyme Q10, thereby halting uncontrolled lipid peroxidation and ferroptosis. Besides, FSP1 constitutes the long sought-after, warfarin-resistant vitamin K reductase in the canonical vitamin K cycle, thus linking vitamin K biology and ferroptosis. We recently reported the first in vivo active FSP1 inhibitor, icFSP1, which induces phase separation of FSP1 prior to cancer cell death induction. Ongoing studies are therefore geared towards understanding the in vivo relevance of these systems in ferroptosis control and their pharmacological tractability as the basis for developing new pharmacotherapies for ferroptosis-related diseases including neurodegeneration and cancer.

Further reading:
Nakamura T, Hipp C, Santos Dias Mourão A, Borggräfe J, Aldrovandi M, Henkelmann B, Wanninger J, Mishima E, Lytton E, Emler D, Proneth B, Sattler M, Conrad M (2023) Phase separation of FSP1 promotes ferroptosis. Nature. 2023 Jun 28. doi: 10.1038/s41586-023-06255-6. Online ahead of print.

Mishima E*, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, Tonnus W, Nepachalovich P, Eggenhofer E, Aldrovandi M, Henkelmann B, Yamada KI, Wanninger J, Zilka O, Sato E, Feederle R, Hass D, Maida A, Mourão ASD, Linkermann A, Geissler EK, Nakagawa K, Abe T, Fedorova M, Proneth B, Pratt DA, Conrad M* (2022) A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature. 608:778-783. (* equal contribution)

Doll S, Porto Freitas F, Shah R, Aldrovandi M, Costa da Silva M, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel C, Mourão A, Buday K, Sato M, Wanninger J, Vignane T, Mohana V, Rehberg M, Flatley A, Schepers A, Kurz A, White A, Sauer M, Sattler M, Tate ET, Schmitz W, Schulze A, O’Donnell V, Proneth B, Popowicz GM, Pratt DA, Friedmann Angeli JP*, Conrad M* (2019) FSP1 is a Glutathione-Independent Ferroptosis Suppressor. Nature. 575:693-698. (*equal contribution)

Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F, Seibt T, Mehr L, Aichler M, Walch A, Lamp D, Jastroch M, Miyamoto S, Wurst W, Ursini F, Arnér ESJ, Fradejas-Villar N, Schweizer U, Zischka H, Friedmann Angeli JP, Conrad M (2018) Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 172:409-422.e21.

Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O'Donnell VB, Kagan VE, Schick JA, Conrad M (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 16:1180-91.