Cell death is an inherent and essential aspect of life. This crucial cellular event is maintained by a finely tuned balance between cell survival and cell death which, when disrupted, has been linked to pathological conditions such as neurodegenerative disorders and carcinogenesis. Cell death modalities were broadly divided into programmed and accidental, which later came to be known as apoptosis and necrosis, respectively. This concept overlooked the emerging notion that necrotic forms of cell death are in fact regulated and kept in check by defined survival pathways.
Cell death pathway
Among these regulated necrotic cell death modalities considerable attention has been given to ferroptosis, a cell death pathway that requires phospholipid peroxidation. Our previous work has helped to characterize this pathway where we identified glutathione peroxidase 4 (Gpx4) as an essential regulator of this pathway. Moreover, we shed light into critical metabolic requirements linked to lipid metabolism that determines sensitivity to ferroptosis. Among our current interest are the discovery and characterization of novel nodes regulating ferroptosis and factors regulating them. In addition, we are pursuing the biochemical events linking phospholipid peroxidation and cell death with a particular interest in the role of lipid-derived electrophiles as potential second messengers. In order to track our goals we rely on a broad array of technologies and collaborations spanning from classical molecular biology and biochemistry, proteomics, CRISPR/Cas9 based screen and engineered cellular models and ultimately in vivo mouse models.
Our long term goal is to provide the rationale for novel pharmacological approaches that will enable us to tip the balance between life and death decision made by a cell, knowledge that will ultimately result in previously unforeseen therapeutic opportunities to treat disorders were unregulated cell death is a root cause.
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. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 2017 Dec 16. pii: S0092-8674(17)31438-1. doi: 10.1016/j.cell.2017.11.048.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017 Oct 5;171(2):273-285. doi: 10.1016/j.cell.2017.09.021
Angeli JPF, Shah R, Pratt DA, Conrad M. Ferroptosis Inhibition: Mechanisms and Opportunities.Trends Pharmacol Sci. 2017 May;38(5):489-498. doi: 10.1016/j.tips.2017.02.005
Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, Pratt DA. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent Sci. 2017 Mar 22;3(3):232-243. doi: 10.1021/acscentsci.7b00028.
Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trümbach D, Mao G, Qu F, Bayir H, Füllekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP*, Conrad M*. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017 Jan;13(1):91-98. doi: 10.1038/nchembio.2239.
Kagan VE, Mao G*, Qu F*, Angeli JP*, Doll S, Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, Kapralov AA, Amoscato AA, Jiang J, Anthonymuthu T, Mohammadyani D, Yang Q, Proneth B, Klein-Seetharaman J, Watkins S, Bahar I, Greenberger J, Mallampalli RK, Stockwell BR, Tyurina YY, Conrad M, Bayır H. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017 Jan;13(1):81-90. doi: 10.1038/nchembio.2238.
Conrad M, Angeli JP, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016 May;15(5):348-66. doi: 10.1038/nrd.2015.6.
Gascón S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D, Deshpande A, Heinrich C, Karow M, Robertson SP, Schroeder T, Beckers J, Irmler M, Berndt C, Angeli JP, Conrad M, Berninger B, Götz M. Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming. Cell Stem Cell. 2016 Mar 3;18(3):396-409. doi: 10.1016/j.stem.2015.12.003.
Conrad M, Friedmann Angeli JP. Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it? Mol Cell Oncol. 2015 Jan 30;2(3):e995047. doi: 10.4161/23723556.2014.995047.
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. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014 Dec;16(12):1180-91. doi: 10.1038/ncb3064.
Dr. José Pedro Friedmann Angeli
Thamara Nishida Xavier da Silva
Dr. Florêncio Porto- Freitas
Supervisor – Biomedicine