title: Glutaminolysis and Transferrin Regulate Ferroptosis.
abstract: Ferroptosis has emerged as a new form of regulated necrosis that is implicated in various human diseases. However, the mechanisms of ferroptosis are not well defined. This study reports the discovery of multiple molecular components of ferroptosis and its intimate interplay with cellular metabolism and redox machinery. Nutrient starvation often leads to sporadic apoptosis. Strikingly, we found that upon deprivation of amino acids, a more rapid and potent necrosis process can be induced in a serum-dependent manner, which was subsequently determined to be ferroptosis. Two serum factors, the iron-carrier protein transferrin and amino acid glutamine, were identified as the inducers of ferroptosis. We further found that the cell surface transferrin receptor and the glutamine-fueled intracellular metabolic pathway, glutaminolysis, played crucial roles in the death process. Inhibition of glutaminolysis, the essential component of ferroptosis, can reduce heart injury triggered by ischemia/reperfusion, suggesting a potential therapeutic approach for treating related diseases.
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Minghui
authors.initials: M
authors.lastname: Gao
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Monian
authors.affiliation: Department of Medicine, Langone Medical Center, New York University, 522 1(st) Avenue, New York, NY 10016, USA.
authors.forename: Nosirudeen
authors.initials: N
authors.lastname: Quadri
authors.affiliation: Department of Medicine, Langone Medical Center, New York University, 522 1(st) Avenue, New York, NY 10016, USA.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: jiangx@mskcc.org.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D003470:Culture Media; D003553:Cystine / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D009336:Necrosis / Q000378:metabolism; D010084:Oxidation-Reduction; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism*
chemical_list: D003470:Culture Media; D011990:Receptors, Transferrin; D014168:Transferrin; D005973:Glutamine; D003553:Cystine; D007501:Iron; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D005978:Glutathione