title: Autophagy promotes ferroptosis by degradation of ferritin.
abstract: Macroautophagy/autophagy is an evolutionarily conserved degradation pathway that maintains homeostasis. Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. However, the relationship between autophagy and ferroptosis at the genetic level remains unclear. Here, we demonstrated that autophagy contributes to ferroptosis by degradation of ferritin in fibroblasts and cancer cells. Knockout or knockdown of Atg5 (autophagy-related 5) and Atg7 limited erastin-induced ferroptosis with decreased intracellular ferrous iron levels, and lipid peroxidation. Remarkably, NCOA4 (nuclear receptor coactivator 4) was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis. Consistently, genetic inhibition of NCOA4 inhibited ferritin degradation and suppressed ferroptosis. In contrast, overexpression of NCOA4 increased ferritin degradation and promoted ferroptosis. These findings provide novel insight into the interplay between autophagy and regulated cell death.
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.
authors.forename: Yangchun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Song
authors.affiliation: b The Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Sun
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: a Department of Surgery , University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh , PA USA.|b The Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong , China.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism*; D005293:Ferritins / Q000737:chemistry*; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; C111382:NCOA4 protein, human; C508724:NcoA4 protein, mouse; D056918:Nuclear Receptor Coactivators; D010879:Piperazines; D017382:Reactive Oxygen Species; C477224:erastin; D005293:Ferritins; D007501:Iron; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7
keywords: NCOA4; autophagy; ferritin; ferritinophagy; ferroptosis; iron; lipid; pancreatic cancer