title: CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation.
abstract: Ferroptosis is a form of non-apoptotic cell death originally identified in cancer cells. However, the key regulator of ferroptosis in mitochondria remains unknown. Here, we show that CDGSH iron sulfur domain 1 (CISD1, also termed mitoNEET), an iron-containing outer mitochondrial membrane protein, negatively regulates ferroptotic cancer cell death. The classical ferroptosis inducer erastin promotes CISD1 expression in an iron-dependent manner in human hepatocellular carcinoma cells (e.g., HepG2 and Hep3B). Genetic inhibition of CISD1 increased iron-mediated intramitochondrial lipid peroxidation, which contributes to erastin-induced ferroptosis. In contrast, stabilization of the iron sulfur cluster of CISD1 by pioglitazone inhibits mitochondrial iron uptake, lipid peroxidation, and subsequent ferroptosis. These findings indicate a novel role of CISD1 in protecting against mitochondrial injury in ferroptosis.
authors: School of Nursing, Jilin University, Changchun, Jilin 130021, China.
authors: Hua
authors: H
authors: Yuan
authors: Department of Hematology, Qingdao Municipal Hospital, Qingdao, Shandong 261041, China.
authors: Xuemei
authors: X
authors: Li
authors: School of Nursing, Jilin University, Changchun, Jilin 130021, China.
authors: Xiuying
authors: X
authors: Zhang
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Rui
authors: R
authors: Kang
authors: School of Nursing, Jilin University, Changchun, Jilin 130021, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China. Electronic address: tangd2@upmc.edu.
authors: Daolin
authors: D
authors: Tang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D000077205:Pioglitazone; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C525595:CISD1 protein, human; D007502:Iron Chelating Agents; D024101:Mitochondrial Proteins; D010879:Piperazines; D045162:Thiazolidinediones; C477224:erastin; D007501:Iron; D003676:Deferoxamine; D000077205:Pioglitazone
keywords: CISD1; Ferroptosis; Iron-sulfur proteins; Lipid peroxidation; Mitochondria