CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation

• Published in: Biochemical and biophysical research communications Vol. 478; no. 2; pp. 838 - 844
• Main Authors: Yuan, Hua, Li, Xuemei, Zhang, Xiuying, Kang, Rui, Tang, Daolin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.09.2016
• Subjects: Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - agonists; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; cell death; CISD1; Deferoxamine - pharmacology; Ferroptosis; Gene Expression Regulation, Neoplastic; Hep G2 Cells; hepatoma; Humans; iron; Iron - metabolism; Iron Chelating Agents - pharmacology; Iron-sulfur proteins; Lipid peroxidation; Lipid Peroxidation - drug effects; membrane proteins; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial membrane; Mitochondrial Proteins - agonists; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; neoplasm cells; Oxidative Stress; Piperazines - antagonists & inhibitors; Piperazines - pharmacology; sulfur; Thiazolidinediones - pharmacology; Iron-sulfur proteins; GPX4; IRP; CISD1; Lipid peroxidation; Q-PCR; Ferroptosis; HCC; MDA; DFO; Mitochondria; Fe2; NRF2; ΔΨm; ROS; VDACs; CCK-8; GSH
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.08.034

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.