TY - JOUR
T1 - SLC25A22 as a Key Mitochondrial Transporter Against Ferroptosis by Producing Glutathione and Monounsaturated Fatty Acids
AU - Liu, Yang
AU - Wang, Yuan
AU - Lin, Zhi
AU - Kang, Rui
AU - Tang, Daolin
AU - Liu, Jiao
N1 - Publisher Copyright:
© Yang Liu et al., 2023; Published by Mary Ann Liebert, Inc.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - Aims: Ferroptosis, a type of oxidative cell death driven by unlimited lipid peroxidation, is emerging as a target for cancer therapy. Although mitochondrial dysfunction may lead to ferroptosis, the underlying molecular mechanisms and metabolic pathways for ferroptosis are incompletely understood. Here, we identify solute carrier family 25 member 22 (SLC25A22), a mitochondrial glutamate transporter, as a driver of ferroptosis resistance in pancreatic ductal adenocarcinoma (PDAC) cells. Results: The downregulation of SLC25A22 expression was associated with increased sensitivity to ferroptosis, but not to apoptosis. Mechanistically, on the one hand, SLC25A22-dependent NAPDH synthesis blocks ferroptotic cell death in PDAC cells through mediating the production of glutathione (GSH), the most important hydrophilic antioxidant. On the other hand, SLC25A22 promotes the expression of stearoyl-CoA desaturase in PDAC cells in an AMP-activated protein kinase-dependent manner, resulting in the production of antiferroptotic monounsaturated fatty acids (MUFAs). The animal study further confirms that SLC25A22 inhibits ferroptosis-mediated tumor suppression. Innovation: SLC25A22 is a novel metabolic repressor of ferroptosis by producing GSH and MUFAs. Conclusion: These findings establish a previously unrecognized metabolic defense pathway to limit ferroptotic cell death in vitro and in vivo. Antioxid. Redox Signal. 39, 166-185.
AB - Aims: Ferroptosis, a type of oxidative cell death driven by unlimited lipid peroxidation, is emerging as a target for cancer therapy. Although mitochondrial dysfunction may lead to ferroptosis, the underlying molecular mechanisms and metabolic pathways for ferroptosis are incompletely understood. Here, we identify solute carrier family 25 member 22 (SLC25A22), a mitochondrial glutamate transporter, as a driver of ferroptosis resistance in pancreatic ductal adenocarcinoma (PDAC) cells. Results: The downregulation of SLC25A22 expression was associated with increased sensitivity to ferroptosis, but not to apoptosis. Mechanistically, on the one hand, SLC25A22-dependent NAPDH synthesis blocks ferroptotic cell death in PDAC cells through mediating the production of glutathione (GSH), the most important hydrophilic antioxidant. On the other hand, SLC25A22 promotes the expression of stearoyl-CoA desaturase in PDAC cells in an AMP-activated protein kinase-dependent manner, resulting in the production of antiferroptotic monounsaturated fatty acids (MUFAs). The animal study further confirms that SLC25A22 inhibits ferroptosis-mediated tumor suppression. Innovation: SLC25A22 is a novel metabolic repressor of ferroptosis by producing GSH and MUFAs. Conclusion: These findings establish a previously unrecognized metabolic defense pathway to limit ferroptotic cell death in vitro and in vivo. Antioxid. Redox Signal. 39, 166-185.
KW - SLC25A22
KW - ferroptosis
KW - lipid peroxidation
KW - mitochondria
UR - http://www.scopus.com/inward/record.url?scp=85164473476&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85164473476&partnerID=8YFLogxK
U2 - 10.1089/ars.2022.0203
DO - 10.1089/ars.2022.0203
M3 - Article
C2 - 37051693
AN - SCOPUS:85164473476
SN - 1523-0864
VL - 39
SP - 166
EP - 185
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 1-3
ER -