SLC25A21 promotes ferroptosis by inducing mitochondrial GPX4 deficiency in colorectal cancer

Mitochondrial 2-oxodicarboxylate carrier (SLC25A21) plays a crucial role in maintaining mitochondrial function and regulating apoptosis. Whether SLC25A21 influences cell death solely through apoptosis remains unclear. Here, we reported that mitochondrial protein Methylcrotonoyl-CoA carboxylase beta chain (MCCC2) co-localized with mitochondrial inner membrane protein SLC25A21 and promoted its lysosomal degradation in colorectal cancer (CRC) cells. The ectopic overexpression of SLC25A21 significantly inhibited the malignant behaviors of CRC cells. Overexpression of SLC25A21 induced cell death and cell cycle arrest at the G2/M phase, and triggered hallmark ferroptotic alterations, including lipid peroxidation (LPO) and reactive oxygen species (ROS) accumulation, increased Malondialdehyde (MDA) contents, GSSG/GSH and NADP + /NADPH ratios, and abnormal mitochondrial morphologies. Mechanistically, SLC25A21 formed a complex with Glutathione Peroxidase 4 (GPX4) and activated the MEK-ERK and p38 MAPK signaling pathways, together reducing the GPX4 pool in mitochondria. Treatment of CRC cells with a GPX4 agonist inhibited SLC25A21-induced ferroptosis, thereby reducing the production of LPO and ROS, and restoring partially malignant behaviors of the cells. In vivo, SLC25A21 inhibited tumor growth by activating ferroptosis. Relatively high expression of SLC25A21 was associated with unfavorable outcomes in multiple patient cohorts, suggesting a complex role for SLC25A21 in CRC progression. Together, we identified SLC25A21-GPX4 interaction as an important regulatory axis in mitochondrial redox maintenance.