Mitochondria-derived methylmalonic acid aggravates ischemia–reperfusion injury by activating reactive oxygen species-dependent ferroptosis

• DOI: 10.1186/s12964-024-01479-z
• Publication Date: 2024-01-18T15:03:49Z
• Authors: Junchen Guo; Shanjie Wang; Xin Wan; Xiaoxuan Liu; Zeng Wang; Chenchen Liang; Zhenming Zhang; Ye Wang; Miao Yan; Pengyan Wu; Shaohong Fang; Bo Yu
• Keywords: GPX4

Abstract Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia–reperfusion (I/R) injury. However, the precise mechanism underlying ferroptosis remains less known. In this study, we investigated pathophysiological mechanisms of methylmalonic acid (MMA) associated with activation cardiomyocytes after I/R. We found an increase level MMA patients acute injury reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. treatment was to be excessive oxidative stress cardiomyocytes, leading ferroptosis-related mice I/R injury, aggravated ferroptosis, which amplified infarct size cardiac dysfunction. Mechanistically, promoted NOX2/4 expression reactive oxygen species (ROS) production aggravating Notably, increased ROS further activated by inhibiting solute carrier family 7 member 11 (SLC7A11) glutathione peroxidase 4 (GPX4) expression. addition, decreased ectopic nuclear distribution factor E2-related 2 (NRF2) increasing interaction between NRF2 kelch-like ECH-associated protein 1 (KEAP1). This impeded GPX4/SLC7A11, downstream NRF2, activating Collectively, our study indicates that activates generation, induces exacerbate cardiomyocyte model. These findings may provide new perspective for clinical warrant investigation.