An mTORC2-driven mitochondrial positioning framework links immunometabolic stress to spatially restricted oxidative membrane damage in mitoxyperilysis

Abstract

Mitoxyperilysis is a recently defined lytic cell death modality characterized by plasma membrane rupture driven by spatially confined mitochondrial oxidative damage under immunometabolic co-stress. However, the upstream mechanisms governing its spatial organization remain poorly defined. Here, we propose a conceptual framework in which mechanistic target of rapamycin complex 2 (mTORC2) may act as a critical spatial regulator linking immunometabolic stress to localized redox injury. Sustained mTORC2 activation suppresses RhoA-dependent cytoskeletal dynamics and lamellipodium formation, thereby impairing membrane dynamics and promoting prolonged mitochondria-plasma membrane contact. This spatial confinement may facilitate localized accumulation of mitochondrial reactive oxygen species (ROS), which could promote lipid peroxidation and ultimately lead to plasma membrane destabilization and lytic cell death. We further compare mitoxyperilysis with other redox-associated cell death modalities, emphasizing its defining feature of spatially restricted oxidative membrane damage. In addition, we discuss its potential relevance in pathological contexts associated with chronic immunometabolic stress. Collectively, this review suggests a potential role for an mTORC2-cytoskeleton-mitochondrial positioning axis as a regulatory module underlying spatially confined oxidative injury and provides new insights into how subcellular organization shapes redox-dependent cell fate decisions. This framework may inform the development of spatially targeted therapeutic strategies in immunometabolic diseases.