Mechanistic insights and therapeutic implications of mitoxyperilysis: a spatially gated mitochondria-dependent lytic cell death.

Programmed cell death (PCD) has expanded to more than ten diverse lytic modalities such as pyroptosis, necroptosis, ferroptosis, and disulfidptosis. In 2025, Wang et al. reported in Cell a previously unrecognized form of lytic cell death, termed mitoxyperilysis, in which plasma membrane rupture is driven not by canonical pore-forming or membrane-disrupting enzymatic effectors, but by mitochondria-mediated oxidative injury localized to the cell periphery. This process is initiated by the synergistic combination of innate immune activation and metabolic disruption, referred to as IIAMD, which induces mitochondrial oxidative damage and promotes the sustained retention of injured mitochondria at the plasma membrane, a preceding state termed mitoxyperiosis. Mechanistically, mTORC2, particularly through its defining subunit RICTOR, functions as a central regulatory switch that licenses the transition from tolerated oxidative stress to lethal membrane rupture. By suppressing RhoA-dependent actin remodeling and lamellipodia formation, mTORC2 prevents the spatial clearance of damaged mitochondria from the cell cortex, thereby allowing locally concentrated oxidative stress to overwhelm membrane repair and antioxidant defenses. This two-step framework establishes the concept of spatial licensing in oxidative cell death, emphasizing that lethality depends not only on the amount of reactive oxygen species, but also on their subcellular topology. However, mitoxyperilysis has not yet been implicated in any human disease on the basis of direct evidence. In this review, we summarize the emerging mechanisms of mitoxyperilysis, compare it with established lytic death pathways, and discuss its potential relevance to inflammatory disease, sepsis, ischemic injury, and cancer, as well as therapeutic strategies targeting mTORC2, RhoA signaling, and mitochondrial protection.