When location makes oxidative stress lethal: mitoxyperilysis at the immunometabolic stress interface

Mitoxyperilysis is a proposed lytic death pathway in which oxidatively damaged mitochondria become membrane-lethal when retained at the plasma membrane. In founding models, TLR stimulation plus carbon restriction engaged MYD88-dependent innate signalling and BAX/BAK1/BID-dependent mitochondrial oxidative stress, while mTORC2–RhoA–actin remodelling prolonged peripheral mitochondrial retention. Mitoxyperiosis denotes prolonged mitochondria-plasma membrane association and localised oxidative membrane injury, whereas mitoxyperilysis denotes the subsequent plasma membrane rupture and lytic cell death. In these models, NINJ1 contributed to terminal rupture and LDH/HMGB1 release without being required for cell death. The damaging oxidant, physical tether, and mechanism linking local injury to membrane failure remain unresolved. Sepsis may reproduce upstream metabolic-redox conditions, but direct evidence for the complete spatial sequence in patient-derived cells is lacking. This review separates founding-model findings from disease-relevant observations and untested steps.