Gasdermins induce the release of mitochondrial DNA during pyroptosis and apoptosis

Pyroptosis and intrinsic apoptosis are two forms of regulated cell death driven by active caspases where plasma membrane permeabilization is induced by gasdermin pores. Caspase-1 induces gasdermin D pore formation during pyroptosis meanwhile caspase-3 promotes gasdermin E pore formation during apoptosis. These two types of cell death are accompanied by mitochondrial outer membrane permeabilization due to BAK/BAX pore formation in the external membrane of mitochondria, and to some extent this complex also affects the inner mitochondrial membrane facilitating mitochondrial DNA relocalisation from the matrix to the cytosol. However, the detailed mechanism responsible for this process has not been investigated. Herein, we reported that gasdermin processing is required to induce mitochondrial DNA release from cells, despite mitochondrial outer membrane permeabilization, during pyroptosis and apoptosis. Gasdermin targeting the plasma membrane promotes a fast-mitochondrial collapse with the initial accumulation of mitochondrial DNA in the cytosol and then facilitate its release from the cell upon plasma membrane rupture. These findings demonstrate a critical role of gasdermin action on the plasma membrane facilitating the release of mitochondrial DNA as a damage-associated molecular pattern.