BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

TLDR

Mitochondrial apoptosis involves BAK/BAX‑induced outer membrane permeabilization, releasing cytochrome c and activating caspases, while mtDNA can trigger cGAS/STING‑mediated interferon production when caspases are inactive, yet the mechanism of cGAS access to mtDNA is unknown. Live‑cell lattice light‑sheet microscopy was employed to visualize the mitochondrial network in mouse embryonic fibroblasts. Following BAK/BAX activation and cytochrome c loss, the mitochondrial network disintegrated, forming large macropores that allowed inner membrane herniation and mtDNA release, while caspases failed to block herniation but dismantled the cell to suppress mtDNA‑induced innate immune signaling.

Abstract

Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce mitochondrial outer membrane permeabilization, leading to cytochrome c release and activation of apoptotic caspases. In the absence of active caspases, mitochondrial DNA (mtDNA) triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon. How cGAS gains access to mtDNA remains unclear. We used live-cell lattice light-sheet microscopy to examine the mitochondrial network in mouse embryonic fibroblasts. We found that after BAK/BAX activation and cytochrome c loss, the mitochondrial network broke down and large BAK/BAX pores appeared in the outer membrane. These BAK/BAX macropores allowed the inner mitochondrial membrane to herniate into the cytosol, carrying with it mitochondrial matrix components, including the mitochondrial genome. Apoptotic caspases did not prevent herniation but dismantled the dying cell to suppress mtDNA-induced innate immune signaling.