Mitochondrial membrane rupture licenses prohibitin 2-mediated bacterial tethering and E3 ligase recruitment to drive mito-xenophagy

Although ubiquitination is required for the recognition of invading bacteria by selective autophagy receptors and subsequent lysosomal destruction (xenophagy), how the host ubiquitin machinery is recruited to intracellular pathogens remains incompletely understood. In our recent study, we revealed that mitochondrial injury serves as an indispensable licensing checkpoint for antibacterial xenophagy. Outer mitochondrial membrane rupture externalizes inner membrane-anchored PHB2/prohibitin 2, which tethers damaged mitochondria to bacteria by engaging PHB (prohibitin) domain-containing proteins on the bacterial cell wall. Concurrently, PHB2 recruits the E3 ligase ARIH1 (ariadne RBR E3 ubiquitin protein ligase 1) or PRKN/Parkin - two well-characterized mitophagy-associated enzymes - which undergo auto-ubiquitination to assemble a localized polyubiquitin coat, ultimately driving organelle-bacterial co-autophagy (mito-xenophagy) independent of canonical mitophagy.