PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression

Mitochondrial damage is a potent trigger of inflammatory cell death; however, how damaged mitochondria transduce stress signals to initiate cell death execution, and how this process is finely regulated, remain incompletely understood. We recently identified that the PINK1-PRKN axis, activated upon mitochondrial depolarization, not only initiates mitophagy but also drives pyroptosis via the ubiquitination and degradation of MCL1, which in turn promotes BAX and BAK1 activation, leading to CASP3 activation and GSDME cleavage. PTEN-L functions as a negative regulator of this pathway by directly dephosphorylating PRKN, which concurrently suppresses both mitophagy and pyroptosis, thereby coupling organelle quality control to inflammatory cell death.