PTEN-L inhibits mitophagy and GSDME-dependent pyroptosis via Parkin dephosphorylation.

Mitochondrial dysfunction is a potent trigger of inflammatory cell death; however, the precise signaling pathways linking mitochondrial damage to pyroptosis remain incompletely understood. Here, we identify a previously unrecognized pathway in which mitochondrial depolarization activates the PINK1-Parkin axis to drive GSDME-mediated pyroptosis, a process negatively regulated by the phosphatase PTEN-L. Upon activation, Parkin promotes the ubiquitination and proteasomal degradation of MCL-1, facilitating mitochondrial translocation and activation of BAX. This triggers cytochrome c release, caspase-3 activation, and subsequent cleavage and plasma membrane targeting of GSDME, ultimately leading to pyroptotic cell death. Conversely, PTEN-L functions as a master negative regulator that counteracts Parkin through dephosphorylation and inactivation of Parkin. This action not only suppresses mitophagy but also stabilizes MCL-1, thereby inhibiting the downstream BAX/BAK-caspase-3-GSDME cascade and subsequent pyroptosis. Thus, our findings reveal a phosphorylation-dependent regulatory switch centered on Parkin that functionally couples mitophagy regulation to GSDME-dependent pyroptosis, delineating a novel mitochondrial signaling pathway that integrates organelle quality control with cellular fate decisions under stress conditions.