AutophagyOct 20, 2026

How PTEN-L controls PRKN to link reduced removal of damaged mitochondria with lower inflammatory cell death

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 21, 2026

Abstract

Mitochondrial damage activates the PINK1-PRKN axis, which drives pyroptosis through specific cellular processes.

Mitochondrial depolarization triggers the PINK1-PRKN pathway, initiating both mitophagy and pyroptosis.
Ubiquitination and degradation of MCL1 are key steps that promote activation of BAX and BAK1.
Activation of BAX and BAK1 leads to CASP3 activation and cleavage of GSDME.
PTEN-L negatively regulates this pathway by dephosphorylating PRKN, which suppresses mitophagy and pyroptosis.
This regulation links organelle quality control to inflammatory cell death.

Simplified

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.

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How PTEN-L controls PRKN to link reduced removal of damaged mitochondria with lower inflammatory cell death

Abstract

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