PARL is a mitochondrial serine-type endopeptidase essential for mitochondrial quality control and cell homeostasis 1. Functionally, PARL mediates proteolytic processing of key mitophagy regulators: it cleaves PINK1 into its mature 52 kDa form after mitochondrial-processing peptidase processing, and processes PGAM5 in response to mitochondrial membrane potential loss 2. PARL regulates the PINK1-PRKN mitophagy pathway through its interaction with prohibitin-2 (PHB2), whereby PHB2 depletion activates PARL to stabilize PINK1 and promote PRKN recruitment to damaged mitochondria 2. Beyond mitophagy, PARL processes additional substrates including CLPB (enhancing protein disaggregase activity), DIABLO/SMAC (required for apoptotic function), STARD7, and TTC19 [UniProt]. PARL also regulates mitochondrial morphology through phosphorylation of the P-beta domain [UniProt]. Disease relevance is substantial: PARL dysfunction impairs mitophagy in fatty acid oxidation-deficient cardiomyopathy 3, while PARL stabilization restricts mitophagy and increases chemoresistance in pancreatic cancer 4. PARL's role in organelle quality control extends to broader inflammatory and neurodegenerative diseases 56. Clinically, modulating PARL activity through upstream regulators like spautin-1 shows therapeutic promise in Alzheimer disease models by promoting PINK1-dependent mitophagy 7.