The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism

Mitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism for the pathogenesis of various diseases, including Parkinson’s disease. The mammalian mitochondrial rhomboid protease, PARL, has been proposed as a regulator of PINK1/PARKIN-mediated mitophagy, which is an essential component of MQC. PARL undergoes an N-terminal autocatalytic cleavage (β cleavage), which is required for efficient mitophagy. We demonstrate that β cleavage responds to mitochondrial stress, triggered by the depletion of mitochondrial ATP. Furthermore, we show that PDK2, a key regulator in metabolic plasticity, phosphorylates PARL and regulates β cleavage. Through regulating β cleavage and the production of a less active enzyme, PACT, PDK2 negatively regulates PINK1/PARKIN-mediated mitophagy. Taken together, we propose that PDK2/PARL senses defects in mitochondrial bioenergetics, integrating mitochondrial metabolism to mitophagy and MQC in human health and disease. [Display omitted] •Defects in mitochondrial energy production trigger PARL β cleavage•β cleavage creates a catalytically less active enzyme, termed PACT•PDK2 phosphorylates PARL to regulate β cleavage and the production of PACT•By modulating PARL β cleavage, PDK2 regulates PINK1/PARKIN-mediated mitophagy PARL β cleavage is essential for the efficient removal of damaged mitochondria by mitophagy. Shi and McQuibban find that PDK2, a master regulator of metabolism, phosphorylates PARL, inhibits β cleavage, and regulates PINK1/PARKIN-mediated mitophagy. Their findings integrate cellular metabolism with mitophagy and mitochondrial quality control in human health and diseases.