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

• Published in: Cell reports (Cambridge) 2017-02, Vol.18 (6), p.1458-1472
• Main Authors: Shi, Guang, McQuibban, G. Angus
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Line, Tumor; Energy Metabolism - physiology; HEK293 Cells; HeLa Cells; Humans; intramembrane proteolysis; metabolism; Metalloproteases - metabolism; Mice; Mitochondria - metabolism; mitochondrial biogenesis; Mitochondrial Degradation - physiology; Mitochondrial Proteins - metabolism; mitophagy; Protein-Serine-Threonine Kinases - metabolism; rhomboid protease; Ubiquitin-Protein Ligases
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.01.029

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.