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

Publication date: 7 February 2017
Source:Cell Reports, Volume 18, Issue 6
Author(s): Guang Shi, G. Angus McQuibban
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.

Graphical abstract

Teaser

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.


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