期刊
CELL REPORTS
卷 18, 期 6, 页码 1458-1472出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.029
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资金
- Canadian Institutes of Health Research [MOP-130281]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-201505969]
- Michael J. Fox Foundation for Parkinson's Research [304692]
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/PARKINmediated mitophagy, which is an essential component of MQC. PARL undergoes an N-terminal autocatalytic cleavage (beta cleavage), which is required for efficient mitophagy. We demonstrate that b 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 b cleavage. Through regulating b 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.
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