The Role of PTEN-L in Modulating PINK1-Parkin-Mediated Mitophagy

Abstract

An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, human cells have evolved sophisticated quality control mechanisms to identify and eliminate abnormal dysfunctional mitochondria. One pivotal mitochondrial quality control pathway is PINK1/Parkin-dependent mitophagy which mediates the selective removal of the dysfunctional mitochondria from the cell by autophagy. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial Ser/Thr kinase that was originally identified as a gene responsible for autosomal recessive early-onset Parkinson's disease (PD). Notably, upon failure of mitochondrial import, Parkin, another autosomal-recessive PD gene, is recruited to mitochondria and mediates the autophagic clearance of deregulated mitochondria. Importantly, recruitment of Parkin to damaged mitochondria hinges on the accumulation of PINK1 on the outer mitochondrial membrane (OMM). Normally, PINK1 is imported from the cytosol through the translocase of the outer membrane (TOM) complex, a large multimeric channel responsible for the import of most mitochondrial proteins. After import, PINK1 is rapidly degraded. Thus, at steady-state, PINK1 levels are kept low. However, upon mitochondrial import failure, PINK1 accumulates and forms a high-molecular weight > 700 kDa complex with TOM on the OMM. Thus, PINK1 functions as sensor, tagging dysfunctional mitochondria for Parkin-mediated mitophagy. Although much has been learned about the function of PINK1 in mitophagy, the biochemical and structural basis of negative regulation of PINK1 operation and functions is far from clear. Recent work unveiled new players as PTEN-l as negative regulator of PINK1 function. Herein, we review key aspects of mitophagy and PINK1/Parkin-mediated mitophagy with highlighting the role of negative regulation of PINK1 function and presenting some of the key future directions in PD cell biology.

Keywords: Mitochondrial quality control; Mitophagy; Neurodegeneration; PINK1; PTEN-L; Parkin; Protein degradation; Protein quality control.