Human telomerase reverse transcriptase positively regulates mitophagy by inhibiting the processing and cytoplasmic release of mitochondrial PINK1

摘要

Mutations in the phosphatase and tensin homologue-induced putative kinase 1 (PINK1) gene have been linked to an early-onset autosomal recessive form of familial Parkinson's disease (PD). PINK1, a mitochondrial serine/threonine-protein kinase, plays an important role in clearing defective mitochondria by mitophagy - the selective removal of mitochondria through autophagy. Evidence suggests that alteration of the PINK1 pathway contributes to the pathogenesis of PD, but the mechanisms by which the PINK1 pathway regulates mitochondrial quality control through mitophagy remain unclear. Human telomerase reverse transcriptase (hTERT) is a catalytic subunit of telomerase that functions in telomere maintenance as well as several non-telomeric activities. For example, hTERT has been associated with cellular immortalization, cell growth control, and mitochondrial regulation. We determined that hTERT negatively regulates the cleavage and cytosolic processing of PINK1 and enhances its mitochondrial localization by inhibiting mitochondrial processing peptidase β (MPPβ). Consequently, hTERT promotes mitophagy following carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced mitochondrial dysfunction and improves the function of damaged mitochondria by modulating PINK1. These findings suggest that hTERT positively regulates PINK1 function, leading to increased mitophagy following mitochondrial damage.