Abstract
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.
Highlights
Parkinson′s disease (PD) is a neurodegenerative disease that predominately affects dopaminergic neurons in a specific area of the midbrain[1]
PINK1 interacts with Human telomerase reverse transcriptase (hTERT) in mammalian cells Based on prior evidence of the non-telomeric and mitochondria-related functions of hTERT, including the modulation of mitochondrial function and the reduction of intracellular ROS14, we examined the biochemical and functional interaction between hTERT and PINK1, and sought to determine if hTERT affected PINK1-mediated mitophagy
To first determine if hTERT binds to PINK1 in mammalian cells, we co-immunoprecipitated cell lysates transfected with a plasmid encoding Myctagged PINK1 alone or with a plasmid encoding HAtagged hTERT
Summary
Parkinson′s disease (PD) is a neurodegenerative disease that predominately affects dopaminergic neurons in a specific area of the midbrain[1]. Various mutations in the phosphatase and tensin homologueinduced putative kinase 1 (PINK1) and parkin genes have been associated with an early-onset form of PD. PINK1 synthesized de novo in the cytosol is rapidly and constitutively imported into the mitochondria by translocase of the PINK1 is cleaved by mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like protease (PARL)[5,6], and the processed form of PINK1 is transported back to the cytosol and degraded rapidly by the proteasome[7,8]. Phosphorylated parkin is subsequently recruited to the mitochondria, where it attaches to the Ub chains of the substrate protein present on the mitochondrial surface.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
