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.
Bibliographical noteFunding Information:
We thank J. Chung for providing plasmid, and J. Shen and H.W. Lee for PINK1-null and hTERT-null MEF cells, respectively. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of ICT & Future Planning, Republic of Korea (2018R1A2B2003955 to K.C.C.). This work was also supported in part by Brain Korea 21(BK21) PLUS program and W.H.S is a fellowship awardee by BK21 PLUS program.
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research