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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Tollip negatively regulates mitophagy by promoting the mitochondrial processing and cytoplasmic release of PINK1

  • Shin, Woo Hyun (Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University) ;
  • Chung, Kwang Chul (Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University)
  • Received : 2022.05.09
  • Accepted : 2022.05.26
  • Published : 2022.10.31
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Abstract

PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinase that phosphorylates several substrates and exerts neuroprotective effects against stress-induced apoptotic cell death. Mutations in PINK1 have been linked to autosomal recessive forms of Parkinson's disease (PD). Mitophagy is a type of autophagy that selectively promotes mitochondrial turnover and prevents the accumulation of dysfunctional mitochondria to maintain cellular homeostasis. Toll-interacting protein (Tollip) was initially identified as a negative regulator of IL-1β receptor signaling, suppressing inflammatory TLR signaling cascades. Recently, Tollip has been reported to play a role in autophagy and is implicated in neurodegeneration. In this study, we determined whether Tollip was functionally linked to PINK1-mediated mitophagy. Our results demonstrated that Tollip promoted the mitochondrial processing of PINK1 and altered the localization of PINK1, predominantly to the cytosol. This action was attributed to increased binding of PINK1 to mitochondrial processing peptidase β (MPPβ) and the subsequent increase in MPPβ-mediated mitochondrial PINK1 cleavage. Furthermore, Tollip suppressed mitophagy following carbonyl cyanide m-chlorophenylhydrazone-induced mitochondrial dysfunction. These findings suggest that Tollip inhibits mitophagy via the PINK1/parkin pathway upon mitochondrial damage, leading to the blockade of PINK1-mediated neuroprotection.

Keywords

Acknowledgement

We thank J. Chung for providing PINK1 plasmid and J. Shen for PINK1-null MEF cells. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT, Korea Government (NRF-2021R1A2C1005469 to K.C.C.).

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