BMB Reports 2022; 55(10): 494-499  https://doi.org/10.5483/BMBRep.2022.55.10.082
Tollip negatively regulates mitophagy by promoting the mitochondrial processing and cytoplasmic release of PINK1
Woo Hyun Shin & Kwang Chul Chung*
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
Correspondence to: Tel: +82-2-2123-2653; Fax: +82-2-312-5657; E-mail: kchung@yonsei.ac.kr
Received: May 9, 2022; Revised: May 26, 2022; Accepted: May 26, 2022; Published online: October 31, 2022.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Mitochondria, Mitophagy, Parkinson’s disease, PINK1, Tollip

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