Tollip negatively regulates mitophagy by promoting the mitochondrial processing and cytoplasmic release of PINK1
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초록
PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinasethat phosphorylates several substrates and exerts neuroprotectiveeffects against stress-induced apoptotic cell death. Mutationsin PINK1 have been linked to autosomal recessive formsof Parkinson’s disease (PD). Mitophagy is a type of autophagythat selectively promotes mitochondrial turnover and preventsthe accumulation of dysfunctional mitochondria to maintain cellularhomeostasis. Toll-interacting protein (Tollip) was initiallyidentified as a negative regulator of IL-1β receptor signaling, suppressinginflammatory TLR signaling cascades. Recently, Tolliphas been reported to play a role in autophagy and is implicatedin neurodegeneration. In this study, we determined whetherTollip was functionally linked to PINK1-mediated mitophagy. Our results demonstrated that Tollip promoted the mitochondrialprocessing of PINK1 and altered the localization of PINK1,predominantly to the cytosol. This action was attributed to increasedbinding of PINK1 to mitochondrial processing peptidaseβ (MPPβ) and the subsequent increase in MPPβ-mediated mitochondrialPINK1 cleavage. Furthermore, Tollip suppressed mitophagyfollowing carbonyl cyanide m-chlorophenylhydrazoneinducedmitochondrial dysfunction. These findings suggest thatTollip inhibits mitophagy via the PINK1/parkin pathway uponmitochondrial damage, leading to the blockade of PINK1-mediatedneuroprotection.
Abstract
PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinasethat phosphorylates several substrates and exerts neuroprotectiveeffects against stress-induced apoptotic cell death. Mutationsin PINK1 have been linked to autosomal recessive formsof Parkinson’s disease (PD). Mitophagy is a type of autophagythat selectively promotes mitochondrial turnover and preventsthe accumulation of dysfunctional mitochondria to maintain cellularhomeostasis. Toll-interacting protein (Tollip) was initiallyidentified as a negative regulator of IL-1β receptor signaling, suppressinginflammatory TLR signaling cascades. Recently, Tolliphas been reported to play a role in autophagy and is implicatedin neurodegeneration. In this study, we determined whetherTollip was functionally linked to PINK1-mediated mitophagy. Our results demonstrated that Tollip promoted the mitochondrialprocessing of PINK1 and altered the localization of PINK1,predominantly to the cytosol. This action was attributed to increasedbinding of PINK1 to mitochondrial processing peptidaseβ (MPPβ) and the subsequent increase in MPPβ-mediated mitochondrialPINK1 cleavage. Furthermore, Tollip suppressed mitophagyfollowing carbonyl cyanide m-chlorophenylhydrazoneinducedmitochondrial dysfunction. These findings suggest thatTollip inhibits mitophagy via the PINK1/parkin pathway uponmitochondrial damage, leading to the blockade of PINK1-mediatedneuroprotection.
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