Unfolding is the driving force for mitochondrial import and degradation of the Parkinson’s disease-related protein DJ-1

Bruno Barros Queliconi, Waka Kojima, Mayumi Kimura, Kenichiro Imai, Chisato Udagawa, Chie Motono, Takatsugu Hirokawa, Shinya Tashiro, Jose M.M. Caaveiro, Kouhei Tsumoto, Koji Yamano, Keiji Tanaka, Noriyuki Matsuda

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Diverse genes associated with familial Parkinson’s disease (familial Parkinsonism) have been implicated in mitochondrial quality control. One such gene, PARK7 encodes the protein DJ-1, pathogenic mutations of which trigger its translocation from the cytosol to the mitochondrial matrix. The translocation of steady-state cytosolic proteins like DJ-1 to the mitochondrial matrix upon missense mutations is rare, and the underlying mechanism remains to be elucidated. Here, we show that the protein unfolding associated with various DJ-1 mutations drives its import into the mitochondrial matrix. Increasing the structural stability of these DJ-1 mutants restores cytosolic localization. Mechanistically, we show that a reduction in the structural stability of DJ-1 exposes a cryptic N-terminal mitochondrial-targeting signal (MTS), including Leu10, which promotes DJ-1 import into the mitochondrial matrix for subsequent degradation. Our work describes a novel cellular mechanism for targeting a destabilized cytosolic protein to the mitochondria for degradation.

Original languageEnglish
Article numberjcs258653
JournalJournal of cell science
Volume134
Issue number22
DOIs
Publication statusPublished - Nov 2021

All Science Journal Classification (ASJC) codes

  • Cell Biology

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