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

2021; The Company of Biologists; Volume: 134; Issue: 22 Linguagem: Inglês

10.1242/jcs.258653

1477-9137

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

Alzheimer's disease research and treatments

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.