Unfolding of PD-related protein DJ-1 triggers mitochondrial translocation

A number of studies report a link between neurodegenerative disease and impaired mitochondrial function. In particular, several gene products associated with familial Parkinson's disease (familial Parkinsonism), including Parkin and PINK1, are implicated in mitochondrial quality control. Another gene linked to recessive familial Parkinsonism, PARK7, encodes the protein DJ-1. Previous work by several researchers, including the group of Noriyuki Matsuda, has shown that wild-type DJ-1 is cytosolic under normal conditions, but that pathogenic mutations in the protein result in its translocation to the mitochondrial matrix. In this study (Queliconi et al., 2021), Matsuda and colleagues investigate the molecular mechanisms underlying DJ-1 translocation and the physiological impact of mitochondrial import. The authors show that protein unfolding as a result of destabilising mutations is the driving force behind the mitochondrial localisation of DJ-1 mutants, and that exposure of a mitochondria-targeting signal (MTS) in the DJ-1 N-terminus is responsible for mitochondrial import. Interestingly, their findings indicate it is unlikely that DJ-1 mutants play a role in Parkinson's disease pathogenesis after transport to the mitochondria. Instead, they find that mitochondrially localised DJ-1 mutants are degraded after import, hinting at the importance of future work into mitochondrial import and degradation in response to protein destabilisation.