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Gautier, Clement A.

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Gautier

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Clement A.

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Gautier, Clement A.

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20102

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Author's Publications: search.filters.isAuthorOfPublication.411c8fa9-c6e1-4285-af3a-116a2eb5a861

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    PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
    (Public Library of Science, 2010) Narendra, Derek P.; Jin, Seok Min; Tanaka, Atsushi; Suen, Der-Fen; Gautier, Clement A.; Shen, Jie; Cookson, Mark R.; Youle, Richard J.
    Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.
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    PINK1 Stabilized by Mitochondrial Depolarization Recruits Parkin to Damaged Mitochondria and Activates Latent Parkin for Mitophagy
    (The Rockefeller University Press, 2010) Matsuda, Noriyuki; Sato, Shigeto; Shiba, Kahori; Okatsu, Kei; Saisho, Keiko; Sou, Yu-shin; Saiki, Shinji; Kawajiri, Sumihiro; Sato, Fumiaki; Kimura, Mayumi; Komatsu, Masaaki; Hattori, Nobutaka; Tanaka, Keiji; Gautier, Clement A.
    Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.