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Nardin 2015 Abstract MiPschool London 2015

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Parkin translocation is triggered by its dephosporylation by calcineurin.

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Nardin A, Scorrano L, Ziviani E (2015)

Event: MiPschool London 2015

During authophagy cytoplasmic material and organelles engulfed by autophagosomes, are delivered to the lysosomes for degradation and recycling of their constituents. The selective autophagy of mitochondria, termed mitophagy, depends on the translocation to damaged organelles of Parkin, an E3 ubiquitin ligase encoded by the Park2 gene mutated in Autosomal Recessive Juvenile Parkinsonism (AR-JP). The cellular signals or covalent modifications linking mitochondrial dysfunction to Parkin translocation are unclear. Here we show that Parkin translocation depends on its dephosporylation by Calcineurin (CaN).

In silico analysis revealed two evolutionary-conserved residuals in Parkin RING 2 domain, Serine 407 and Threonine 410, which scored high for modification by phosphorylation. A combination of genetic and small molecule inhibitors identified that the CaN-dependent dephosphorylation of these two Parkin residues is required for CCCP-induced Parkin translocation to mitochondria. Our results identify in cytoplasmic Ca2+ and in the Ca2+-dependent phosphatase Calcineurin two key modulatos of Parkin translocation in response to mitochondrial depolarization.


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Coupling state: ET 



Affiliations

1-Dulbecco-Telethon Inst, Venetian Inst Mol Med, Padova, Italy 2-Dept Biol, Univ Padova, Italy. - [email protected]