Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering


Parkinson's disease is a neurodegenerative disorder caused by degeneration of the midbrain dopaminergic system in addition to other nervous systems. PINK1 and parkin, which encode mitochondrial protein kinase and cytosolic Ub ligase, respectively, were identified as the genes responsible for the autosomal recessive form of juvenile Parkinson's disease. Activation of PINK1 upon reduction of mitochondrial membrane potential recruits Parkin from the cytosol activating its Ub ligase activity, which ensures removal of damaged mitochondria through mitophagy. However, how PINK1 recruits Parkin to the damaged mitochondria remained unclear. Here, we describe that the phosphorylation of polyUb chain by PINK1 is a key event to recruit Parkin on the mitochondria. Parkin binds to, and is activated by, phospho-polyUb generated by Parkin in collaboration with PINK1. Expression of a phospho-polyUb mimetic protein on mitochondria rescued mitochondrial degeneration caused by loss of PINK1 in Drosophila. Our study suggests the existence of an amplification cascade of Parkin activation and mitochondrial translocation, in which a ‘seed' of phosphorylated polyUb on the mitochondria, generated by PINK1 and Parkin, triggers a chain reaction of Parkin recruitment and activation.


Vyšlo v časopise: Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004861
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004861

Souhrn

Parkinson's disease is a neurodegenerative disorder caused by degeneration of the midbrain dopaminergic system in addition to other nervous systems. PINK1 and parkin, which encode mitochondrial protein kinase and cytosolic Ub ligase, respectively, were identified as the genes responsible for the autosomal recessive form of juvenile Parkinson's disease. Activation of PINK1 upon reduction of mitochondrial membrane potential recruits Parkin from the cytosol activating its Ub ligase activity, which ensures removal of damaged mitochondria through mitophagy. However, how PINK1 recruits Parkin to the damaged mitochondria remained unclear. Here, we describe that the phosphorylation of polyUb chain by PINK1 is a key event to recruit Parkin on the mitochondria. Parkin binds to, and is activated by, phospho-polyUb generated by Parkin in collaboration with PINK1. Expression of a phospho-polyUb mimetic protein on mitochondria rescued mitochondrial degeneration caused by loss of PINK1 in Drosophila. Our study suggests the existence of an amplification cascade of Parkin activation and mitochondrial translocation, in which a ‘seed' of phosphorylated polyUb on the mitochondria, generated by PINK1 and Parkin, triggers a chain reaction of Parkin recruitment and activation.


Zdroje

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