Journal Article

DZNE-2020-02441

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.

Geisler, S. ; Holmström, K. M. ; Treis, A. ; Skujat, D. ; Weber, S. S. ; Fiesel, F. C. ; Kahle, P. (Corresponding author)DZNE* ; Springer, W. (Corresponding author)

2010
Taylor & Francis Abingdon, Oxon

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Please use a persistent id in citations: doi:10.4161/auto.6.7.13286

Abstract: Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.

Keyword(s): Animals (MeSH) ; Autophagy: genetics (MeSH) ; HEK293 Cells (MeSH) ; HeLa Cells (MeSH) ; Humans (MeSH) ; Mitochondria: pathology (MeSH) ; Mitochondria: physiology (MeSH) ; Mutation (MeSH) ; Parkinson Disease: genetics (MeSH) ; Parkinson Disease: pathology (MeSH) ; Parkinson Disease: physiopathology (MeSH) ; Protein Kinases: genetics (MeSH) ; Protein Kinases: metabolism (MeSH) ; RNA, Small Interfering: genetics (MeSH) ; RNA, Small Interfering: metabolism (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Ubiquitin-Protein Ligases: metabolism (MeSH) ; RNA, Small Interfering ; Ubiquitin-Protein Ligases ; parkin protein ; Protein Kinases ; PTEN-induced putative kinase

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Contributing Institute(s):

1. Functional Neurogenetics (AG Kahle 2)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2010

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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