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PMID:20798600

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Citation

Geisler, S, Holmström, KM, Treis, A, Skujat, D, Weber, SS, Fiesel, FC, Kahle, PJ and Springer, W (2010) The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6:871-8

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.

Links

PubMed

Keywords

Animals; Autophagy/genetics; HEK293 Cells; HeLa Cells; Humans; Mitochondria/pathology; Mitochondria/physiology; Mutation; Parkinson Disease/genetics; Parkinson Disease/pathology; Parkinson Disease/physiopathology; Protein Kinases/genetics; Protein Kinases/metabolism; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PRKN

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BXM7

F

Seeded From UniProt

complete

HUMAN:PINK1

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PINK1

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRKN2

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BXM7

F

Seeded From UniProt

complete

HUMAN:PINK1

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60260

F

Seeded From UniProt

complete

HUMAN:PINK1

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PINK1

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PINK1

involved_in

GO:0000422: autophagy of mitochondrion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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