Parkin-induced mitophagy in the pathogenesis of Parkinson disease.
Knockout of the ubiquitin ligase Parkin, the gene product of the Parkinson associated Park2, leads to loss of mitochondrial integrity and function in Drosophila melanogaster. Although Parkin is primarily cytosolic, we have found that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential and subsequently promotes their autophagy. Here we report that Parkin recruitment is voltage-dependent and independent of changes in ATP or pH. These findings suggest that Parkin promotes mitophagy of dysfunctional mitochondria following loss of mitochondrial membrane potential and implicates the targeted elimination of mitochondria in the pathogenesis of Parkinson disease.
Narendra
Derek
D
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Tanaka
Atsushi
A
Suen
Der-Fen
DF
Youle
Richard J
RJ
D001343:Autophagy; D002460:Cell Line; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000473:pathology*; D008954:Models, Biological; D010300:Parkinson Disease / Q000473:pathology*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein