Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation

A Kathrin Lutz, Nicole Exner, Mareike E Fett, Julia S Schlehe, Karina Kloos, Kerstin Lämmermann, Bettina Brunner, Annerose Kurz-Drexler, Frank Vogel, Andreas S Reichert, Lena Bouman, Daniela Vogt-Weisenhorn, Wolfgang Wurst, Jörg Tatzelt, Christian Haass, Konstanze F Winklhofer
Journal of Biological Chemistry 2009 August 21, 284 (34): 22938-51
Loss-of-function mutations in the parkin gene (PARK2) and PINK1 gene (PARK6) are associated with autosomal recessive parkinsonism. PINK1 deficiency was recently linked to mitochondrial pathology in human cells and Drosophila melanogaster, which can be rescued by parkin, suggesting that both genes play a role in maintaining mitochondrial integrity. Here we demonstrate that an acute down-regulation of parkin in human SH-SY5Y cells severely affects mitochondrial morphology and function, a phenotype comparable with that induced by PINK1 deficiency. Alterations in both mitochondrial morphology and ATP production caused by either parkin or PINK1 loss of function could be rescued by the mitochondrial fusion proteins Mfn2 and OPA1 or by a dominant negative mutant of the fission protein Drp1. Both parkin and PINK1 were able to suppress mitochondrial fragmentation induced by Drp1. Moreover, in Drp1-deficient cells the parkin/PINK1 knockdown phenotype did not occur, indicating that mitochondrial alterations observed in parkin- or PINK1-deficient cells are associated with an increase in mitochondrial fission. Notably, mitochondrial fragmentation is an early phenomenon upon PINK1/parkin silencing that also occurs in primary mouse neurons and Drosophila S2 cells. We propose that the discrepant findings in adult flies can be explained by the time of phenotype analysis and suggest that in mammals different strategies may have evolved to cope with dysfunctional mitochondria.

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