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Poole, AC, Thomas, RE, Andrews, LA, McBride, HM, Whitworth, AJ and Pallanck, LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc. Natl. Acad. Sci. U.S.A. 105:1638-43
Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-of-function mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.
Animals; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Drosophila/genetics; Drosophila/metabolism; Drosophila/ultrastructure; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Eye/anatomy & histology; Eye/metabolism; GTP-Binding Proteins/genetics; GTP-Binding Proteins/metabolism; Gene Dosage; Humans; Membrane Fusion/genetics; Membrane Proteins/metabolism; Mitochondria/genetics; Mitochondria/ultrastructure; Mitochondrial Swelling; Mutation; Parkinson Disease/enzymology; Parkinson Disease/genetics; Parkinson Disease/pathology; Protein Kinases/genetics; Protein Kinases/metabolism; Ubiquitin-Protein Ligases
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