The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila

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Abstract
Mutations in PTEN-induced kinase 1 ( pink1 ) or parkin cause autosomal-recessive and some sporadic forms of Parkinson's disease. pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial integrity in Drosophila . Mitochondrial morphology is maintained by a dynamic balance between the opposing actions of mitochondrial fusion, controlled by Mitofusin ( mfn ) and Optic atrophy 1 ( opa1 ), and mitochondrial fission, controlled by drp1 . Here, we explore interactions between pink1 / parkin and the mitochondrial fusion/fission machinery. Muscle-specific knockdown of the fly homologue of Mfn ( Marf ) or opa1 , or overexpression of drp1 , results in significant mitochondrial fragmentation. Mfn -knockdown flies also display altered cristae morphology. Interestingly, knockdown of Mfn or opa1 or overexpression of drp1 , rescues the phenotypes of muscle degeneration, cell death, and mitochondrial abnormalities in pink1 or parkin mutants. In the male germline, we also observe genetic interactions between pink1 and the testes-specific mfn homologue fuzzy onion , and between pink1 and drp1 . Our data suggest that the pink1 / parkin pathway promotes mitochondrial fission and/or inhibits fusion by negatively regulating mfn and opa1 function, and/or positively regulating drp1 . However, pink1 and parkin mutant flies show distinct mitochondrial phenotypes from drp1 mutant flies, and flies carrying a heterozygous mutation in drp1 enhance the pink1 -null phenotype, resulting in lethality. These results suggest that pink1 and parkin are likely not core components of the drp1 -mediated mitochondrial fission machinery. Modification of fusion and fission may represent a novel therapeutic strategy for Parkinson's disease.