title: Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila.
abstract: Loss of mitochondrial function often leads to neurodegeneration and is thought to be one of the underlying causes of neurodegenerative diseases such as Parkinson's disease (PD). However, the precise events linking mitochondrial dysfunction to neuronal death remain elusive. PTEN-induced putative kinase 1 (PINK1) and Parkin (Park), either of which, when mutated, are responsible for early-onset PD, mark individual mitochondria for destruction at the mitochondrial outer membrane. The specific molecular pathways that regulate signaling between the nucleus and mitochondria to sense mitochondrial dysfunction under normal physiological conditions are not well understood. Here, we show that Drosophila Clueless (Clu), a highly conserved protein required for normal mitochondrial function, can associate with Translocase of the outer membrane (TOM) 20, Porin and PINK1, and is thus located at the mitochondrial outer membrane. Previously, we found that clu genetically interacts with park in Drosophila female germ cells. Here, we show that clu also genetically interacts with PINK1, and our epistasis analysis places clu downstream of PINK1 and upstream of park. In addition, Clu forms a complex with PINK1 and Park, further supporting that Clu links mitochondrial function with the PINK1-Park pathway. Lack of Clu causes PINK1 and Park to interact with each other, and clu mutants have decreased mitochondrial protein levels, suggesting that Clu can act as a negative regulator of the PINK1-Park pathway. Taken together, these results suggest that Clu directly modulates mitochondrial function, and that Clu's function contributes to the PINK1-Park pathway of mitochondrial quality control.
authors.affiliation: Department of Biochemistry and Molecular Biology, 4301 Jones Bridge Road, Uniformed Services University, Bethesda, MD 20814, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Sen
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sreehari
authors.initials: S
authors.lastname: Kalvakuri
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.affiliation: Department of Biochemistry and Molecular Biology, 4301 Jones Bridge Road, Uniformed Services University, Bethesda, MD 20814, USA rachel.cox@usuhs.edu.
authors.forename: Rachel T
authors.initials: RT
authors.lastname: Cox
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C531978:ab protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila
keywords: Clueless; Mitochondria; PINK1; Parkin; TOM20