Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila
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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2015-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/8/6/577 |
| _version_ | 1819083376615751680 |
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| author | Aditya Sen Sreehari Kalvakuri Rolf Bodmer Rachel T. Cox |
| author_facet | Aditya Sen Sreehari Kalvakuri Rolf Bodmer Rachel T. Cox |
| author_sort | Aditya Sen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T20:31:35Z |
| format | Article |
| id | doaj.art-71fc619bdfcf494ea83d64caf75f5b98 |
| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-21T20:31:35Z |
| publishDate | 2015-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-71fc619bdfcf494ea83d64caf75f5b982022-12-21T18:51:12ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032015-06-018657758910.1242/dmm.019208019208Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in DrosophilaAditya Sen0Sreehari Kalvakuri1Rolf Bodmer2Rachel T. Cox3 Department of Biochemistry and Molecular Biology, 4301 Jones Bridge Road, Uniformed Services University, Bethesda, MD 20814, USA Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA Department of Biochemistry and Molecular Biology, 4301 Jones Bridge Road, Uniformed Services University, Bethesda, MD 20814, USA 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.http://dmm.biologists.org/content/8/6/577CluelessMitochondriaTOM20PINK1Parkin |
| spellingShingle | Aditya Sen Sreehari Kalvakuri Rolf Bodmer Rachel T. Cox Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila Disease Models & Mechanisms Clueless Mitochondria TOM20 PINK1 Parkin |
| title | Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila |
| title_full | Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila |
| title_fullStr | Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila |
| title_full_unstemmed | Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila |
| title_short | Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila |
| title_sort | clueless a protein required for mitochondrial function interacts with the pink1 parkin complex in drosophila |
| topic | Clueless Mitochondria TOM20 PINK1 Parkin |
| url | http://dmm.biologists.org/content/8/6/577 |
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