Abstract
ABSTRACTLoss 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.
Highlights
Mitochondrial function is intimately linked to cellular health
They show that Clu forms a complex with PTENinduced kinase 1 (PINK1), and interacts with Park, but only when the mitochondrial membrane potential is lost with the addition of the ionophore carbonyl cyanide mchlorophenyl hydrazone (CCCP)
In this study, using IPs we show that Clu can associate with three proteins located on the mitochondrial outer membrane, the outer membrane 20 (TOM20), Porin and PINK1
Summary
Mitochondrial function is intimately linked to cellular health These organelles provide the majority of ATP for the cell in addition to being the sites for major metabolic pathways such as fatty acid β-oxidation and heme biosynthesis. Mitochondria are crucial for apoptosis, and they can irreparably damage the cell via oxidation when their biochemistry is abnormally altered Given these many roles, tissues and cell types with high energy demands, such as neurons, are sensitive to changes in mitochondrial function (Chen and Chan, 2009). Tissues and cell types with high energy demands, such as neurons, are sensitive to changes in mitochondrial function (Chen and Chan, 2009) This is true for germ cell mitochondria because mitochondria are inherited.
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