Abstract
Dysfunctional mitochondria have been implicated in aging and age-related disorders such as Parkinson’s diseases (PD). We previously showed that pink1 and parkin, two familial PD genes, function in a linear pathway to maintain mitochondrial integrity and function. Studies of mammalian cell lines also suggest that these genes regulate mitochondrial autophagy(mitophagy). Overexpressing Parkin promotes proteostasis and function of aged muscles both in fruit flies and mice, and recent studies also indicated that mitochondrial ubiquitination are accumulated in aged muscles. However, the underlying mechanisms for pink1 and parkin mediated mitophagy on longevity is not fully understood. Here, we found that mitochondrial ubiquitination increased in indirect flight muscles (IFMs) in an age-dependent manner. Overexpression of pink1 or parkin in IFMs can abolish mitochondrial ubiquitination, restore ATP level and extend lifespan, while blocking autophagy via ATG1 knock-down suppress these effects in aged IFMs. Taken together, these results show that pink1/parkin promotes mitophagy of mitochondrial ubiquitination in aged muscles and extend lifespan in an Atg1-dependent manner. Our study provides physiological evidence that mitophagy of mitochondrial ubiquitination mediated by PINK1/ Parkin is crucial for muscle function and highlights the role of mitophagy in the pathogenesis of chronic diseases like PD.
Highlights
Mitochondrial dysfunction and accumulation of mitochondrial DNA mutations are hallmarks of chronic diseases, including neurodegenerative diseases [1, 2]
To test whether a subset of these FK2-positive foci was mitochondria, a mitochondria matrix targeted GFP was expressed in muscles under the control of the UASGAL4 system by IFMGal4, which is exclusively expressed in indirect flight muscles in late pupae and adult stage [21]
Atg1 knock-down substantially block the rescuing effect of Parkin overexpression in aged IFMs in terms of mitochondrial ubiquitylation, ATP level, climbing ability and lifespan (Figs 3 and 4B). These results indicate that Atg1 and autophagy are downstream of pink1 and parkin to maintain the mitochondrial proteostasis in Drosophila IFMs
Summary
Mitochondrial dysfunction and accumulation of mitochondrial DNA mutations are hallmarks of chronic diseases, including neurodegenerative diseases [1, 2]. Mitochondria are plastic and extremely dynamic organelles. Fission-fusion and transportation, mitochondrial autophagy(mitophagy) is proposed to play an important role in mitochondrial quality control[3, 4]. Pink (PTEN induced putative kinase 1) and parkin are two familial genes associated with Parkinson’s diseases (PD). We and others have shown that pink and parkin. Pink or parkin promotes mitochondrial proteostasis and extends lifespan in Drosophila
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