title: Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan.
abstract: Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.
authors: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA.
authors: Anil
authors: A
authors: Rana
authors: Michael
authors: M
authors: Rera
authors: David W
authors: DW
authors: Walker
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D025821:Polyubiquitin; D044767:Ubiquitin-Protein Ligases; C487430:park protein, Drosophila
keywords: energy metabolism; healthspan; mitophagy; neuronal aging; proteostasis
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