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. Longlived 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 fusionpromoting 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.energy metabolism | healthspan | mitophagy | neuronal aging | proteostasis A dvanced age is a major risk factor for many neurodegenerative disorders, including both Alzheimer's disease and Parkinson disease (PD), and yet the molecular mechanisms that link aging and neurodegeneration are poorly understood. To understand this connection, it is necessary to identify the molecular events and pathways that integrate aging and neurodegenerative disease. Several lines of evidence suggest that a decline in the ability to prevent and eliminate protein misfolding (1) and impaired mitochondrial function (2) are important factors in the increased risk of disease and death associated with aging. More specifically, although the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized (3), recent work in the nematode Caenorhabditis elegans (4-6) and the fruit fly Drosophila melanogaster (7) has shown that aging per se is associated with increased aggregation of a large number of proteins. At the same time, a decline in mitochondrial gene expression and/or energetic capacity is a hallmark of aging across diverse species (2, 8), whereas a failure to eliminate dysfunctional mitochondria has been implicated in the pathophysiology of a number of neurodegenerative diseases, including PD (9).The ubiquitin-proteasome system (UPS) is a critical component of the cellular pro...

Proteostasis and longevity: when does aging really begin?

“…Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms [2][3][4][5][6][7]. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage.…”

“…Despite this, why organisms age remains a complex mystery that if understood could have profound implications for the quality of human health. While the physiological decline associated with old age is easily recognizable, the mechanisms that determine aging are poorly understood; however, widescale loss of protein homeostasis (proteostasis) is proposed to be one of the "primary hallmarks of aging" [1].Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms [2][3][4][5][6][7]. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage.…”

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis

“…It has been reported that PARK2 overexpression increases mitochondrial activity during aging in association with life-span extension, further supporting the notion that PARK2 has a pivotal role in mitochondrial quality control in terms of regulation of senescenceassociated disorders. 31 However, the precise mechanism for the decrease in PARK2 levels in COPD lung remains unclear. Furthermore, several lines of evidence demonstrate the participation of other receptors during autophagosomal recognition of mitochondria, including BNIP3L, BNIP3, and FUNDC1, hence the potential involvement of those receptors in mitophagy regulation of cigarette-induced cellular senescence need to be examined in future studies.…”

Increased levels of hyper-stable protein aggregates in plasma of older adults

“…An ominous consequence of proteostasis disruption is the accumulation of aggregated proteins, thereby accelerating cellular aging and increasing the risk of disease. Indeed, protein aggregation is associated with many age-related disorders, and increased protein oxidation and aggregation are observed in aged organisms (Knoefler et al 2012;Morimoto 2008;Rana et al 2013). An even greater challenge to proteostasis would occur if proteins were to aggregate into hyper-stable/degradation-resistant species, as these would be more likely to persist and further compromise the organism.…”