Sazan Ismael and Yuan Zhang
March 28, 2017
MCB 7410
Abstract
Age-related changes in proteostasis and mitochondrial dynamics
Protein homeostasis is the protein quality control system that protects proteins function
and retard mutant, misfolded, and damaged protein aggregation. Chaperones and cochaperons are the main component of this system, which determines the folding condition
in the cell, and redirect misfolded proteins for proper folding or removal by ubiquitinproteasome system [1]. Protein aggregation and mitochondria dysfunction have been
associated with aging and neurodegenerative disease such as Parkinson’s disease (PD). A
reduced activity of the 26S proteasome during aging has been linked to protein
aggregation. [2] In healthy mitochondria, Pink 1 (PTEN-induced protein kinase 1)
proteins are transported from mitochondria to the cytoplasm and subsequently degraded
by the 26S proteasome. [3] When mitochondria are damaged, their low membrane
potentials cause Pink 1 to anchor to the outer mitochondrial membrane (OMM), which
then recruits Parkin, an E3 ligase, to its surface. Parkin ubiquitylates a number of OMM
proteins, which signals the degradation of damaged mitochondria by mitophagy.[4] In
this paper, Rana and colleagues discovered that constitutive, adult-onset, and neuronspecific overexpression of Parkin extended the lifespan of Drosoplila without a
significant tradeoff on their food consumption. They examined the protein aggregation
level of young and old flies in treatment groups inducing and not inducing Parkin
overexpression (OE). By comparing their K48 ubiquitylation levels, which is known for
targeting proteins for degradation by the 26S proteasome, more protein aggregates were
detected in aging than young flies in both Parkin OE and wild-type. Also, a significant
less K48 ubiquitylation was observed in flies overexpressing Parkin than the control
group during aging, while no difference was observed in young flies. In addition, the
protein level for one of the Parkin targets, Mfn (Mitochontria fusion promoting factor)
was significantly reduced in Parkin OE flies than the control group during aging, while
both young and long-lived Parkin OE flies showed much higher mitochondria
fragmentation. Further, higher protein activities for a number of mitochondrial markers
were detected in both young and long-lived Parkin OE flies. Taken together, their
findings offered novel insight aimed at better understanding the underlying mechanisms
driving Parkin-mediated aging, proteotoxicity, and mitochondrial homeostasis.
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