Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy

By N. Chan, Anna M Salazar, A. Pham, Michael J. Sweredoski, Natalie J. Kolawa, Robert L. J. Graham, S. Hess, D. C. Chan. Human Molecular Genetics, 2011

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Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4e28028f99e943b8b0d43d0339de431bd9a56eab

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Citations in the corpus

Mitochondria: In Sickness and in Health (2012, background): “On the mitochondrial surface Parkin ubiquitinates a specific subset of OMproteins, resulting in their proteasomal degradation by a mechanism that resembles ER-associated degradation pathway (Neutzner et al., 2007; Yoshii et al., 2011; Ziviani et al., 2010; Chan et al., 2011; Heo et al., 2010; Tanaka”
A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, background): “…a series of proteins on the mitochondrial surface, which are then recognized by autophagic adaptor proteins and delivered to the autophagosome (Narendra et al, 2008; Gegg et al, 2010; Lee et al, 2010; Matsuda et al, 2010; Tanaka et al, 2010; Chan et al, 2011; Chen & Dorn, 2013; Sarraf et al, 2013).”
Molecular mechanisms and physiological functions of mitophagy (2021, positive): “Other OMM proteins that undergo Parkin-mediated ubiquitylation have later been identified by mass spectrometry (Chan et al , 2011; Sarraf et al , 2013), suggesting that Parkin can ubiquitylate a large number of proteins on the surface of mitochondria.”
Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control (2014, methodology): “Kinetic studies of mitophagic clearance of entire mitochondria by PINK1 and parkin have demonstrated that this process occurs on the scale of several hours to days (Chan et al, 2011; Yoshii et al, 2011).”
Quantitative proteomics reveal a feed-forward model for mitochondrial PARKIN translocation and UB chain synthesis (2014, neutral): “…vivo) or fragments of PARKIN not activated by PINK1 (in vitro) that are prone to artifacts (Matsuda et al., 2006; Rankin et al., 2014; Riley et al., 2013; Chan et al., 2011; Geisler et al., 2010; Sims et al., 2012; van Wijk et al., 2012; Lazarou et al., 2013; Lim et al., 2013; Birsa et al., 2014).”
The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “In this process, parkin ubiquitinates multiple mitochondrial substrates, including proteins involved in mitochondrial fusion [303, 304], leading to their degradation by the UPS and mitophagy [305].”
Mitophagy: mechanisms, pathophysiological roles, and analysis (2012, background): “…membrane depolarization, proteasomes can be recruited to the mitochondria in a Parkin-dependent manner, which leads to the degradation of mitochondrial outer membrane and intermembrane space proteins but not the inner-membrane and matrix proteins (Chan et al. , 2011 ; Yoshii et al. , 2011 ).”
Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin (2012, background): “Although Parkin was not found to stably interact with the PINK1/TOM complex, PINK1 mediated recruitment of Parkin to mitochondria was found to induce degradation of TOM complex components (Chan et al., 2011; Yoshii et al., 2011).”
The pathways of mitophagy for quality control and clearance of mitochondria (2012, background): “Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin.”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “Monitoring loss of a single protein such as TOMM20 by western blot or fluorescence microscopy to follow mitophagy may thus be misleading, as noted above.(787) MitoTracker dyes are widely used to stain mitochondria and, when colocalized with GFP-LC3, they can function as a marker for mitophagy.”