Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy.

By Matthew E Gegg, J. Cooper, K. Chau, M. Rojo, A. Schapira, J. Taanman. Human Molecular Genetics, 2010

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Mitochondrial dysfunction and perturbed degradation of proteins have been implicated in Parkinson's disease (PD) pathogenesis. Mutations in the Parkin and PINK1 genes are a cause of familial PD. PINK1 is a putative kinase associated with mitochondria, and loss of PINK1 expression leads to mitochondrial dysfunction, which increases with time. Parkin is suggested to be downstream of PINK1 and also mediates the removal of damaged mitochondria by macroautophagy (mitophagy). We investigated whether mitochondrial dysfunction in dopaminergic SH-SY5Y cells following decreased PINK1 expression by RNAi may in part be due to the inhibition of mitophagy. Reduced flux through the macroautophagy pathway was found to be coincident with the inhibition of ATP synthesis following 12 days of PINK1 silencing. Overexpression of parkin in these cells restored both autophagic flux and ATP synthesis. Overexpression and RNAi studies also indicated that PINK1 and parkin were required for mitophagy following CCCP-induced mitochondrial damage. The ubiquitination of several mitochondrial proteins, including mitofusin 1 and mitofusin 2, were detected within 3 h of CCCP treatment. These post-translational modifications were reduced following the silencing of parkin or PINK1. The ubiquitination of mitochondrial proteins appears to identify mitochondria for degradation and facilitate mitophagy. PINK1 and parkin are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to PD pathogenesis.

Subfields: Epidemiology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/a98ec9dac1d0f4c99d4d31cdfa85e48ccd901681

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Citations in the corpus

Mitochondrial Cristae: Where Beauty Meets Functionality. (2016, background): “For example, Mitofusin 2 is ubiquitinated by the E3 Ub-ligase Parkin [77,78] and phosphorylated by c-Jun N terminal kinase (JNK) [79].”
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).”
Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy (2011, background): “In mammals, Mfn1 and Mfn2 are polyubiquitinated (31) and degraded (32) in response to Parkin activation.”
Etiology and pathogenesis of Parkinson's disease (2011, background): “Work in PINK1-knockout mouse embryonic fibroblasts and dopaminergic cell lines indicates that parkin and PINK1 involvement in mitophagy includes the ubiquitination of mfn 1 and 2 by parkin.(58) These interactions between parkin and PINK1 explain the data that parkin can rescue biochemical phenotypes”
Ubiquitination and selective autophagy (2012, background): “In addition to K63-linked ubiquitination, other Parkin substrates relevant for mitophagy, such as mitofusin, can be ubiquitinated.(83) Mitofusins are small”
Mitochondria: In Sickness and in Health (2012, background): “We provide a current view of how mitochondrial functions impinge on health and disease.”
The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “Mfn1 and Mfn2 are ubiquitinated and degraded by the proteasome in a Parkin-dependent manner (Gegg et al., 2010; Poole et al., 2010; Rakovic et al., 2011; Tanaka et al., 2010; Ziviani et al., 2010).”
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, neutral): “…of parkin-induced mitophagy, it has been observed that parkin mediates ubiquitination and proteasomal degradation of Mfn1 and Mfn2 in response to mitochondrial uncoupling (Poole et al , 2008; Gegg et al , 2010; Tanaka et al , 2010; Ziviani et al , 2010; Chan et al , 2011; Glauser et al , 2011).”
PINK1- and Parkin-mediated mitophagy at a glance (2012, background): “So far, two mitochondrial substrates of endogenous Parkin have been identified, the closely related mitochondrial fusion proteins mitofusin (MFN) 1 and 2 (Gegg et al., 2010; Poole et al., 2010; Rakovic et al., 2011; Tanaka et al., 2010; Ziviani et al., 2010).”
Mitochondrial dynamics and mitochondrial quality control (2014, background): “In addition to regulating mitochondria fusion and fission, Parkin-induced ubiquitination of Miro induces mitochondrial arrest, which can segregate damaged mitochondria from healthy mitochondria prior to mitophagy [60].”