Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1

Abstract

J. Neurochem. (2011) 118, 636–645. Abstract Mutations in the parkin gene cause early‐onset, autosomal recessive Parkinson’s disease. Parkin functions as an E3 ubiquitin ligase to mediate the covalent attachment of ubiquitin monomers or linked chains to protein substrates. Substrate ubiquitination can target proteins for proteasomal degradation or can mediate a number of non‐degradative functions. Parkin has been shown to preserve mitochondrial integrity in a number of experimental systems through the regulation of mitochondrial fission. Upon mitochondrial damage, parkin translocates to mitochondria to mediate their selective elimination by autophagic degradation. The mechanism underlying this process remains unclear. Here, we demonstrate that parkin interacts with and selectively mediates the atypical poly‐ubiquitination of the mitochondrial fusion factor, mitofusin 1, leading to its enhanced turnover by proteasomal degradation. Our data supports a model whereby the translocation of parkin to damaged mitochondria induces the degradation of mitofusins leading to impaired mitochondrial fusion. This process may serve to selectively isolate damaged mitochondria for their removal by autophagy.

Select E2 enzymes differentially regulate parkin activation and mitophagy

“…In addition, a SCF complex has been shown to generate stabilizing ubiquitin modifications of MFN proteins that result in mitochondrial fusion (Anton et al, 2013). These activating modifications however are counterbalanced by destabilizing ubiquitylation events that are mediated through HUWE1 (Leboucher et al, 2012) or Parkin (Gegg et al, 2010;Poole et al, 2010;Glauser et al, 2011) upon stress. Therefore, a reduction of UBE2R1 levels might shift the balance towards degradation of MFN proteins resulting in mitochondrial fragmentation, which in turn could cause activation and translocation of Parkin (Narendra et al, 2008).…”

Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation

“…1D, lane 6). Mitofusin 1/2 (Mfn1/2) is a genuine substrate of Parkin and is ubiquitylated upon dissipation of ⌬⌿m (17,(43)(44)(45). WT HA-Parkin ubiquitylated Mfn2 following CCCP treatment (Fig.…”

Analysis of ER-mitochondria contacts by correlative fluorescence microscopy and soft X-ray tomography of mammalian cells

“…In accordance with these functions, mitochondrial defects and consequent changes in their morphology have been linked to several human diseases. Numerous mitochondrial diseases and other cell-destructive processes, such as aging and apoptosis, have been linked to a fragmented mitochondrial network, which has resulted from enhanced fission activity (Arduino et al, 2011;Glauser et al, 2011;Nakamura et al, 2011;Song et al, 2011;Elgass et al, 2013).…”