Abstract
Mitochondrial autophagy or mitophagy is a key process that allows selective sequestration and degradation of dysfunctional mitochondria to prevent excessive reactive oxygen species, and activation of cell death. Recent studies revealed that ubiquitin–proteasome complex activity and mitochondrial membrane rupture are key steps preceding mitophagy, in combination with the ubiquitination of specific outer mitochondrial membrane (OMM) proteins. The deubiquitinating enzyme ubiquitin‐specific peptidase 14 (USP14) has been shown to modulate both proteasome activity and autophagy. Here, we report that genetic and pharmacological inhibition of USP14 promotes mitophagy, which occurs in the absence of the well‐characterised mediators of mitophagy, PINK1 and Parkin. Critical to USP14‐induced mitophagy is the exposure of the LC3 receptor Prohibitin 2 by mitochondrial fragmentation and mitochondrial membrane rupture. Genetic or pharmacological inhibition of USP14 in vivo corrected mitochondrial dysfunction and locomotion behaviour of PINK1/Parkin mutant Drosophila model of Parkinson's disease, an age‐related progressive neurodegenerative disorder that is correlated with diminished mitochondrial quality control. Our study identifies a novel therapeutic target that ameliorates mitochondrial dysfunction and in vivo PD‐related symptoms.
Highlights
Mitochondria generate ATP through oxidative phosphorylation at the inner mitochondrial membrane
To ensure IU1 is effective in human and mouse cells and increases proteasome activity, we used a substrate that is dependent on ubiquitin and ubiquitin–proteasome system (UPS)
The efficient clearance of dysfunctional mitochondria is modelled to be dependent on three key steps: (i) mitochondrialshaping and outer membrane protein post-translational modifications (Gomes et al, 2011; Kageyama et al, 2014); (ii) UPSmediated mitochondrial membrane rupture (Tanaka et al, 2010; Yoshii et al, 2011); and (iii) engulfment of mitochondria by autophagic vesicles (Wei et al, 2017)
Summary
Mitochondria generate ATP through oxidative phosphorylation at the inner mitochondrial membrane. Key pivotal elements in the orchestration of mitophagy are proteasome localisation to depolarised mitochondria, the degradation of outer mitochondrial membrane (OMM)ubiquitinated proteins, and the disruption of the mitochondrial membrane (Tanaka et al, 2010; Chan et al, 2011; Yoshii et al, 2011). It was not clear, how mitochondrial membrane rupture can facilitate mitophagy until recently, when Wei et al (2017) demonstrated that OMM rupture leads to the exposure of Prohibitin 2, which functions as a receptor for LC3 to form mitophagic vesicles (Wei et al, 2017).
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