USP 14 inhibition corrects an in vivo model of impaired mitophagy

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.

USP14 as a Therapeutic Target Against Neurodegeneration: A Rat Brain Perspective

“…Though USP14 is more pronounced for its therapeutic potential in cancer (Shinji et al, 2006;Liao et al, 2018;Han et al, 2019), its role in neurodegenerative disorders is also known (Boselli et al, 2017;Min et al, 2017;Chakraborty et al, 2018). It is well accepted that the influence of USP14 on proteasome complex activity is inversely correlated (Lee et al, 2010;Kim and Goldberg, 2017).…”

“…Among the DUBs, USP14 is unique as it can influence autophagy (Xu et al, 2016) and UPS activity (Lee et al, 2010;Kim and Goldberg, 2017) independently, both are the prerequisites for mitophagy. Recently, it was demonstrated that USP14 inhibition enhances mitophagy and protects against the disease progression in Drosophila model (Chakraborty et al, 2018). So the current understanding depicts that higher levels of USP14 may influence UPS activity, autophagy, and in turn mitophagy levels.…”

“…Inhibitors of USP14 are available. A popularly used inhibitor -IU1 increases UPS activity, enhances Tau degradation in primary cultured neurons and increases mitochondrial elimination in neuronal cell lines (Lee et al, 2010;Boselli et al, 2017;Chakraborty et al, 2018). For evaluating the potential of USP14 inhibitor in rodent models of PD, here we discuss some of the key factors that might influence the outcome of the experiments.…”

“…Secondly, if evaluation of USP14 as a therapeutic agent is connected with mitophagy, it should be kept in mind that mitophagy, in general, may depend to a certain extent on PHB2 (Wei et al, 2017) and USP14 mediated mitophagy is PHB2 dependent (Chakraborty et al, 2018). However, PHB2 levels should not be considered directly as an indicator of neuron's ability to thrust for mitophagy.…”

Interaction Between Mitochondrial DNA Variants and Mitochondria/Endoplasmic Reticulum Contact Sites: A Perspective Review

“…All cell lines were cultured in DMEM solution that contained 4.5 g/L d-glucose, 10% FBS, 2 mm l-glutamine, 100 U/mL penicillin, 100 mg/mL streptomycin, 1 mM sodium-pyruvate, and a 1% solution of nonessential amino acid. TEM samples and image acquisition was performed as reported in Chakraborty et al (2018). The width of contact sites is highlighted with white arrowhead.…”