USP14 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 mitochon...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2018-09-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809014 |
| _version_ | 1827015098206519296 |
|---|---|
| author | Joy Chakraborty Sophia von Stockum Elena Marchesan Federico Caicci Vanni Ferrari Aleksandar Rakovic Christine Klein Angelo Antonini Luigi Bubacco Elena Ziviani |
| author_facet | Joy Chakraborty Sophia von Stockum Elena Marchesan Federico Caicci Vanni Ferrari Aleksandar Rakovic Christine Klein Angelo Antonini Luigi Bubacco Elena Ziviani |
| author_sort | Joy Chakraborty |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:58:27Z |
| format | Article |
| id | doaj.art-291aa43de92046d2919c57ef5223240c |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:35Z |
| publishDate | 2018-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-291aa43de92046d2919c57ef5223240c2024-10-28T08:56:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-09-01101111710.15252/emmm.201809014USP14 inhibition corrects an in vivo model of impaired mitophagyJoy Chakraborty0Sophia von Stockum1Elena Marchesan2Federico Caicci3Vanni Ferrari4Aleksandar Rakovic5Christine Klein6Angelo Antonini7Luigi Bubacco8Elena Ziviani9Department of Biology, University of PadovaFondazione Ospedale San Camillo IRCCSFondazione Ospedale San Camillo IRCCSDepartment of Biology, University of PadovaDepartment of Biology, University of PadovaInstitute of Neurogenetics, University of LübeckInstitute of Neurogenetics, University of LübeckDepartment of Neuroscience, University of PadovaDepartment of Biology, University of PadovaDepartment of Biology, University of PadovaAbstract 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.https://doi.org/10.15252/emmm.201809014mitochondrial membrane rupturemitophagyproteasomeUSP14 |
| spellingShingle | Joy Chakraborty Sophia von Stockum Elena Marchesan Federico Caicci Vanni Ferrari Aleksandar Rakovic Christine Klein Angelo Antonini Luigi Bubacco Elena Ziviani USP14 inhibition corrects an in vivo model of impaired mitophagy EMBO Molecular Medicine mitochondrial membrane rupture mitophagy proteasome USP14 |
| title | USP14 inhibition corrects an in vivo model of impaired mitophagy |
| title_full | USP14 inhibition corrects an in vivo model of impaired mitophagy |
| title_fullStr | USP14 inhibition corrects an in vivo model of impaired mitophagy |
| title_full_unstemmed | USP14 inhibition corrects an in vivo model of impaired mitophagy |
| title_short | USP14 inhibition corrects an in vivo model of impaired mitophagy |
| title_sort | usp14 inhibition corrects an in vivo model of impaired mitophagy |
| topic | mitochondrial membrane rupture mitophagy proteasome USP14 |
| url | https://doi.org/10.15252/emmm.201809014 |
| work_keys_str_mv | AT joychakraborty usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT sophiavonstockum usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT elenamarchesan usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT federicocaicci usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT vanniferrari usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT aleksandarrakovic usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT christineklein usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT angeloantonini usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT luigibubacco usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy AT elenaziviani usp14inhibitioncorrectsaninvivomodelofimpairedmitophagy |