miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase
The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphory...
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doaj-26e5a978ddf84efc93df828ddc9db0592020-11-25T01:38:34ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-01-0121135510.3390/ijms21010355ijms21010355miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin LigaseAnthea Di Rita0Teresa Maiorino1Krenare Bruqi2Floriana Volpicelli3Gian Carlo Bellenchi4Flavie Strappazzon5IRCCS Fondazione Santa Lucia, 00143 Rome, ItalyIRCCS Fondazione Santa Lucia, 00143 Rome, ItalyIRCCS Fondazione Santa Lucia, 00143 Rome, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80131 Naples, ItalyIRCCS Fondazione Santa Lucia, 00143 Rome, ItalyIRCCS Fondazione Santa Lucia, 00143 Rome, ItalyThe selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.https://www.mdpi.com/1422-0067/21/1/355micrornamitochondriamir-218parkin/prknmitophagy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anthea Di Rita Teresa Maiorino Krenare Bruqi Floriana Volpicelli Gian Carlo Bellenchi Flavie Strappazzon |
spellingShingle |
Anthea Di Rita Teresa Maiorino Krenare Bruqi Floriana Volpicelli Gian Carlo Bellenchi Flavie Strappazzon miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase International Journal of Molecular Sciences microrna mitochondria mir-218 parkin/prkn mitophagy |
author_facet |
Anthea Di Rita Teresa Maiorino Krenare Bruqi Floriana Volpicelli Gian Carlo Bellenchi Flavie Strappazzon |
author_sort |
Anthea Di Rita |
title |
miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase |
title_short |
miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase |
title_full |
miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase |
title_fullStr |
miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase |
title_full_unstemmed |
miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase |
title_sort |
mir-218 inhibits mitochondrial clearance by targeting prkn e3 ubiquitin ligase |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2020-01-01 |
description |
The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases. |
topic |
microrna mitochondria mir-218 parkin/prkn mitophagy |
url |
https://www.mdpi.com/1422-0067/21/1/355 |
work_keys_str_mv |
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1725052960224837632 |