miR-27a and miR-27b Regulate Autophagic Clearance of Damaged Mitochondria by Targeting PTEN-induced Putative Kinase 1 (PINK1)

Authors

Jaekwang Kim, Mayo Clinic
Fabienne C. Fiesel, Mayo Clinic
Krystal C. Belmonte, Mayo Clinic
Roman Hudec, Mayo Clinic
Wang-Xia Wang, University of KentuckyFollow
Chaeyoung Kim, Mayo Clinic
Peter T. Nelson, University of KentuckyFollow
Wolfdieter Springer, Mayo Clinic
Jungsu Kim, Mayo Clinic

Abstract

Background: Loss-of-function mutations in PINK1 and PARKIN are the most common causes of autosomal recessive Parkinson’s disease (PD). PINK1 is a mitochondrial serine/threonine kinase that plays a critical role in mitophagy, a selective autophagic clearance of damaged mitochondria. Accumulating evidence suggests mitochondrial dysfunction is one of central mechanisms underlying PD pathogenesis. Therefore, identifying regulatory mechanisms of PINK1 expression may provide novel therapeutic opportunities for PD. Although post-translational stabilization of PINK1 upon mitochondrial damage has been extensively studied, little is known about the regulation mechanism of PINK1 at the transcriptional or translational levels.

Results: Here, we demonstrated that microRNA-27a (miR-27a) and miR-27b suppress PINK1 expression at the translational level through directly binding to the 3′-untranslated region (3′UTR) of its mRNA. Importantly, our data demonstrated that translation of PINK1 is critical for its accumulation upon mitochondrial damage. The accumulation of PINK1 upon mitochondrial damage was strongly regulated by expression levels of miR-27a and miR-27b. miR-27a and miR-27b prevent mitophagic influx by suppressing PINK1 expression, as evidenced by the decrease of ubiquitin phosphorylation, Parkin translocation, and LC3-II accumulation in damaged mitochondria. Consequently, miR-27a and miR-27b inhibit lysosomal degradation of the damaged mitochondria, as shown by the decrease of the delivery of damaged mitochondria to lysosome and the degradation of cytochrome c oxidase 2 (COX2), a mitochondrial marker. Furthermore, our data demonstrated that the expression of miR-27a and miR-27b is significantly induced under chronic mitophagic flux, suggesting a negative feedback regulation between PINK1-mediated mitophagy and miR-27a and miR-27b.

Conclusions: We demonstrated that miR-27a and miR-27b regulate PINK1 expression and autophagic clearance of damaged mitochondria. Our data further support a novel negative regulatory mechanism of PINK1-mediated mitophagy by miR-27a and miR-27b. Therefore, our results considerably advance our understanding of PINK1 expression and mitophagy regulation and suggest that miR-27a and miR-27b may represent potential therapeutic targets for PD.

Document Type

Article

Publication Date

7-26-2016

Notes/Citation Information

Published in Molecular Neurodegeneration, v. 11, 55, p. 1-15.

© 2016 The Author(s).

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Digital Object Identifier (DOI)

https://doi.org/10.1186/s13024-016-0121-4

Funding Information

This work was supported, in part, by Mayo Clinic Foundation (W.S), Marriott Family Foundation (W.S), Gerstner Family Career Development Award (W.S), GHR Foundation (J.K.), Mayo Clinic Center for Individualized Medicine (J.K. and W.S), Center for Regenerative Medicine (W.S.), the Center for Biomedical Discovery (W.S.), Neuroscience Focused Research Team Award (W.S.), the Michael J. Fox Foundation for Parkinson's Research (W.S.), the Foundation for Mitochondrial Medicine (W.S.), NIH grants AG016574 (J.K.), AG005681 (J.K), AG028383 (P.T.N), NS085830 (P.T.N) and NS085070 (W.S).

Repository Citation

Kim, Jaekwang; Fiesel, Fabienne C.; Belmonte, Krystal C.; Hudec, Roman; Wang, Wang-Xia; Kim, Chaeyoung; Nelson, Peter T.; Springer, Wolfdieter; and Kim, Jungsu, "miR-27a and miR-27b Regulate Autophagic Clearance of Damaged Mitochondria by Targeting PTEN-induced Putative Kinase 1 (PINK1)" (2016). Pathology and Laboratory Medicine Faculty Publications. 13.
https://uknowledge.uky.edu/pathology_facpub/13