title: miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1).
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA. kim.jaekwang@mayo.edu.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA.
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA.
authors.forename: Krystal C
authors.initials: KC
authors.lastname: Belmonte
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Hudec
authors.affiliation: Department of Pathology, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Wang-Xia
authors.initials: WX
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA.
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA.|Neurobiology of Disease Program, Mayo Graduate School, Jacksonville, FL, 32224, USA.
authors.forename: Wolfdieter
authors.initials: W
authors.lastname: Springer
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Rd S, Jacksonville, FL, 32224, USA. kim.jungsu@mayo.edu.|Neurobiology of Disease Program, Mayo Graduate School, Jacksonville, FL, 32224, USA. kim.jungsu@mayo.edu.
authors.forename: Jungsu
authors.identifier: 0000-0002-6931-8581
authors.initials: J
authors.lastname: Kim
mesh_terms: D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000099202:PTEN-Induced Putative Kinase
chemical_list: D035683:MicroRNAs; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C531388:MIRN27 microRNA, human
keywords: Mitophagy; PINK1; Parkinson’s disease; miR-27a; miR-27b