Abstract
BackgroundLoss-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.ResultsHere, 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0121-4) contains supplementary material, which is available to authorized users.
Highlights
Loss-of-function mutations in PTEN-induced putative kinase 1 (PINK1) and PARKIN are the most common causes of autosomal recessive Parkinson’s disease (PD)
We demonstrated that miR-27a and miR-27b inhibit PINK1 stabilization, thereby preventing autophagic degradation of impaired mitochondria
PINK1 expression is regulated by miRNAs PINK1 messenger RNAs (mRNAs) (NM_032409) has a long 3′untranslated region (UTR), ~840 nucleotides, raising the possibility that its expression may be regulated by miRNAs which often target 3′-untranslated region (3′UTR) sequences
Summary
Loss-of-function mutations in PINK1 and PARKIN are the most common causes of autosomal recessive Parkinson’s disease (PD). Accumulating evidence suggests mitochondrial dysfunction is one of central mechanisms underlying PD pathogenesis. Identifying regulatory mechanisms of PINK1 expression may provide novel therapeutic opportunities for PD. Mutations in several genes, such as SNCA (α-synuclein), Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PARK2 (PARKIN), and PTEN-induced putative kinase 1 (PINK1) [1], have been shown to cause familial early-onset PD, accounting for 5–10 % of all cases [2]. Mounting evidence suggests mitochondrial dysfunction as a central mechanism in PD pathogenesis [3]. A better understanding of how the integrity and function of mitochondria are maintained following insults may provide novel opportunities for PD treatment
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