The Might of MicroRNA in Mitochondria

HomeCirculation ResearchVol. 110, No. 12The Might of MicroRNA in Mitochondria Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Might of MicroRNA in Mitochondria Michael V.G. Latronico and Gianluigi Condorelli Michael V.G. LatronicoMichael V.G. Latronico From the IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy (M.V.G.L., G.C.); and the Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Milan, Italy (G.C.). Search for more papers by this author and Gianluigi CondorelliGianluigi Condorelli From the IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy (M.V.G.L., G.C.); and the Institute of Genetics and Biomedical Research, National Research Council of Italy (CNR), Milan, Italy (G.C.). Search for more papers by this author Originally published8 Jun 2012https://doi.org/10.1161/CIRCRESAHA.112.271312Circulation Research. 2012;110:1540–1542The mitochondrion is endowed with all the elements necessary for protein synthesis: it harbors its own genome—in the guise of a circular ≈16.5-kb chromosome—and transcription and translation apparatus. However, mitochondrial DNA (mtDNA) has just 37 genes, which encode 22 mitochondrial tRNAs, 2 mitochondrial rRNAs, and only 13 protein subunits belonging to respiratory complexes I, III, IV, and V1; all the subunits of complex II and the >1000 other proteins needed within the mitochondrion for its proper functioning are transcribed from nuclear genes, synthesized in the cytosol, and then transported into the organelle, where many are then posttranslationally processed before being located into position. The limited size of mtDNA also means that most of the machinery needed to regulate mitochondrial gene expression derives from nuclear genes.2 To date, the mechanisms underlying the coordinated expression of mitochondrial-encoded and nuclear gene–encoded transcripts remain to be fully elucidated.Article, see p 1596The quintessential regulatory mechanisms of molecular biology are mediated by proteins, and a number of protein import mechanisms have been discovered for mitochondria.3 The contribution of regulatory noncoding (nc) RNAs to gene expression is a more recent discovery.4 Although mtDNA lacks introns and harbors only 2 (≈900 bp) regulatory regions for replication and transcription, several ncRNA candidates have been reported to be transcribed within mammalian mitochondria.5,6 Translocation into the mitochondrion of nuclear-derived RNAs—specifically of infrastructural tRNAs—was hypothesized to occur in the late 1960s, but this was not taken seriously for decades, and the mechanisms have remained more elusive.7 However, light is beginning to be shed on how ncRNAs are involved in the regulation of mitochondrial function, and with the discovery of microRNA (miRNA),8 studies may now be taking on a new impetus. In fact, apart from the presence in the cytosol of miRNA regulating mRNAs that encode proteins involved in mitochondria-related activities (Table), a small number of miRNAs were reported very recently to be present within the mitochondrial matrix itself. Kren and colleagues discovered in purified mitochondria from rat liver 15 nuclear-encoded miRNAs, constituting a unique mitochondrial miRNA profile or “miRNome.”9 Interrogation of MiRanda and TargetScan for potential targeted mRNAs revealed apoptosis/cell-death and cell-cycle/cell-division as among the most significant processes, but only one possible interaction with mtDNA-derived mRNA (ie, between miR-130a and cytochrome c oxidase III) and no interactions with nuclear-derived transcripts expressed in the mitochondrion. A subsequent study in mice by Bian and colleagues described a mitochondrial miRNome made up of 20 miRNAs that were specifically enriched in liver mitochondria with respect to whole liver tissue.10 Notably, the miRNome was altered on injection of mice with a diabetes-inducing dose of streptozotocin, indicating for the first time that mitochondria-associated miRNAs may be involved in mitochondrial dysfunction in disease.10Table. Some MicroRNAs With Targets Important to Mitochondrial FunctionmiRNATargetmiRNA LocationModelReferencemiR-338COXIVCytosolSympathetic neurons, rat16miR-23a/bGlutaminaseCytosolLymphoma cells, human17miR-210COXX; iron-sulfur cluster homologCytosolColon epithelial cells, human18miR-15aUncoupling protein-2CytosolPancreatic β cells, mouse19miR-126Insulin receptor substrate-1CytosolBreast cancer cells, human20miR-696Peroxisome proliferator-activated receptor-γ coactivator 1-αCytosolSkeletal myocytes, mouse21miR-743aMalate dehydrogenaseCytosolBrain neurons, mouse22miR-17*Mitochondrial antioxidant enzymesCytosolCancer cells, human23miR-130aCOXIII†MitochondriaLiver, rat9miR-181cCOXIMitochondriaCardiomyocytes, rat13†Not validated.More recently, unique sets of mitochondrial miRNAs, or “mitomiRs,” were described for human skeletal muscle and HeLa cells.11,12 Systematic BLAST interrogation revealed only 2 mitomiRs (ie, miR-328 and miR-494) to be highly conserved across metazoans, with most not being conserved beyond primates or humans.12 The mitomiRs were found to have thermodynamic features and size distinct from canonical miRNAs and to be expressed almost entirely from nuclear genes in loci relevant to mitochondrial function. MitomiRs appeared to lack preferential targeting of nuclear-encoded mitochondrial genes when compared with a set of cytosolic-enriched miRNAs, but most were predicted by RNA22, RegRNA, miRWalk, or TargetScan algorithms to target multiple mtDNA sites, including many within all the mtDNA-encoded protein genes except ND4L.12 Interestingly, human mtDNA also seems to harbor mitomiR sequences (namely, miR-1974, miR-1977, and miR-1978), but it remains to be ascertained whether miRNAs are actually transcribed from these mitochondrial genes.12In this issue of Circulation Research, Das and colleagues13 add a new piece to the puzzle of miRNA-mediated regulation of mitochondria, reporting that the rat mitomiR miR-181c is involved in electron chain complex IV remodeling in cardiomyocytes (Figure). Similarly to the other reports on mitomiRs, rat cardiomyocyte mitochondria were found to harbor a unique miRNA expression pattern, with miR-181c enriched 2-fold in the mitochondrial fraction with respect to whole heart because of translocation of the miRNA into the organelles. Immunoprecipitation assay of Argonaute 2—the catalytic component found in the ribonucleic protein complex of which miRNAs are part—revealed that miR-181c and cytochrome c oxidase subunit 1 (COX1) mRNA coimmunoprecipated in material from the mitochondrial pellet. COX1 mRNA was confirmed as a target for miR-181c with a luciferase assay. Overexpression of miR-181c in primary neonatal cardiomyocyte cultures caused a decrease in COX1 protein content but not in the amount of its mRNA, a finding suggestive of reduced translation rather than mRNA degradation; in addition, there was an increased rate of O2 consumption by complex IV, caused probably by increased generation of reactive oxygen species. Intriguingly, the mRNAs of COX2 and COX3—two other complex IV subunits that are transcribed in a polycistronic unit from mtDNA along with COX1—were found upregulated. The authors hypothesize that this remodeling of complex IV might be due to a miR-181c-activated feedback loop that increases transcription of mtDNA, but because miR-181c binds only to COX1 mRNA, inhibiting its translation, COX1 protein levels decrease while the other subunits become more abundant.Download figureDownload PowerPointFigure. Possible functions of mitochondrial miRNAs. Diagram illustrating the role of miR-181c in mitochondrial function (left-most portion), as reported by Das and colleagues.13 Thirteen mitochondrial protein-encoding genes, including those for CoxI, II, and III, are transcribed from the heavy and light stands of the circular mtDNA, and their mRNAs translated (1). Argonaute and nuclear-encoded miRNAs are imported from the cytosol into the mitochondrion by as yet unknown mechanism(s) (2). The miR-181c ribonucleic protein complex binds to the cognate site on the 3′ untranslated region of the mRNA of CoxI, inhibiting its translation (3). An unknown mechanism stimulates mtDNA transcription (4), leading to complex IV remodeling and ETC dysfunction. Some possible functions of mitochondrial miRNAs are also given (right-most portion). Many miRNAs present in the cytosol are already known to regulate nuclear-encoded mitochondrial genes (see Table), and miRNAs present in the mitochondrial matrix (such as miR-181c) regulate mtDNA-encoded genes. Mitochondrial miRNAs may also be important in eliminating translation of unwanted mRNAs. The release into the cytosol of mitochondrial miRNAs may play a role in apoptosis. mtDNA may harbor functional miRNA genes (5). Ago indicates argonaute; CoxI, CoxII, and CoxIII, mitochondrial genes encoding cytochrome c oxidase subunits 1 to 3; ETC, electron transport chain; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; I, II, III, IV, and V, ETC complexes I to V.This is the first report validating a mitomiR target. However, because of the high species specificity of the mitochondrial miRNome, the role of miR-181c for humans must be ascertained. On this point, a paralog, miR-181a, was reported among the most highly expressed mitomRs reported in human myotubes,11 and this might reflect on differences in the mitochondrial miRNome between cardiac- and skeletal-muscle cells. Nonetheless, the effect of miR-181c on complex IV remodeling is interesting, and work must be done on elucidating the miR-181c-mediated mechanism of mtDNA transcription stimulation.The location of miRNAs within the mitochondrion establishes a formidable intraorganellar mechanism for the fine-tuning of function to the metabolic demands of an organ: this is especially important for the heart, where not only must mitochondria adequately support incessant beat-to-beat energetic requirements, but they must also be able to respond quickly to any change in cardiac work load in the space of a few contractions. However, the occurrence of mitomiRs encoded by nuclear genes raises the question of what mechanism got them there in the first place. To date, a hexanucleotide sequence has been reported to effect translocation of miRNAs from the cytosol to the nucleus,14 but whether a similar sequence exists for nuclear-encoded mitomiRs needs clarification.Das and colleagues13 also indicate that dysregulation of mitomiR expression might be linked to cardiac disease. Unfortunately, they do not go further than overexpressing miR-181c in vitro: it would be instructive to know in the future whether the expression of this and other mitomiRs are altered for example in cell cultures subjected to hypoxic conditions or in animal models of cardiovascular disease and whether mitomiRs are directly responsible for mitochondrial dysfunction.Ultimately, the significance of the report by Das and colleagues13 lies in the fact that it turns attention to a novel mechanism operative in the cardiomyocyte for mitochondrial regulation, that is, one mediated by microRNA. Considering the fundamental importance of mitochondria for cardiac function, and the role this organelle has in cardiovascular diseases, studies on mitomiRs will undoubtedly have great impact on our understanding of the heart. We hope that future discoveries in mitomiR function and advances in mitochondrial gene therapy techniques15 may one day bring to improved treatments for a range of cardiac disorders.Sources of FundingThis work was supported by Fondation LeDucq and Fondazione Cariplo (C.G.).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Gianluigi Condorelli, MD, PhD, IRCCS Istituto Clinico Humanitas, Via Manzoni 56, Rozzano (MI), Italy 20089, or Department of Medicine, University of California San Diego, La Jolla, CA 92093-0613C. E-mail [email protected]eduReferences1. 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