Depletion Of Dicer Research Articles

Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis

MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-β (PDGFR-β)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-β. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-β. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p.

Impaired microRNA processing in neutrophils from rheumatoid arthritis patients confers their pathogenic profile. Modulation by biological therapies.

The aim of this study was to investigate the microRNA (miRNA) expression pattern in neutrophils from rheumatoid arthritis (RA) patients and its contribution to their pathogenic profile and to analyze the effect of specific autoantibodies or inflammatory components in the regulation of miRNA in RA neutrophils and its modulation by biological therapies. Neutrophils were isolated from paired peripheral blood (PB) and synovial fluid samples of 40 patients with RA and from PB of 40 healthy donors. A miRNA array was performed using nCounter technology. Neutrophils from healthy donors were treated in vitrowith antibodies to citrullinated protein antigens isolated from RA patients and tumor necrosis factor-a (TNF-a) or interleukin-6. A number of cytokines and chemokines were analyzed. In vitro treatments of RA-neutrophils with tocilizumab or infliximab were carried out. Transfections with pre-miRNA and DICER downregulation experiments were further performed. RA-neutrophils showed a global downregulation of miRNA and genes involved in their biogenesis, alongside with an upregulation of various potential mRNA targets related to migration and inflammation. Decreased levels of miRNA and DICER correlated with autoimmunity, inflammation and disease activity. Citrullinated protein antigens and TNF-a decreased the expression of numerous miRNA and their biogenesis-related genes, increasing their potential mRNA targets. Infliximab reversed those effects. Transfections with pre-miRNA-223, -126 and -148a specifically modulated genes regulating inflammation, survival and migration whereas DICER depletion influenced the inflammatory profile of neutrophils. Taken together RA-neutrophils exhibited a global low abundance of miRNA induced by autoantibodies and inflammatory markers, which potentially contributed to their pathogenic activation. miRNA biogenesis was significantly impaired in RAneutrophils and further associated with a greater downregulation of miRNA mainly related to migration and inflammation in synovial fluid neutrophils. Finally, anti-TNF-a and anti-interleukin-6 receptor treatments can modulate miRNA levels in the neutrophils, minimizing their inflammatory profile.

Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3.

Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT- Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT- Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointerstitial fibrosis. Meanwhile, PT- Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT- Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2-3 mo old), significantly more Smad2/3 was induced in obstructed PT- Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.

Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage.

The endoribonuclease Dicer is a key component of the human RNA interference pathway and is known for its role in cytoplasmic microRNA production. Recent findings suggest that noncanonical Dicer generates small noncoding RNA to mediate the DNA damage response (DDR). Here, we show that human Dicer is phosphorylated in the platform-Piwi/Argonaute/Zwille-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks. We further demonstrate that turnover of damage-induced nuclear, double-stranded (ds) RNA requires additional phosphorylation of carboxy-terminal Dicer residues (S1728 and S1852). DNA damage-induced nuclear Dicer accumulation is conserved in mammals. Dicer depletion causes endogenous DNA damage and delays the DDR by impaired recruitment of repair factors MDC1 and 53BP1. Collectively, we place Dicer within the context of the DDR by demonstrating a DNA damage-inducible phosphoswitch that causes localized processing of nuclear dsRNA by p-Dicer to promote DNA repair.

MicroRNA-independent functions of DGCR8 are essential for neocortical development and TBR1 expression.

Recent evidence indicates that the miRNA biogenesis factors DROSHA, DGCR8, and DICER exert non-overlapping functions, and have also roles in miRNA-independent regulatory mechanisms. However, it is currently unknown whether miRNA-independent functions of DGCR8 play any role in the maintenance of neuronal progenitors and during corticogenesis. Here, by phenotypic comparison of cortices from conditional Dgcr8 and Dicer knockout mice, we show that Dgcr8 deletion, in contrast to Dicer depletion, leads to premature differentiation of neural progenitor cells and overproduction of TBR1-positive neurons. Remarkably, depletion of miRNAs upon DCGR8 loss is reduced compared to DICER loss, indicating that these phenotypic differences are mediated by miRNA-independent functions of DGCR8. We show that Dgcr8 mutations induce an earlier and stronger phenotype in the developing nervous system compared to Dicer mutants and that miRNA-independent functions of DGCR8 are critical for corticogenesis. Finally, our data also suggest that the Microprocessor complex, with DROSHA and DGCR8 as core components, directly regulates the Tbr1 transcript, containing evolutionarily conserved hairpins that resemble miRNA precursors, independently of miRNAs.

Argonaute proteins regulate HIV-1 multiply spliced RNA and viral production in a Dicer independent manner.

Argonaute (Ago) proteins associate with microRNAs (miRNAs) to form the core of the RNA-induced silencing complex (RISC) that mediates post-transcriptional gene silencing of target mRNAs. As key players in anti-viral defense, Ago proteins are thought to have the ability to interact with human immunodeficiency virus type 1 (HIV-1) RNA. However, the role of this interaction in regulating HIV-1 replication has been debated. Here, we used high throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) to explore the interaction between Ago2 and HIV-1 RNA in infected cells. By only considering reads of 50 nucleotides length in our analysis, we identified more than 30 distinct binding sites for Ago2 along the viral RNA genome. Using reporter assays, we found four binding sites, located near splice donor sites, capable of repressing Luciferase gene expression in an Ago-dependent manner. Furthermore, inhibition of Ago1 and Ago2 levels in cells expressing HIV-1 led to an increase of viral multiply spliced transcripts and to a strong reduction in the extracellular CAp24 level. Depletion of Dicer did not affect these activities. Our results highlight a new role of Ago proteins in the control of multiply spliced HIV-1 transcript levels and viral production, independently of the miRNA pathway.

Depletion of Dicer promotes epithelial ovarian cancer progression by elevating PDIA3 expression

Dicer is an essential component of the microRNA (miRNA) processing machinery whose low expression is associated with advanced stage and poor clinical outcome in epithelial ovarian cancer. To investigate the functional relevance of Dicer in epithelial ovarian cancer and to identify its downstream effectors, two-dimensional gel electrophoresis combined with mass spectrometry was used for proteomic profiling. Dicer depletion promoted ovarian cancer cell proliferation and migration accompanied by a global upregulation of proteins. Twenty-six proteins, 7 upregulated and 19 downregulated, were identified. The functions of the identified proteins and their interactions were bioinformatically analyzed. Among them, protein disulfide-isomerase A3 (PDIA3) was considered to be a potential target protein of Dicer. PDIA3 repression by siRNA could significantly relieve the proliferation- and migration-promoting effect mediated by Dicer depletion in vitro and in vivo. Moreover, the miRNAs targeting PDIA3 were decreased in cells with Dicer depletion. In summary, low Dicer expression contributes to epithelial ovarian cancer progression by elevating PDIA3 expression.

Ablation of Dicer leads to widespread perturbation of signaling pathways

Dicer is an essential ribonuclease involved in the biogenesis of miRNAs. Previous studies have reported downregulation of Dicer in multiple cancers including hepatocellular carcinoma. To identify signaling pathways that are altered upon Dicer depletion, we carried out quantitative phosphotyrosine profiling of liver tissue from Dicer knockout mice. We employed antibody-based enrichment of phosphotyrosine containing peptides coupled with SILAC spike-in approach for quantitation. High resolution mass spectrometry-based analysis identified 349 phosphotyrosine peptides corresponding to 306 unique phosphosites of which 75 were hyperphosphorylated and 78 were hypophosphorylated. Several receptor tyrosine kinases including MET, PDGF receptor alpha, Insulin-like growth factor 1 and Insulin receptor as well as non-receptor tyrosine kinases such as Src family kinases were found to be hyperphosphorylated upon depletion of Dicer. In addition, signaling molecules such as IRS-2 and STAT3 were hyperphosphorylated. Activation of these signaling pathways has been implicated previously in various types of cancers. Interestingly, we observed hypophosphorylation of molecules including focal adhesion kinase and paxillin. Our study profiles the perturbed signaling pathways in response to dysregulated miRNAs resulting from depletion of Dicer. Our findings warrant further studies to investigate oncogenic effects of downregulation of Dicer in cancers.

NF-κB-DICER-miRs Axis Regulates TNF-α Expression in Responses to Endotoxin Stress

Unbalanced tumor necrosis factor (TNF)-α production is associated with pathogenesis of a variety of human diseases. However, the molecular pathways maintaining TNF-α homeostasis remain elusive. Here, we report that NF-κB/p65-DICER-miRs axis negatively regulates TNF-α production. We demonstrated that NF-κB bound to DICER promoter and transcriptionally regulated DICER expression. In addition, the NF-κB/DICER signaling suppresses TNF-α expression by generating mature forms of miR-125b and miR-130a which negatively regulate TNF-α mRNA. Furthermore, we showed that the hepatocyte-specific depletion of Dicer in mice resulted in TNF-α overproduction and sensitized the mice to endotoxin, which could be corrected by administration of miR-125b mimics. These data suggest that NF-κB/p65-DICER-miRs axis involved in maintaining of TNF-α homeostasis, and injection of miR-125b as a potential therapeutic method for septic shock.

Ago2 facilitates Rad51 recruitment and DNA double-strand break repair by homologous recombination

DNA double-strand breaks (DSBs) are highly cytotoxic lesions and pose a major threat to genome stability if not properly repaired. We and others have previously shown that a class of DSB-induced small RNAs (diRNAs) is produced from sequences around DSB sites. DiRNAs are associated with Argonaute (Ago) proteins and play an important role in DSB repair, though the mechanism through which they act remains unclear. Here, we report that the role of diRNAs in DSB repair is restricted to repair by homologous recombination (HR) and that it specifically relies on the effector protein Ago2 in mammalian cells. Interestingly, we show that Ago2 forms a complex with Rad51 and that the interaction is enhanced in cells treated with ionizing radiation. We demonstrate that Rad51 accumulation at DSB sites and HR repair depend on catalytic activity and small RNA-binding capability of Ago2. In contrast, DSB resection as well as RPA and Mre11 loading is unaffected by Ago2 or Dicer depletion, suggesting that Ago2 very likely functions directly in mediating Rad51 accumulation at DSBs. Taken together, our findings suggest that guided by diRNAs, Ago2 can promote Rad51 recruitment and/or retention at DSBs to facilitate repair by HR.

Mutant p53 Regulates Dicer through p63-dependent and -independent Mechanisms to Promote an Invasive Phenotype

The control and processing of microRNAs (miRs) is critical in the regulation of all cellular responses. Previous studies have suggested that a reduction in the expression of certain miRs, or an overall decrease in miR processing through the partial depletion of Dicer, can promote enhanced metastatic potential. We show here that Dicer depletion can promote the invasive behavior of cells that is reflected in enhanced recycling and activation of the growth factor receptors Met and EGF receptor. These responses are also seen in response to the expression of tumor-derived mutant p53s, and we show that mutant p53 can down-regulate Dicer expression through both direct inhibition of the TAp63-mediated transcriptional activation of Dicer and a TAp63-independent control of Dicer protein expression. Our results delineate a clear relationship between mutant p53, TAp63, and Dicer that might contribute to the metastatic function of mutant p53 but, interestingly, also reveal TAp63-independent functions of mutant p53 in controlling Dicer activity.

Suppression of Induced microRNA-15b Prevents Rapid Loss of Cardiac Function in a Dicer Depleted Model of Cardiac Dysfunction

BackgroundDicer endonuclease, critical for maturation of miRNAs, is depleted in certain forms of cardiomyopathy which results in differential expression of certain microRNAs. We sought to elucidate the mechanisms underlying the rapid loss of cardiac function following cardiac-specific Dicer depletion in adult mice.ResultsConditional Dicer deletion in the adult murine myocardium demonstrated compromised heart function, mitochondrial dysfunction and oxidant stress. Elevated miR-15b was observed as an early response to Dicer depletion and was found to silence Pim-1 kinase, a protein responsible for maintaining mitochondrial integrity and function. Anti-miRNA based suppression of induced miRNA-15b rescued the function of Dicer-depleted adult heart and attenuated hypertrophy.ConclusionsAnti-miRNA based suppression of inducible miRNA-15b can prevent rapid loss of cardiac function in a Dicer-depleted adult heart and can be a key approach worthy of therapeutic consideration.

Requirements for human Dicer and TRBP in microRNA-122 regulation of HCV translation and RNA abundance

MicroRNA-122 (miR-122) promotes Hepatitis C Virus (HCV) RNA stability, accumulation, and translation through hybridization with the 5′ untranslated region (5′ UTR) of the HCV genome. Depletion of Dicer and TRBP, proteins involved in miRNA biogenesis, reduced HCV RNA accumulation, mature duplex miR-122 abundance, and miR-122 directed mRNA translation suppression, suggesting roles in miR-122 processing. HCV RNA accumulation independent of endogenous mature duplex miR-122 was not affected by Dicer knockdown, suggesting that Dicer is required solely for miR-122 biogenesis, but TRBP knockdown reduced HCV RNA accumulation in this system, suggesting an additional role in supporting HCV RNA accumulation. Mature duplex miR-122 and pre-miR-122 hairpin, but not single-stranded miR-122 (guide or ⁎ strand), augmented HCV RNA accumulation and translation, and Dicer and TRBP were essential for the activity of pre-miR-122 in mouse fibroblasts. Thus, canonical miRNA processing and strand selection is essential for the activity of miR-122 on HCV translation and RNA accumulation.

Dicer is required for proliferation, viability, migration and differentiation in corticoneurogenesis

In mice, microRNAs (miRNAs) are required for embryonic viability, and previous reports implicate miRNA participation in brain cortical neurogenesis. Here, we provide a more comprehensive analysis of miRNA involvement in cortical brain development. To accomplish this we used mice in which Dicer, the RNase III enzyme necessary for canonical miRNA biogenesis, is depleted from Nestin-expressing progenitors and progeny cells. We systematically assessed how Dicer depletion impacts proliferation, cell death, migration and differentiation in the developing brain. Using markers for proliferation and in vivo labeling with thymidine analogs, we found reduced numbers of proliferating cells, and altered cell cycle kinetics from embryonic day 15.5 (E15.5). Progenitor cells were distributed aberrantly throughout the cortex rather than restricted to the ventricular and subventricular zones. Activated Caspase3 was elevated, reflecting increased cortical cell death as early as E15.5. Cajal–Retzius-positive cells were more numerous at E15.5 and were dysmorphic relative to control cortices. Consistent with this, Reelin levels were enhanced. Doublecortin and Rnd2 were also increased and showed altered distribution, supporting a strong regulatory role for miRNAs in both early and late neuronal migration. In addition, GFAP staining at E15.5 was more intense and disorganized throughout the cortex with Dicer depletion. These results significantly extend earlier works, and emphasize the impact of miRNAs on neural progenitor cell proliferation, apoptosis, migration, and differentiation in the developing mammalian brain.

Re-dicing the pancreatic β-cell: do microRNAs define cellular identity?

Re-dicing the pancreatic β-cell: do microRNAs define cellular identity?

Depletion of key protein components of the RISC pathway impairs pre-ribosomal RNA processing

Little is known about whether components of the RNA-induced silencing complex (RISC) mediate the biogenesis of RNAs other than miRNA. Here, we show that depletion of key proteins of the RISC pathway by antisense oligonucleotides significantly impairs pre-rRNA processing in human cells. In cells depleted of Drosha or Dicer, different precursors to 5.8S rRNA strongly accumulated, without affecting normal endonucleolytic cleavages. Moderate yet distinct processing defects were also observed in Ago2-depleted cells. Physical links between pre-rRNA and these proteins were identified by co-immunoprecipitation analyses. Interestingly, simultaneous depletion of Dicer and Drosha led to a different processing defect, causing slower production of 28S rRNA and its precursor. Both Dicer and Ago2 were detected in the nuclear fraction, and reduction of Dicer altered the structure of the nucleolus, where pre-rRNA processing occurs. Together, these results suggest that Drosha and Dicer are implicated in rRNA biogenesis.

Glucocorticoids Modulate MicroRNA Expression and Processing during Lymphocyte Apoptosis

Glucocorticoids modulate immune development and function through the induction of lymphocyte apoptosis via mechanisms requiring alterations in gene expression. Recently, short, noncoding, microRNAs have been identified as key regulators of lymphocyte function; however, it is unknown whether glucocorticoids regulate noncoding microRNAs and whether this regulation contributes to lymphocyte apoptosis. We now show by both microarray and deep sequencing analysis that microRNAs are substantially repressed during glucocorticoid-induced apoptosis of primary rat thymocytes. Mechanistic studies revealed that primary microRNA transcripts were not repressed, whereas the expression of the key microRNA processing enzymes: Dicer, Drosha, and DGCR8/Pasha, were significantly reduced at both the mRNA and protein levels during glucocorticoid-induced apoptosis. To delineate the role of Dicer depletion and microRNA repression in apoptosis, we silenced Dicer expression in two human leukemic cell lines and demonstrated that Dicer depletion significantly enhanced glucocorticoid-induced apoptosis in both model systems. Finally, in vitro and in vivo overexpression of the conserved miR-17-92 polycistron, which was repressed significantly by dexamethasone treatment in both our microarray and deep sequencing studies, blunted glucocorticoid-induced apoptosis. These studies provide evidence of altered post-transcriptional microRNA expression and the repression of the microRNA bioprocessing pathway during glucocorticoid-induced apoptosis of lymphocytes, suggesting a role for microRNA processors and specific microRNAs in cell life/death decisions.

FMR1/FXR1 and the miRNA pathway are required for eye and neural crest development

FMR1 and FXR1 are RNA binding proteins interacting with the miRNA-induced silencing complex, RISC. Here we describe for the first time the function of these proteins during eye and neural crest (NC) development in Xenopus laevis. A loss of FMR1 or FXR1 results in abnormal eye development as well as defects in cranial cartilage derived from cranial NC cells. We further investigated the possible mechanism of these phenotypes by showing that a depletion of Dicer, an important enzyme for generating all mature miRNAs, in the anterior neural tissue also leads to eye and cranial cartilage defects. Furthermore, we examined the function of 12 miRNAs during anterior neural development. We show a specific requirement of six selected miRNAs during eye and cranial cartilage development. Mir-130a, -219, and -23b are involved in eye formation only whereas loss of miR-200b, miR-96 and miR-196a results in strong defects during eye as well as cranial cartilage development. Our results suggest an essential role for FMR1 and FXR1 for eye and NC development in X. laevis likely through an interaction with the miRNA pathway.

Dicer knockdown induces fibronectin-1 expression in HEK293T cells via induction of Egr1

Background Dicer is a multidomain ribonuclease III enzyme involved in the biogenesis of microRNAs (miRNAs) and small interfering RNAs (siRNAs); depletion of Dicer was found to impair the migration of endothelial cells. Methods siRNA transfection, cell migration assay, real-time RT–PCR, chromatin immunoprecipitation, Western blotting, ELISA, caspase-3 activity assay, and annexin-V–FITC assay were utilized. Results Knockdown of Dicer impairs the migratory capacity of HEK293T cells and induces fibronectin-1. The upregulation of fibronectin-1 is dependent on Egr1. Fibronectin-1/Dicer double-knockdown cells showed a marked increase in apoptosis compared with fibronectin-1 single knockdown cells. Conclusions Decreased Dicer expression induces fibronectin-1 expression via an Egr1-dependent manner. General significance Our data suggest that upregulation of fibronectin-1 protects Dicer knockdown HEK293T cells against apoptosis.

Abstract 5321: Dicer Depletion in Adult Hearts Induces Oxidative Stress, Mitochondrial Dysfunction and Causes Rapid Loss of Cardiac Function

Introduction. Dicer, an RNAse III endonuclease, plays a key role in the processing of miRNA into their functional mature form. A number of recent reports point towards a central role of miRNA in cardiac development and function. However, the short-term effects of dicer deficiency on the function of the adult heart and underlying mechanisms remain to be elucidated. Oxidative stress and dysregulated mitochondrial function are known to play a major role in acute cardiac pathologies. Hypothesis . Arrest of miR maturation by heart-specific dicer knock-out in adult animals result in rapid loss of cardiac function caused by mitochondrial dysfunction and oxidative stress. Methods . Mice homozygous for Dicer-floxed alleles (Dicer fl/fl ) and transgenic Myh6-cre/Esr1 mice were crossed to generate double-transgenic (Myh6-cre/Esr1-Dicer fl/fl ) mice. At 8 weeks of age Myh6-cre/Esr1-Dicer fl/fl mice were treated with vehicle or tamoxifen (tam; 20 mg/kg per day) daily ip injections for five consecutive days. To determine the acute functional consequences of Dicer depletion, heart function was determined using gated cardiac MRI and echocardiography. Myocardial miR profiling was performed using a bead array system. Candidate miRs were verified using quantitative PCR. Results . Tam injection for 5 days effectively depleted Dicer protein in myocardium. miRNA array data show significant (p< 0.05, n=3) decrease in the levels of a number of abundant mature miRNA including miR-1, miR-133 a&b. Following 5 days of Tam injection, a significant (p< 0.05, n=5) decrease in ejection fraction (32±9%↓), stroke volume (23±7%↓) and cardiac output (28.3±6%↓) was noted in Dicer −/− compared to Dicer +/+ mice. Studies with isolated mitochondria showed a significant decrease in energy dependent pore opening and increase in uncoupled mitochondria in the heart of Dicer −/− mice. Such compromise in mitochondrial function was associated with structural disintegration and increased (30±7.5%↑; p<0.05, n=3) tissue oxidative stress. Conclusions . This study provides first evidence demonstrating that depletion of dicer in adult mice results in mitochondrial dysfunction and oxidative stress in the myocardium which is followed by acute loss of cardiac functions.