MicroRNAs as regulators of mitochondrial function: Role in cancer suppression

Background

Mitochondria, essential to the cell homeostasis maintenance, are central to the intrinsic apoptotic pathway and their dysfunction is associated with multiple diseases. Recent research documents that microRNAs (miRNAs) regulate important signalling pathways in mitochondria, and many of these miRNAs are deregulated in various diseases including cancers.

Scope of review

In this review, we summarise the role of miRNAs in the regulation of the mitochondrial bioenergetics/function, and discuss the role of miRNAs modulating the various metabolic pathways resulting in tumour suppression and their possible therapeutic applications.

Major conclusions

MiRNAs have recently emerged as key regulators of metabolism and can affect mitochondria by modulating mitochondrial proteins coded by nuclear genes. They were also found in mitochondria. Reprogramming of the energy metabolism has been postulated as a major feature of cancer. Modulation of miRNAs levels may provide a new therapeutic approach for the treatment of mitochondria-related pathologies, including neoplastic diseases.

General significance

The elucidation of the role of miRNAs in the regulation of mitochondrial activity/bioenergetics will deepen our understanding of the molecular aspects of various aspects of cell biology associated with the genesis and progression of neoplastic diseases. Eventually, this knowledge may promote the development of innovative pharmacological interventions. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

MicroRNAs in skeletal and cardiac muscle development

MicroRNAs (miRNAs) are a recently discovered class of small non-coding RNAs, which are approximately 22 nucleotides in length. miRNAs negatively regulate gene expression by translational repression and target mRNA degradation. It has become clear that miRNAs are involved in many biological processes, including development, differentiation, proliferation, and apoptosis. Interestingly, many miRNAs are expressed in a tissue-specific manner and several miRNAs are specifically expressed in cardiac and skeletal muscles. In this review, we focus on those miRNAs that have been shown to be involved in muscle development. Compelling evidences have demonstrated that muscle miRNAs play an important role in the regulation of muscle proliferation and differentiation processes. However, it appears that miRNAs are not essential for early myogenesis and muscle specification. Importantly, dysregulation of miRNAs has been linked to muscle-related diseases, such as cardiac hypertrophy. A mutation resulting in a gain-of-function miRNA target site in the myostatin gene leads to down regulation of the targeted protein in Texel sheep. miRNAs therefore are a new class of regulators of muscle biology and they might become novel therapeutic targets in muscle-related human diseases.     

MicroRNAs: Novel Regulators of Oligodendrocyte Differentiation and Potential Therapeutic Targets in Demyelination-Related Diseases

MicroRNAs (miRNAs or miRs) are a class of endogenous small non-coding RNAs that consist of about 22 nucleotides and play critical roles in various biological processes, including cell proliferation, differentiation, apoptosis, and tumorigenesis. In recent years, some specific miRNA, such as miR-219, miR-138, miR-9, miR-23, and miR-19b were found to participate in the regulation of oligodendrocyte (OL) differentiation and myelin maintenance, as well as in the pathogenesis of demyelination-related diseases (e.g., multiple sclerosis, ischemic stroke, and leukodystrophy). These miRNAs control their target mRNA or regulate the protein levels of some signaling pathways, and participate in OL differentiation and the pathogenesis of demyelination-related diseases. During pathologic processes, the expression levels of specific miRNAs are dynamically altered. Therefore, miRNAs act as diagnostic and prognostic indicators of defects in OL differentiation and demyelination-related diseases, and they can provide potential targets for therapeutic drug development.     

MicroRNAs as a therapeutic target for cardiovascular diseases

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.     

Advances in microRNAs: implications for immunity and inflammatory diseases

Since their discovery in 1993 and the introduction of the term microRNA in 2001, it has become evident that microRNAs (miRNAs) involved in many biological processes, including development, differentiation, proliferation and apoptosis. The function of miRNA the control of protein production in cells by sequence-specific targeting of mRNAs for translational repression or mRNA degradati Interestingly, immune genes are apparently preferentially targeted by miRNAs compared to the average of the human genome, indicat the significance of miRNA-mediated regulation for normal immune responses. Here, we review what is known about the role of miRN in the pathogenesis of immune-related diseases such as chronic inflammatory skin diseases, autoimmunity and viral infections.     

MicroRNAs and intestinal pathophysiology

MicroRNAs (miRNAs) represent an abundant class of endogenously expressed small RNAs, which is believed to control the expression of proteins through specific interaction with their mRNAs. MiRNAs are non-coding RNAs of 18 to 24 nucleotides that negatively regulate target mRNAs by binding to their 3'-untranslated regions (UTR). Most eukaryotic cells utilize miRNA to regulate vital functions such as cell differentiation, proliferation or apopotosis. The diversity of miRNAs and of their mRNA targets strongly indicate that they play a key role in the regulation of protein expression. To date, more than 500 different miRNAs have been identified in animals and plants. There are at least 326 miRNAs in the human genome, comprising 1-4% of all expressed human genes, which makes miRNAs one of the largest classes of gene regulators. A single miRNA can bind to and regulate many different mRNA targets and, conversely, several different miRNAs can bind to and cooperatively control a single mRNA target. The correlation between the expression of miRNAs and their effects on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidences. Recent studies showed that abnormal expression of miRNAs represents a common feature of cancer cells and that they can function as tumor suppressor genes or as oncogenes. Therefore, this diversity of action for miRNAs on several target genes could be one of the common mechanisms involved in the deregulation of protein expression observed during intestinal disorders. In this review, the emergent functions of miRNAs in colorectal cancer and their potential role in the intestinal inflammatory process are discussed.     

Individual mRNA expression profiles reveal the effects of specific microRNAs

Background  

MicroRNAs (miRNAs) are oligoribonucleotides with an important role in regulation of gene expression at the level of translation. Despite imperfect target complementarity, they can also significantly reduce mRNA levels. The validity of miRNA target gene predictions is difficult to assess at the protein level. We sought, therefore, to determine whether a general lowering of predicted target gene mRNA expression by endogenous miRNAs was detectable within microarray gene expression profiles.     

A meta-analysis revealed insights into the sources,conservation and impact of microRNA 5′-isoforms in four model species

MicroRNA (miRNA) 5′-isoforms, or 5′-isomiRs, are small-RNA species that originate from the same genomic loci as the major miRNAs with their 5′ ends shifted from the 5′ ends of the miRNAs by a few nucleotides. Although 5′-isomiRs have been reported, their origins, properties and potential functions remain to be examined. We systematically studied 5′-isomiRs in human, mouse, fruitfly and worm by analysing a large collection of small non-coding RNA and mRNA profiling data. The results revealed a broad existence of 5′-isomiRs in the four species, many of which were conserved and could arise from genomic loci of canonical and non-canonical miRNAs. The well-conserved 5′-isomiRs have several features, including a preference of the 3p over the 5p arms of hairpins of conserved mammalian miRNAs, altered 5′-isomiRs across species and across tissues, and association with structural variations of miRNA hairpins. Importantly, 5′-isomiRs and their major miRNAs may have different mRNA targets and thus potentially play distinct roles of gene regulation, as shown by an integrative analysis combining miRNA and mRNA profiling data from psoriatic and normal human skin and from murine miRNA knockout assays. Indeed, 18 5′-isomiRs had aberrant expression in psoriatic human skin, suggesting their potential function in psoriasis pathogenesis. The results of the current study deepened our understanding of the diversity and conservation of miRNAs, their plasticity in gene regulation and potential broad function in complex diseases.     

microRNAs参与动脉粥样硬化疾病的发生

microRNAs (miRNAs)是一类非编码的小分子RNA（～22 nt）,可在转录后水平调控基因表达.miRNAs参与调控机体的多种生理和病理过程.近来研究表明,miRNAs可能与动脉粥样硬化疾病的发生和发展密切相关,在血管新生、炎症和脂蛋白代谢等方面发挥了关键作用.本文就miRNAs与动脉粥样硬化疾病相关的研究进展进行综述,为研究miRNAs在动脉粥样硬化的发病机制中的作用,以及为miRNAs能够作为诊断动脉粥样硬化疾病的生物标志物提供思路.