Non-Coding RNAs of Mitochondrial Origin: Roles in Cell Division and Implications in Cancer.

Non-coding RNAs (ncRNAs) are a heterogeneous group, in terms of structure and sequence length, consisting of RNA molecules that do not code for proteins. These ncRNAs have a central role in the regulation of gene expression and are virtually involved in every process analyzed, ensuring cellular homeostasis. Although, over the years, much research has focused on the characterization of non-coding transcripts of nuclear origin, improved bioinformatic tools and next-generation sequencing (NGS) platforms have allowed the identification of hundreds of ncRNAs transcribed from the mitochondrial genome (mt-ncRNA), including long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miR). Mt-ncRNAs have been described in diverse cellular processes such as mitochondrial proteome homeostasis and retrograde signaling; however, the function of the majority of mt-ncRNAs remains unknown. This review focuses on a subgroup of human mt-ncRNAs whose dysfunction is associated with both failures in cell cycle regulation, leading to defects in cell growth, cell proliferation, and apoptosis, and the development of tumor hallmarks, such as cell migration and metastasis formation, thus contributing to carcinogenesis and tumor development. Here we provide an overview of the mt-ncRNAs/cancer relationship that could help the future development of new biomedical applications in the field of oncology.

Roles of non-coding RNA in diabetic cardiomyopathy.

In recent years, the incidence of diabetes has been increasing rapidly, posing a serious threat to human health. Diabetic cardiomyopathy (DCM) is characterized by cardiomyocyte hypertrophy, myocardial fibrosis, apoptosis, ventricular remodeling, and cardiac dysfunction in individuals with diabetes, ultimately leading to heart failure and mortality. However, the underlying mechanisms contributing to DCM remain incompletely understood. With advancements in molecular biology technology, accumulating evidence has shown that numerous non-coding RNAs (ncRNAs) crucial roles in the development and progression of DCM. This review aims to summarize recent studies on the involvement of three types of ncRNAs (micro RNA, long ncRNA and circular RNA) in the pathophysiology of DCM, with the goal of providing innovative strategies for the prevention and treatment of DCM.

Mechanistic and therapeutic perspectives of non-coding RNA-modulated apoptotic signaling in diabetic retinopathy.

Diabetic retinopathy (DR), a significant and vision-endangering complication associated with diabetes mellitus, constitutes a substantial portion of acquired instances of preventable blindness. The progression of DR appears to prominently feature the loss of retinal cells, encompassing neural retinal cells, pericytes, and endothelial cells. Therefore, mitigating the apoptosis of retinal cells in DR could potentially enhance the therapeutic approach for managing the condition by suppressing retinal vascular leakage. Recent advancements have highlighted the crucial regulatory roles played by non-coding RNAs (ncRNAs) in diverse biological processes. Recent advancements have highlighted that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), act as central regulators in a wide array of biogenesis and biological functions, exerting control over gene expression associated with histogenesis and cellular differentiation within ocular tissues. Abnormal expression and activity of ncRNAs has been linked to the regulation of diverse cellular functions such as apoptosis, and proliferation. This implies a potential involvement of ncRNAs in the development of DR. Notably, ncRNAs and apoptosis exhibit reciprocal regulatory interactions, jointly influencing the destiny of retinal cells. Consequently, a thorough investigation into the complex relationship between apoptosis and ncRNAs is crucial for developing effective therapeutic and preventative strategies for DR. This review provides a fundamental comprehension of the apoptotic signaling pathways associated with DR. It then delves into the mutual relationship between apoptosis and ncRNAs in the context of DR pathogenesis. This study advances our understanding of the pathophysiology of DR and paves the way for the development of novel therapeutic strategies.

Special Issue "The Role of Non-Coding RNAs Involved in Cardiovascular Diseases and Cellular Communication".

Despite the great progress in diagnosis, prevention, and treatment, cardiovascular diseases (CVDs) are still the most prominent cause of death worldwide [...].

Perspective and Therapeutic Potential of the Noncoding RNA-Connexin Axis.

Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of ncRNAs in cell physiology and their pivotal roles in various diseases have been identified. One target regulated by ncRNAs is connexin (Cx), a protein that forms gap junctions and hemichannels and facilitates intercellular molecule exchange. The aberrant expression and misdistribution of connexins have been implicated in central nervous system diseases, cardiovascular diseases, bone diseases, and cancer. Current databases and technologies have enabled researchers to identify the direct or indirect relationships between ncRNAs and connexins, thereby elucidating their correlation with diseases. In this review, we selected the literature published in the past five years concerning disorders regulated by ncRNAs via corresponding connexins. Among it, microRNAs that regulate the expression of Cx43 play a crucial role in disease development and are predominantly reviewed. The distinctive perspective of the ncRNA-Cx axis interprets pathology in an epigenetic manner and is expected to motivate research for the development of biomarkers and therapeutics.

Exploring the Regulatory Landscape of Dementia: Insights from Non-Coding RNAs.

Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.

Recent advances in the reciprocal regulation of m6A modification with non-coding RNAs and its therapeutic application in acute myeloid leukemia.

N6-methyladenosine (m6A) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation, maturation, splicing, and export. m6A also participates in the modification of multiple types of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, thereby affecting their metabolism and functions. Increasing evidence has revealed that m6A regulators, such as writers, erasers, and readers, perform m6A-dependent modification of ncRNAs, thus affecting cancer progression. Moreover, ncRNAs modulate m6A regulators to affect cancer development and progression. In this review, we summarize recent advances in understanding m6A modification and ncRNAs and provide insights into the interaction between m6A modification and ncRNAs in cancer. We also discuss the potential clinical applications of the mechanisms underlying the interplay between m6A modifications and ncRNAs in acute myeloid leukemia (AML). Therefore, clarifying the mutual regulation between m6A modifications and ncRNAs is of great significance to identify novel therapeutic targets for AML and has great clinical application prospects.

Posttranscriptional Regulation by Proteins and Noncoding RNAs.

Posttranscriptional regulation comprises those mechanisms occurring after the initial copy of the DNA sequence is transcribed into an intermediate RNA molecule (i.e., messenger RNA) until such a molecule is used as a template to generate a protein. A subset of these posttranscriptional regulatory mechanisms essentially are destined to process the immature mRNA toward its mature form, conferring the adequate mRNA stability, providing the means for pertinent introns excision, and controlling mRNA turnover rate and quality control check. An additional layer of complexity is added in certain cases, since discrete nucleotide modifications in the mature RNA molecule are added by RNA editing, a process that provides large mature mRNA diversity. Moreover, a number of posttranscriptional regulatory mechanisms occur in a cell- and tissue-specific manner, such as alternative splicing and noncoding RNA-mediated regulation. In this chapter, we will briefly summarize current state-of-the-art knowledge of general posttranscriptional mechanisms, while major emphases will be devoted to those tissue-specific posttranscriptional modifications that impact on cardiac development and congenital heart disease.

Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis.

Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.

A programmable seekRNA guides target selection by IS1111 and IS110 type insertion sequences.

IS1111 and IS110 insertion sequence (IS) family members encode an unusual DEDD transposase type and exhibit specific target site selection. The IS1111 group include identifiable subterminal inverted repeats (sTIR) not found in the IS110 type1. IS in both families include a noncoding region (NCR) of significant length and, as each individual IS or group of closely related IS selects a different site, we had previously proposed that an NCR-derived RNA was involved in target selection2. Here, we find that the NCR is usually downstream of the transposase gene in IS1111 family IS and upstream in the IS110 type. Four IS1111 and one IS110 family members that target different sequences are used to demonstrate that the NCR determines a short seeker RNA (seekRNA) that co-purified with the transposase. The seekRNA is essential for transposition of the IS or a cargo flanked by IS ends from and to the preferred target. Short sequences matching both top and bottom strands of the target are present in the seekRNA but their order in IS1111 and IS110 family IS is reversed. Reprogramming the seekRNA and donor flank to target a different site is demonstrated, indicating future biotechnological potential for these systems.

Molecular insights into regulatory RNAs in the cellular machinery.

It is apparent that various functional units within the cellular machinery are derived from RNAs. The evolution of sequencing techniques has resulted in significant insights into approaches for transcriptome studies. Organisms utilize RNA to govern cellular systems, and a heterogeneous class of RNAs is involved in regulatory functions. In particular, regulatory RNAs are increasingly recognized to participate in intricately functioning machinery across almost all levels of biological systems. These systems include those mediating chromatin arrangement, transcription, suborganelle stabilization, and posttranscriptional modifications. Any class of RNA exhibiting regulatory activity can be termed a class of regulatory RNA and is typically represented by noncoding RNAs, which constitute a substantial portion of the genome. These RNAs function based on the principle of structural changes through cis and/or trans regulation to facilitate mutual RNA‒RNA, RNA‒DNA, and RNA‒protein interactions. It has not been clearly elucidated whether regulatory RNAs identified through deep sequencing actually function in the anticipated mechanisms. This review addresses the dominant properties of regulatory RNAs at various layers of the cellular machinery and covers regulatory activities, structural dynamics, modifications, associated molecules, and further challenges related to therapeutics and deep learning.

Non-Coding RNAs in HIV Infection, NeuroHIV, and Related Comorbidities.

NeuroHIV affects approximately 30-60% of people living with HIV-1 (PLWH) and is characterized by varying degrees of cognitive impairments, presenting a multifaceted challenge, the underlying cause of which is chronic, low-level neuroinflammation. Such smoldering neuroinflammation is likely an outcome of lifelong reliance on antiretrovirals coupled with residual virus replication in the brains of PLWH. Despite advancements in antiretroviral therapeutics, our understanding of the molecular mechanism(s) driving inflammatory processes in the brain remains limited. Recent times have seen the emergence of non-coding RNAs (ncRNAs) as critical regulators of gene expression, underlying the neuroinflammatory processes in HIV infection, NeuroHIV, and their associated comorbidities. This review explores the role of various classes of ncRNAs and their regulatory functions implicated in HIV infection, neuropathogenesis, and related conditions. The dysregulated expression of ncRNAs is known to exacerbate the neuroinflammatory responses, thus contributing to neurocognitive impairments in PLWH. This review also discusses the diagnostic and therapeutic potential of ncRNAs in HIV infection and its comorbidities, suggesting their utility as non-invasive biomarkers and targets for modulating neuroinflammatory pathways. Understanding these regulatory roles could pave the way for novel diagnostic strategies and therapeutic interventions in the context of HIV and its comorbidities.

Bridge RNAs direct programmable recombination of target and donor DNA.

Genomic rearrangements, encompassing mutational changes in the genome such as insertions, deletions or inversions, are essential for genetic diversity. These rearrangements are typically orchestrated by enzymes that are involved in fundamental DNA repair processes, such as homologous recombination, or in the transposition of foreign genetic material by viruses and mobile genetic elements1,2. Here we report that IS110 insertion sequences, a family of minimal and autonomous mobile genetic elements, express a structured non-coding RNA that binds specifically to their encoded recombinase. This bridge RNA contains two internal loops encoding nucleotide stretches that base-pair with the target DNA and the donor DNA, which is the IS110 element itself. We demonstrate that the target-binding and donor-binding loops can be independently reprogrammed to direct sequence-specific recombination between two DNA molecules. This modularity enables the insertion of DNA into genomic target sites, as well as programmable DNA excision and inversion. The IS110 bridge recombination system expands the diversity of nucleic-acid-guided systems beyond CRISPR and RNA interference, offering a unified mechanism for the three fundamental DNA rearrangements-insertion, excision and inversion-that are required for genome design.

Structural mechanism of bridge RNA-guided recombination.

Insertion sequence (IS) elements are the simplest autonomous transposable elements found in prokaryotic genomes1. We recently discovered that IS110 family elements encode a recombinase and a non-coding bridge RNA (bRNA) that confers modular specificity for target DNA and donor DNA through two programmable loops2. Here we report the cryo-electron microscopy structures of the IS110 recombinase in complex with its bRNA, target DNA and donor DNA in three different stages of the recombination reaction cycle. The IS110 synaptic complex comprises two recombinase dimers, one of which houses the target-binding loop of the bRNA and binds to target DNA, whereas the other coordinates the bRNA donor-binding loop and donor DNA. We uncovered the formation of a composite RuvC-Tnp active site that spans the two dimers, positioning the catalytic serine residues adjacent to the recombination sites in both target and donor DNA. A comparison of the three structures revealed that (1) the top strands of target and donor DNA are cleaved at the composite active sites to form covalent 5'-phosphoserine intermediates, (2) the cleaved DNA strands are exchanged and religated to create a Holliday junction intermediate, and (3) this intermediate is subsequently resolved by cleavage of the bottom strands. Overall, this study reveals the mechanism by which a bispecific RNA confers target and donor DNA specificity to IS110 recombinases for programmable DNA recombination.

Toward a Categorization of Virus-ncRNA Interactions in the World of RNA to Disentangle the Tiny Secrets of Dengue Virus.

In recent years, the function of noncoding RNAs (ncRNAs) as regulatory molecules of cell physiology has begun to be better understood. Advances in viral molecular biology have shown that host ncRNAs, cellular factors, and virus-derived ncRNAs and their interplay are strongly disturbed during viral infections. Nevertheless, the folding of RNA virus genomes has also been identified as a critical factor in regulating canonical and non-canonical functions. Due to the influence of host ncRNAs and the structure of RNA viral genomes, complex molecular and cellular processes in infections are modulated. We propose three main categories to organize the current information about RNA-RNA interactions in some well-known human viruses. The first category shows examples of host ncRNAs associated with the immune response triggered in viral infections. Even though miRNAs introduce a standpoint, they are briefly presented to keep researchers moving forward in uncovering other RNAs. The second category outlines interactions between virus-host ncRNAs, while the third describes how the structure of the RNA viral genome serves as a scaffold for processing virus-derived RNAs. Our grouping may provide a comprehensive framework to classify ncRNA-host-cell interactions for emerging viruses and diseases. In this sense, we introduced them to organize DENV-host-cell interactions.

Non-Coding RNA as Biomarkers and Their Role in the Pathogenesis of Gastric Cancer-A Narrative Review.

Non-coding RNAs (ncRNAs) represent a broad family of molecules that regulate gene expression, including microRNAs, long non-coding RNAs and circular RNAs, amongst others. Dysregulated expression of ncRNAs alters gene expression, which is implicated in the pathogenesis of several malignancies and inflammatory diseases. Gastric cancer is the fifth most frequently diagnosed cancer and the fourth most common cause of cancer-related death. Studies have found that altered expression of ncRNAs may contribute to tumourigenesis through regulating proliferation, apoptosis, drug resistance and metastasis. This review describes the potential use of ncRNAs as diagnostic and prognostic biomarkers. Moreover, we discuss the involvement of ncRNAs in the pathogenesis of gastric cancer, including their interactions with the members of major signalling pathways.

Exploring the role non-coding RNAs during myocardial cell fate.

Myocardial cell fate specification takes place during the early stages of heart development as the precardiac mesoderm is configured into two symmetrical sets of bilateral precursor cells. Molecular cues of the surrounding tissues specify and subsequently determine the early cardiomyocytes, that finally matured as the heart is completed at early postnatal stages. Over the last decade, we have greatly enhanced our understanding of the transcriptional regulation of cardiac development and thus of myocardial cell fate. The recent discovery of a novel layer of gene regulation by non-coding RNAs has flourished their implication in epigenetic, transcriptional and post-transcriptional regulation of cardiac development. In this review, we revised the current state-of-the-art knowledge on the functional role of non-coding RNAs during myocardial cell fate.

Bioinformatic prediction of proteins relevant to functions of the bacterial OLE ribonucleoprotein complex.

OLE (ornate, large, extremophilic) RNAs are members of a noncoding RNA class present in many Gram-positive, extremophilic bacteria. The large size, complex structure, and extensive sequence conservation of OLE RNAs are characteristics consistent with the hypothesis that they likely function as ribozymes. The OLE RNA representative from Halalkalibacterium halodurans is known to localize to the phospholipid membrane and requires at least three essential protein partners: OapA, OapB, and OapC. However, the precise biochemical functions of this unusual ribonucleoprotein (RNP) complex remain unknown. Genetic disruption of OLE RNA or its partners revealed that the complex is beneficial under diverse stress conditions. To search for additional links between OLE RNA and other cellular components, we used phylogenetic profiling to identify proteins that are either correlated or anticorrelated with the presence of OLE RNA in various bacterial species. This analysis revealed strong correlations between the essential protein-binding partners of OLE RNA and organisms that carry the ole gene. Similarly, proteins involved in sporulation are correlated, suggesting a potential role for the OLE RNP complex in spore formation. Intriguingly, the Mg2+ transporter MpfA is strongly anticorrelated with OLE RNA. Evidence indicates that MpfA is structurally related to OapA and therefore MpfA may serve as a functional replacement for some contributions otherwise performed by the OLE RNP complex in species that lack this device. Indeed, OLE RNAs might represent an ancient RNA class that enabled primitive organisms to sense and respond to major cellular stresses.IMPORTANCEOLE (ornate, large, extremophilic) RNAs were first reported nearly 20 years ago, and they represent one of the largest and most intricately folded noncoding RNA classes whose biochemical function remains to be established. Other RNAs with similar size, structural complexity, and extent of sequence conservation have proven to catalyze chemical transformations. Therefore, we speculate that OLE RNAs likewise operate as ribozymes and that they might catalyze a fundamental reaction that has persisted since the RNA World era-a time before the emergence of proteins in evolution. To seek additional clues regarding the function of OLE RNA, we undertook a computational effort to identify potential protein components of the OLE ribonucleoprotein (RNP) complex or other proteins that have functional links to this device. This analysis revealed known protein partners and several additional proteins that might be physically or functionally linked to the OLE RNP complex. Finally, we identified a Mg2+ transporter protein, MpfA, that strongly anticorrelates with the OLE RNP complex. This latter result suggests that MpfA might perform at least some functions that are like those carried out by the OLE RNP complex.

Noncoding RNAs in regulation of plant secondary metabolism.

Plant secondary metabolites (PSMs) are a large class of structurally diverse molecules, mainly consisting of terpenoids, phenolic compounds, and nitrogen-containing compounds, which play active roles in plant development and stress responses. The biosynthetic processes of PSMs are governed by a sophisticated regulatory network at multiple levels. Noncoding RNAs (ncRNAs) such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) may serve as post-transcriptional regulators for plant secondary metabolism through acting on genes encoding either transcription factors or participating enzymes in relevant metabolic pathways. High-throughput sequencing technologies have facilitated the large-scale identifications of ncRNAs potentially involved in plant secondary metabolism in model plant species as well as certain species with enriched production of specific types of PSMs. Moreover, a series of miRNA-target modules have been functionally characterized to be responsible for regulating PSM biosynthesis and accumulation in plants under abiotic or biotic stresses. In this review, we will provide an overview of current findings on the ncRNA-mediated regulation of plant secondary metabolism with special attention to its participation in plant stress responses, and discuss possible issues to be addressed in future fundamental research and breeding practice.

Targeting the Wnt/ß-catenin cascade in osteosarcoma: The potential of ncRNAs as biomarkers and therapeutics.

Osteosarcoma (OS) is a bone cancer which stems from several sources and presents with diverse clinical features, making evaluation and treatment difficult. Chemotherapy tolerance and restricted treatment regimens hinder progress in survival rates, requiring new and creative therapeutic strategies. The Wnt/ß-catenin system has been recognised as an essential driver of OS development, providing potential avenues for therapy. Non-coding RNAs (ncRNAs), such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), are essential in modulating the Wnt/ß-catenin cascade in OS. MiRNAs control the system by targeting vital elements, while lncRNAs and circRNAs interact with system genes, impacting OS growth and advancement. This paper thoroughly analyses the intricate interplay between ncRNAs and the Wnt/ß-catenin cascade in OS. We examine how uncontrolled levels of miRNAs, lncRNAs, and circRNAs lead to an abnormal Wnt/ß-catenin network, which elevates the development, spread, and susceptibility to the treatment of OS. We emphasise the potential of ncRNAs as diagnostic indicators and avenues for treatment in OS care. The review offers valuable insights for academics and clinicians studying OS aetiology and creating new treatment techniques for the ncRNA-Wnt/ß-catenin cascade. Utilising the oversight roles of ncRNAs in the Wnt/ß-catenin system shows potential for enhancing the outcomes of patients and progressing precision medicine in OS therapy.