bims-smotar Biomed News
on Small molecule targeting of RNA
Issue of 2023–02–12
seventeen papers selected by
Rabia T. Khan, Serna Bio
  1. Rock, scissors, paper: How RNA structure informs function.
  2. DeepsmirUD: Prediction of Regulatory Effects on microRNA Expression Mediated by Small Molecules Using Deep Learning.
  3. bpRNA-align: Improved RNA Secondary Structure Global Alignment for Comparing and Clustering RNA Structures.
  4. Primitive Oligomeric RNAs at the Origins of Life on Earth.
  5. An old friend with a new face: tRNA-derived small RNAs with big regulatory potential in cancer biology.
  6. Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.
  7. Regulation of Gene Expression by m6Am RNA Modification.
  8. NMR of RNA - Structure and interactions.
  9. G-Quadruplexes in Repeat Expansion Disorders.
  10. The tRNA identity landscape for aminoacylation and beyond.
  11. RNA localization to the mitotic spindle is essential for early development and is regulated by kinesin-1 and dynein.
  12. Long Noncoding RNAs and Cancer Stem Cells: Dangerous Liaisons Managing Cancer.
  13. The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration.
  14. Regulation of NcRNA-protein binding in diabetic foot.
  15. Dynamic and Reversible Decoration of DNA-Based Scaffolds.
  16. Long Non-coding RNA KTN1-AS1 Targets miR-505 to Promote Glioblastoma Progression.
  17. Non-Coding RNAs Regulating Mitochondrial Functions and the Oxidative Stress Response as Putative Targets against Age-Related Macular Degeneration (AMD).
  1. Plant Cell. 2023 Feb 07. pii: koad026. [Epub ahead of print]
    Rock, scissors, paper: How RNA structure informs function.
    Sarah M Assmann, Hong-Li Chou, Philip C Bevilacqua.
      RNA can fold back on itself to adopt a wide range of structures. These range from relatively simple hairpins to intricate three dimensional folds, and can be accompanied by regulatory interactions with both metabolites and macromolecules. The last 50 years have witnessed elucidation of an astonishing array of RNA structures including tRNAs, ribozymes, riboswitches, the ribosome, the spliceosome, and most recently entire RNA structuromes. These advances in RNA structural biology have deepened insight into fundamental biological processes including gene editing, transcription, translation, and structure-based detection and response to temperature and other environmental signals. These discoveries reveal that RNA can be relatively static, like a rock; that it can have catalytic functions of cutting bonds, like scissors; and that it can adopt myriad functional shapes, like paper. We relate these extraordinary discoveries in the biology of RNA structure to the plant way of life. We trace plant-specific discovery of ribozymes and riboswitches, alternative splicing, organellar ribosomes, thermometers, whole-transcriptome structuromes and pan-structuromes, and conclude that plants have a special set of RNA structures that confer unique types of gene regulation. We finish with a consideration of future directions for the RNA structure-function field.
    DOI:  https://doi.org/10.1093/plcell/koad026
  2. Int J Mol Sci. 2023 Jan 18. pii: 1878. [Epub ahead of print]24(3):
    DeepsmirUD: Prediction of Regulatory Effects on microRNA Expression Mediated by Small Molecules Using Deep Learning.
    Jianfeng Sun, Jinlong Ru, Lorenzo Ramos-Mucci, Fei Qi, Zihao Chen, Suyuan Chen, Adam P Cribbs, Li Deng, Xia Wang.
      Aberrant miRNA expression has been associated with a large number of human diseases. Therefore, targeting miRNAs to regulate their expression levels has become an important therapy against diseases that stem from the dysfunction of pathways regulated by miRNAs. In recent years, small molecules have demonstrated enormous potential as drugs to regulate miRNA expression (i.e., SM-miR). A clear understanding of the mechanism of action of small molecules on the upregulation and downregulation of miRNA expression allows precise diagnosis and treatment of oncogenic pathways. However, outside of a slow and costly process of experimental determination, computational strategies to assist this on an ad hoc basis have yet to be formulated. In this work, we developed, to the best of our knowledge, the first cross-platform prediction tool, DeepsmirUD, to infer small-molecule-mediated regulatory effects on miRNA expression (i.e., upregulation or downregulation). This method is powered by 12 cutting-edge deep-learning frameworks and achieved AUC values of 0.843/0.984 and AUCPR values of 0.866/0.992 on two independent test datasets. With a complementarily constructed network inference approach based on similarity, we report a significantly improved accuracy of 0.813 in determining the regulatory effects of nearly 650 associated SM-miR relations, each formed with either novel small molecule or novel miRNA. By further integrating miRNA-cancer relationships, we established a database of potential pharmaceutical drugs from 1343 small molecules for 107 cancer diseases to understand the drug mechanisms of action and offer novel insight into drug repositioning. Furthermore, we have employed DeepsmirUD to predict the regulatory effects of a large number of high-confidence associated SM-miR relations. Taken together, our method shows promise to accelerate the development of potential miRNA targets and small molecule drugs.
    Keywords:  deep learning; drug discovery; miRNAs; regulatory effect prediction; small molecule compounds
    DOI:  https://doi.org/10.3390/ijms24031878
  3. RNA. 2023 Feb 09. pii: rna.079211.122. [Epub ahead of print]
    bpRNA-align: Improved RNA Secondary Structure Global Alignment for Comparing and Clustering RNA Structures.
    Brittany Lasher, David Anthony Hendrix.
      Ribonucleic acid (RNA) is a polymeric molecule that is fundamental to biological processes, with structure being more highly conserved than primary sequence and often key to its function. Advances in RNA structure characterization have resulted in an increase in the number of accurate secondary structures. The task of uncovering common RNA structural motifs with a collective function through structural comparison, providing a level of similarity, remains challenging and could be used to improve RNA secondary structure databases and discover new RNA families. In this work, we present a novel secondary structure alignment method, bpRNA-align. bpRNA-align is a customized global structural alignment method, utilizing an inverted (gap extend costs more than gap open) and context-specific affine gap penalty along with a structural, feature-specific substitution matrix to provide similarity scores. We evaluate our similarity scores in comparison to other methods, using affinity propagation clustering, applied to a benchmarking data set of known structure types. bpRNA-align shows improvement in clustering performance over a broad range of structure types.
    Keywords:  RNA; RNA secondary structure; RNA structural alignment; RNA structural clustering; clustering
    DOI:  https://doi.org/10.1261/rna.079211.122
  4. Int J Mol Sci. 2023 Jan 23. pii: 2274. [Epub ahead of print]24(3):
    Primitive Oligomeric RNAs at the Origins of Life on Earth.
    Jacques Demongeot, Michel Thellier.
      There are several theories on the origin of life, which differ by choosing the preponderant factor of emergence: main function (autocatalysis versus replication), initial location (black smokers versus ponds) or first molecule (RNA versus DNA). Among the two last ones, the first assumes that an RNA world involving a collaboration of small RNAs with amino-acids pre-existed and the second that DNA-enzyme-lipid complexes existed first. The debate between these classic theories is not closed and the arguments for one or the other of these theories have recently fueled a debate in which the two have a high degree of likelihood. It therefore seems interesting to propose a third intermediate way, based on the existence of an RNA that may have existed before the latter stages postulated by these theories, and therefore may be the missing link towards a common origin of them. To search for a possible ancestral structure, we propose as candidate a small RNA existing in ring or hairpin form in the early stages of life, which could have acted as a "proto-ribosome" by favoring the synthesis of the first peptides. Remnants of this putative candidate RNA exist in molecules nowadays involved in the ribosomal factory, the concentrations of these relics depending on the seniority of these molecules within the translation process.
    Keywords:  ancient ribosomal proteins; origin of life; ring world; small RNAs
    DOI:  https://doi.org/10.3390/ijms24032274
  5. Br J Cancer. 2023 Feb 09.
    An old friend with a new face: tRNA-derived small RNAs with big regulatory potential in cancer biology.
    Arianna Di Fazio, Monika Gullerova.
      Transfer RNAs (tRNAs) are small non-coding RNAs (sncRNAs) essential for protein translation. Emerging evidence suggests that tRNAs can also be processed into smaller fragments, tRNA-derived small RNAs (tsRNAs), a novel class of sncRNAs with powerful applications and high biological relevance to cancer. tsRNAs biogenesis is heterogeneous and involves different ribonucleases, such as Angiogenin and Dicer. For many years, tsRNAs were thought to be just degradation products. However, accumulating evidence shows their roles in gene expression: either directly via destabilising the mRNA or the ribosomal machinery, or indirectly via regulating the expression of ribosomal components. Furthermore, tsRNAs participate in various biological processes linked to cancer, including apoptosis, cell cycle, immune response, and retroviral insertion into the human genome. It is emerging that tsRNAs have significant therapeutic potential. Endogenous tsRNAs can be used as cancer biomarkers, while synthetic tsRNAs and antisense oligonucleotides can be employed to regulate gene expression. In this review, we are recapitulating the regulatory roles of tsRNAs, with a focus on cancer biology.
    DOI:  https://doi.org/10.1038/s41416-023-02191-4
  6. Int J Mol Sci. 2023 Jan 31. pii: 2645. [Epub ahead of print]24(3):
    Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma.
    Hanley N Abramson.
      Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease's five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common. This review focuses on the current pipeline, along with the contemporary roles and future prospects for small molecules in MM therapy. While small molecules offer prospective benefits in terms of oral bioavailability, cellular penetration, simplicity of preparation, and improved cost-benefit considerations, they also pose problems of toxicity due to off-target effects. Highlighted in the discussion are recent developments in the applications of alkylating agents, immunomodulators, proteasome inhibitors, apoptosis inducers, kinesin spindle protein inhibitors, blockers of nuclear transport, and drugs that affect various kinases involved in intracellular signaling pathways. Molecular and cellular targets are described for each class of agents in relation to their roles as drivers of MM.
    Keywords:  cereblon E3 ligase modulators; melflufen; myeloma; selinexor; venetoclax
    DOI:  https://doi.org/10.3390/ijms24032645
  7. Int J Mol Sci. 2023 Jan 23. pii: 2277. [Epub ahead of print]24(3):
    Regulation of Gene Expression by m6Am RNA Modification.
    Bianca Cesaro, Marco Tarullo, Alessandro Fatica.
      The field of RNA modification, also referred to as "epitranscriptomics," is gaining more and more interest from the scientific community. More than 160 chemical modifications have been identified in RNA molecules, but the functional significance of most of them still needs to be clarified. In this review, we discuss the role of N6,2'-O-dimethyladenosine (m6Am) in gene expression regulation. m6Am is present in the first transcribed nucleotide close to the cap in many mRNAs and snRNAs in mammals and as internal modification in the snRNA U2. The writer and eraser proteins for these modifications have been recently identified and their deletions have been utilized to understand their contributions in gene expression regulation. While the role of U2 snRNA-m6Am in splicing regulation has been reported by different independent studies, conflicting data were found for the role of cap-associated m6Am in mRNA stability and translation. However, despite the open debate on the role of m6Am in mRNA expression, the modulation of regulators produced promising results in cancer cells. We believe that the investigation on m6Am will continue to yield relevant results in the future.
    Keywords:  RNA modification; gene expression; m6Am
    DOI:  https://doi.org/10.3390/ijms24032277
  8. Curr Opin Struct Biol. 2023 Feb 04. pii: S0959-440X(23)00006-4. [Epub ahead of print]79 102532
    NMR of RNA - Structure and interactions.
    Maja Marušič, Maria Toplishek, Janez Plavec.
      RNA was shown to have a more substantial role in the regulation of diverse cellular processes than anticipated until recently. Answers to questions what is the structure of specific RNAs, how structure changes to accommodate different functional roles, and how RNA senses other biomolecules and changes its fold upon interaction create a complete representation of RNA involved in cellular processes. Nuclear magnetic resonance (NMR) spectroscopy encompasses a collection of methods and approaches that offer insight into several structural aspects of RNAs. We review the most recent advances in the field of viral, long non-coding, regulatory, and four-stranded RNAs, with an emphasis on the detection of dynamic sub-states and in view of chemical modifications that expand RNA's function.
    DOI:  https://doi.org/10.1016/j.sbi.2023.102532
  9. Int J Mol Sci. 2023 Jan 25. pii: 2375. [Epub ahead of print]24(3):
    G-Quadruplexes in Repeat Expansion Disorders.
    Ye Teng, Ming Zhu, Zhidong Qiu.
      The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and structures have been confirmed in the past two decades. G-rich repeat sequences, such as CGG and GGGGCC, are reported to form functional G-quadruplexes, participating in many important bioprocesses. In this review, we conducted an overview concerning the contribution of G-quadruplex in repeat expansion disorders and summarized related mechanisms in current pathological studies, including the increasing genetic instabilities in replication and transcription, the toxic RNA foci formed in neurons, and the loss/gain function of proteins and peptides. Furthermore, novel strategies targeting G-quadruplex repeats were developed based on the understanding of disease mechanism. Small molecules and proteins binding to G-quadruplex in repeat expansions were investigated to protect neurons from dysfunction and delay the progression of neurodegeneration. In addition, the effects of environment on the stability of G-quadruplex were discussed, which might be critical factors in the pathological study of repeat expansion disorders.
    Keywords:  G-quadruplex; RNA foci; neurodegeneration; repeat expansion disorder
    DOI:  https://doi.org/10.3390/ijms24032375
  10. Nucleic Acids Res. 2023 Feb 06. pii: gkad007. [Epub ahead of print]
    The tRNA identity landscape for aminoacylation and beyond.
    Richard Giegé, Gilbert Eriani.
      tRNAs are key partners in ribosome-dependent protein synthesis. This process is highly dependent on the fidelity of tRNA aminoacylation by aminoacyl-tRNA synthetases and relies primarily on sets of identities within tRNA molecules composed of determinants and antideterminants preventing mischarging by non-cognate synthetases. Such identity sets were discovered in the tRNAs of a few model organisms, and their properties were generalized as universal identity rules. Since then, the panel of identity elements governing the accuracy of tRNA aminoacylation has expanded considerably, but the increasing number of reported functional idiosyncrasies has led to some confusion. In parallel, the description of other processes involving tRNAs, often well beyond aminoacylation, has progressed considerably, greatly expanding their interactome and uncovering multiple novel identities on the same tRNA molecule. This review highlights key findings on the mechanistics and evolution of tRNA and tRNA-like identities. In addition, new methods and their results for searching sets of multiple identities on a single tRNA are discussed. Taken together, this knowledge shows that a comprehensive understanding of the functional role of individual and collective nucleotide identity sets in tRNA molecules is needed for medical, biotechnological and other applications.
    DOI:  https://doi.org/10.1093/nar/gkad007
  11. J Cell Sci. 2023 Feb 08. pii: jcs.260528. [Epub ahead of print]
    RNA localization to the mitotic spindle is essential for early development and is regulated by kinesin-1 and dynein.
    Carolyn M Remsburg, Kalin D Konrad, Jia L Song.
      Mitosis is a fundamental and highly regulated process that acts to faithfully segregate chromosomes into two identical daughter cells. Transcript localization of genes involved in mitosis to the mitotic spindle may be an evolutionarily conserved mechanism to ensure that mitosis occurs in a timely manner. We identified many RNA transcripts that encode proteins involved in mitosis localized at the mitotic spindles in dividing sea urchin embryos and mammalian cells. Disruption of microtubule polymerization, kinesin-1, or dynein results in lack of spindle localization of these transcripts in the sea urchin embryo. Further, results indicate that the cytoplasmic polyadenylation element (CPE) within the 3'UTR of Aurora B, a recognition sequence of CPEB, is essential for RNA localization to the mitotic spindle. Blocking this sequence results in arrested development during early cleavage stages, suggesting that RNA localization to the mitotic spindle may be a regulatory mechanism of cell division that is important for early development.
    Keywords:  Dynein; Embryonic development; Kinesin-1; Mitosis; RNA localization
    DOI:  https://doi.org/10.1242/jcs.260528
  12. Int J Mol Sci. 2023 Jan 17. pii: 1828. [Epub ahead of print]24(3):
    Long Noncoding RNAs and Cancer Stem Cells: Dangerous Liaisons Managing Cancer.
    Silvia Anna Ciafrè, Monia Russo, Alessandro Michienzi, Silvia Galardi.
      Decades of research have investigated the mechanisms that lead to the origin of cancer, striving to identify tumor-initiating cells. These cells, also known as cancer stem cells, are characterized by the ability to self-renew, to give rise to differentiated tumor populations, and on a larger scale, are deemed responsible not only for tumor initiation but also for recurrent tumors, often resistant to chemotherapy and radiotherapy. Long noncoding RNAs are RNA molecules longer than 200 nt, lacking the ability to code for proteins, with recognized roles as fine regulators of gene expression. They can exert these functions through a variety of mechanisms, acting at almost all steps of gene expression, from modulation of the epigenetic state of chromatin to modulation of protein stability. In all cases, lncRNAs do not work alone, but they always interact with other RNA molecules, either coding or non-coding, or with protein factors. In this review, we summarize the latest results obtained about the involvement of lncRNAs in the initiating cells of several types of tumors, and highlight the different mechanisms through which they work, while discussing how the modulation of a lncRNA can affect several aspects of tumor onset and progression.
    Keywords:  RNA-binding protein; cancer stem cells; ceRNAs; epigenetic regulation; lncRNAs
    DOI:  https://doi.org/10.3390/ijms24031828
  13. Int J Mol Sci. 2023 Jan 23. pii: 2247. [Epub ahead of print]24(3):
    The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration.
    Irene Faravelli, Giulietta M Riboldi, Paola Rinchetti, Francesco Lotti.
      In the cell, RNA exists and functions in a complex with RNA binding proteins (RBPs) that regulate each step of the RNA life cycle from transcription to degradation. Central to this regulation is the role of several molecular chaperones that ensure the correct interactions between RNA and proteins, while aiding the biogenesis of large RNA-protein complexes (ribonucleoproteins or RNPs). Accurate formation of RNPs is fundamentally important to cellular development and function, and its impairment often leads to disease. The survival motor neuron (SMN) protein exemplifies this biological paradigm. SMN is part of a multi-protein complex essential for the biogenesis of various RNPs that function in RNA metabolism. Mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy (SMA). A fundamental question in SMA biology is how selective motor system dysfunction results from reduced levels of the ubiquitously expressed SMN protein. Recent clarification of the central role of the SMN complex in RNA metabolism and a thorough characterization of animal models of SMA have significantly advanced our knowledge of the molecular basis of the disease. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP biogenesis. We discuss developments in our understanding of SMN activity as a molecular chaperone of RNPs and how disruption of SMN-dependent RNA pathways can contribute to the SMA phenotype.
    Keywords:  RNA metabolism; SMN complex; mRNA splicing; neurodegeneration; spinal muscular atrophy; survival motor neuron
    DOI:  https://doi.org/10.3390/ijms24032247
  14. Biomed Pharmacother. 2023 Feb 06. pii: S0753-3322(23)00149-X. [Epub ahead of print]160 114361
    Regulation of NcRNA-protein binding in diabetic foot.
    Yujia Zhang, Jing Zhang, Zhou Xu, Deju Zhang, Panpan Xia, Jitao Ling, Xiaoyi Tang, Xiao Liu, Rui Xuan, Meiying Zhang, Jianping Liu, Peng Yu.
      Non-coding RNA (ncRNA) is a special type of RNA transcript that makes up more than 90 % of the human genome. Although ncRNA typically does not encode proteins, it indirectly controls a wide range of biological processes, including cellular metabolism, development, proliferation, transcription, and post-transcriptional modification. NcRNAs include small interfering RNA (siRNA), PIWI-interacting RNA (piRNA), tRNA-derived small RNA (tsRNA), etc. The most researched of these are miRNA, lncRNA, and circRNA, which are crucial regulators in the onset of diabetes and the development of associated consequences. The ncRNAs indicated above are linked to numerous diabetes problems by binding proteins, including diabetic foot (DF), diabetic nephropathy, diabetic cardiomyopathy, and diabetic peripheral neuropathy. According to recent studies, Mir-146a can control the AKAP12 axis to promote the proliferation and migration of diabetic foot ulcer (DFU) cells, while lncRNA GAS5 can activate HIF1A/VEGF pathway by binding to TAF15 to promote DFU wound healing. However, there are still many unanswered questions about the mechanism of action of ncRNAs. In this study, we explored the mechanism and new progress of ncRNA-protein binding in DF, which can provide help and guidance for the application of ncRNA in the early diagnosis and potential targeted intervention of DFU.
    Keywords:  diabetic foot; diabetic foot ulcer; micro RNA; non-coding RNA
    DOI:  https://doi.org/10.1016/j.biopha.2023.114361
  15. Adv Mater. 2023 Feb 04. e2211274
    Dynamic and Reversible Decoration of DNA-Based Scaffolds.
    Nada Farag, Milan Đorđević, Erica Del Grosso, Francesco Ricci.
      We demonstrate here an approach to achieve dynamic and reversible decoration of DNA-based scaffolds. To do this, we employ rationally engineered DNA tiles containing enzyme-responsive strands covalently conjugated to different molecular labels. These strands are designed to be recognized and degraded by specific enzymes (i.e., Ribonuclease H, RNase H or Uracil DNA Glycosylase, UDG) inducing their spontaneous de-hybridization from the assembled tile and replacement by a new strand conjugated to a different label. Multiple enzyme-responsive strands that specifically respond to different enzymes allow for dynamic, orthogonal, and reversible decoration of the DNA structures. As a proof-of-principle of our strategy, we demonstrate the possibility to orthogonally control the distribution of different labels (i.e., fluorophores and small molecules) on the same scaffold without crosstalk. By doing so we obtain DNA scaffolds that display different antibodies recognition patterns. Our approach offers the possibility to control the decoration of higher-order supramolecular assemblies (including origami) with several functional moieties to achieve functional biomaterials with improved adaptability, precision, and sensing capabilities. This article is protected by copyright. All rights reserved.
    Keywords:  DNA nanotechnology; DNA tiles; decoration; functionalization; self-assembly
    DOI:  https://doi.org/10.1002/adma.202211274
  16. Behav Neurol. 2023 ;2023 4190849
    Long Non-coding RNA KTN1-AS1 Targets miR-505 to Promote Glioblastoma Progression.
    Kai Guo, Lingling Fang, Mingjian Li, Aizheng Li, Na Liu.
      Glioblastoma (GBM) is a highly malignant cancer, the prognosis of which is pretty poor. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs, which play important roles in carcinogenesis process of many cancers including GBM. In this study, we want to clarify the expression, biological function, and molecular mechanism of lncRNA KTN1 antisense RNA 1 (KTN1-AS1) in GBM tumor progression. We found that KTN1-AS1 expression was upregulated in GBM tissues and cell lines. KTN1-AS1 played oncogenic roles to facilitate proliferation, migration, and invasion of GBM cells. Then, we revealed that miR-505 was a target of KTN1-AS1, and its expression was decreased in GBM. KTN1-AS1 contributed to GBM progression by mediating miR-505. Finally, we demonstrated that KTN1-AS1 upregulated some target oncogenes of miR-505 including ZEB2, HMGB1, and RUNX2 in GBM cells. All in all, we concluded that the highly expressed KTN1-AS1 in GBM played oncogenic roles to facilitate GBM progression by targeting miR-505.
    DOI:  https://doi.org/10.1155/2023/4190849
  17. Int J Mol Sci. 2023 Jan 30. pii: 2636. [Epub ahead of print]24(3):
    Non-Coding RNAs Regulating Mitochondrial Functions and the Oxidative Stress Response as Putative Targets against Age-Related Macular Degeneration (AMD).
    Juha M T Hyttinen, Janusz Blasiak, Kai Kaarniranta.
      Age-related macular degeneration (AMD) is an ever-increasing, insidious disease which reduces the quality of life of millions of elderly people around the world. AMD is characterised by damage to the retinal pigment epithelium (RPE) in the macula region of the retina. The origins of this multi-factorial disease are complex and still not fully understood. Oxidative stress and mitochondrial imbalance in the RPE are believed to be important factors in the development of AMD. In this review, the regulation of the mitochondrial function and antioxidant stress response by non-coding RNAs (ncRNAs), newly emerged epigenetic factors, is discussed. These molecules include microRNAs, long non-coding RNAs, and circular non-coding RNAs. They act mainly as mRNA suppressors, controllers of other ncRNAs, or by interacting with proteins. We include here examples of these RNA molecules which affect various mitochondrial processes and antioxidant signaling of the cell. As a future prospect, the possibility to manipulate these ncRNAs to strengthen mitochondrial and antioxidant response functions is discussed. Non-coding RNAs could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, either by suppressing or increasing their expression. In addition to AMD, it is possible that non-coding RNAs could be regulators in other oxidative stress-related degenerative diseases.
    Keywords:  age-related macular degeneration; epigenetic therapy; mitochondria; non-coding RNA; oxidative stress
    DOI:  https://doi.org/10.3390/ijms24032636
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