bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–02–15
thirteen papers selected by
Hana Antonicka, McGill University
  1. Structural basis of TACO1-mediated efficient mitochondrial translation.
  2. Hidden in plain sight: illuminating the tRNA landscape by sequencing.
  3. Mechanisms and disease relevance of mitochondrial translation in humans.
  4. Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.
  5. Advanced deep learning strategies in nanopore RNA sequencing.
  6. Illuminating Mitochondrial RNA G-Quadruplexes as Structural Brakes on RNA Granule Assembly and OXPHOS.
  7. RMzyme: regulations of RNA-modifying enzymes in humans.
  8. Protocol for rapid tRNA enrichment and chemiluminescent northern blot detection of tRNA and tRNA-derived fragments.
  9. Ab initio prediction of RNA structure ensembles with RNAnneal.
  10. RBPscan: A quantitative in vivo tool for profiling RNA-binding protein interactions.
  11. A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
  12. Cognate amino acid therapies provide preclinical benefit in 19 C. elegans models of ARS2 deficiency.
  13. Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.
  1. Nat Commun. 2026 Feb 09.
    Structural basis of TACO1-mediated efficient mitochondrial translation.
    Shuhui Wang, Michele Brischigliaro, Yuekang Zhang, Chunxiang Wu, Wei Zheng, Antoni Barrientos, Yong Xiong.
      Translation elongation is a universally conserved step in protein synthesis, relying on elongation factors that engage the ribosomal L7/L12 stalk to mediate aminoacyl-tRNA delivery, accommodation, and ribosomal translocation. Using in organello cryo-electron microscopy, we reveal how the mitochondrial translation accelerator TACO1 promotes efficient elongation on human mitoribosomes. TACO1 binds the mitoribosomal region typically bound by elongation factor Tu (mtEF-Tu), bridging the large and small subunits via contacts with 16S rRNA, bL12m, A-site tRNA, and uS12m. While active throughout elongation, TACO1 is especially critical when translating polyproline motifs. Its absence prolongs mtEF-Tu residence in A/T states, causes persistent mitoribosomal stalling and premature subunit dissociation. Structural analyses indicate that TACO1 competes with mtEF-Tu for mitoribosome binding, stabilizes A-site tRNA, and enhances peptidyl transfer through a mechanism distinct from EF-P and eIF5A. These findings suggest that bacterial TACO1 orthologs may serve analogous roles, highlighting an evolutionarily conserved strategy for maintaining elongation efficiency during challenging translation events.
    DOI:  https://doi.org/10.1038/s41467-026-69156-y
  2. Genome Biol. 2026 Feb 13.
    Hidden in plain sight: illuminating the tRNA landscape by sequencing.
    Katherine Marlow, Zhangli Su.
      Transfer RNAs (tRNAs) are essential for decoding mRNAs into proteins and are increasingly recognized as dynamic regulators of gene expression. Their function is shaped by intricate layers of post-transcriptional processing, modification, aminoacylation, and fragmentation, all of which have been implicated in human disease. Recent advances in high-throughput sequencing have transformed our ability to profile tRNAs and their associated modifications, uncovering their roles in cancer, neuronal function, immune response, and stress response. In this review, we summarize emerging tRNA sequencing technologies and highlight how these approaches reveal fundamental insights into tRNA regulation and its therapeutic potential.
    Keywords:  Genomics; Nanopore; RNA modification; TRNA; TRNA-derived fragments; Translation
    DOI:  https://doi.org/10.1186/s13059-026-03995-2
  3. Nat Rev Mol Cell Biol. 2026 Feb 13.
    Mechanisms and disease relevance of mitochondrial translation in humans.
    Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.
      Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41580-026-00948-2
  4. RNA. 2026 Feb 08. pii: rna.080883.125. [Epub ahead of print]
    Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.
    Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Translation elongation defects cause ribosome stalling and activate the integrated stress response (ISR). During the ISR, translation initiation suppression and ribosome runoff drive mRNA condensation into stress granules. However, the effects of partial translation elongation inhibition on stress granules are poorly defined. We demonstrate that intermediate levels of tRNA synthetase inhibitors activate the ISR and cause assembly of stress granules in a parabolic dose-response pattern. These stress granules are limited in size and number due to ribosome association with mRNAs. Assembly of stress granules by intermediate levels of the prolyl-tRNA synthetase inhibitor halofuginone requires the canonical stress granule scaffolding proteins G3BP1/2 and GCN2-mediated ISR activation. We performed a candidate-based comparative analysis of the composition of stress granules induced by intermediate levels of halofuginone or canonical stressors arsenite or thapsigargin. The stress granules induced by halofuginone, arsenite, or thapsigargin harbor polyadenylated RNA and the canonical stress granule proteins PABPC1, G3BP1, and UBAP2L. We observe stress- and transcript- specific differences in the localization of candidate RNA molecules to stress granules. These results demonstrate that partial translation elongation inhibition permits stress granule assembly through the balance of ISR activation and mRNA association with ribosomes, with implications for the stress response associated with amino acid or tRNA deficiency, therapeutic tRNA synthetase inhibition, or diseases associated with tRNA synthetase mutations.
    Keywords:  integrated stress response; stress granules; tRNA synthetase; translation; translation elongation
    DOI:  https://doi.org/10.1261/rna.080883.125
  5. RNA Biol. 2026 Feb 09.
    Advanced deep learning strategies in nanopore RNA sequencing.
    Crystal Ling, Benjamin Lebeau, Kwoh Chee Keong, Melissa Fullwood.
      The epitranscriptome comprises chemical modifications found on RNA molecules that play essential roles in co- and post-transcriptional gene regulation. Dysregulation of these modifications has been implicated in various diseases, fuelling interest in evaluating them as emerging biomarkers and therapeutic targets. Nanopore direct RNA sequencing provides a powerful platform for profiling diverse RNA modifications at single-molecule resolution, but the complexity of the signals requires advanced computational approaches for interpretation. Artificial intelligence, particularly deep learning (DL), has become central to this effort. While classical DL architectures such as convolutional and recurrent neural networks have been widely applied, more recent approaches employ specialized learning frameworks and ensemble strategies to address challenges of data scarcity, noise, and biological variability while providing higher resolution output. In this review, we summarize these developments and highlight future multidisciplinary opportunities at the intersection of artificial intelligence and biology for characterizing the epitranscriptome obtained with direct RNA nanopore sequencing.
    Keywords:  Deep learning; Epitranscriptome; RNA modifications; direct RNA sequencing; nanopore sequencing
    DOI:  https://doi.org/10.1080/15476286.2026.2627968
  6. Adv Sci (Weinh). 2026 Feb 12. e23462
    Illuminating Mitochondrial RNA G-Quadruplexes as Structural Brakes on RNA Granule Assembly and OXPHOS.
    Gui-Xue Tang, Jia-Tong Yan, Mao-Lin Li, Cui Zhou, Jian Wang, Shuo-Bin Chen, Zhi-Shu Huang, Jia-Heng Tan.
      G-quadruplexes (G4s) have been extensively investigated in cells, with established methods available for studying nuclear DNA G4s, cytoplasmic RNA G4s, and even mitochondrial DNA G4s. However, mitochondrial RNA (mtRNA) G4s have remained largely unexplored in cells due to the lack of suitable tools, leaving their biological functions poorly understood. Here, through rational molecular design, we developed MitoQUMA, a fluorescent probe that allows the visualization of mtRNA G4 dynamics in live cells. Using this probe, we observed that, unlike cytoplasmic RNA G4s, which generally promote phase separation to form RNA granules, excessive formation of mtRNA G4s correlates with reduced assembly of mitochondrial RNA granules (MRGs). A MitoQUMA-based chemical genetic screen revealed that the Wnt/β-catenin pathway regulates this mitochondrial event by modulating GRSF1 expression, thereby affecting mtRNA G4 abundance and processing. When RNA processing is compromised, mtRNA maturation is impaired, and MRG becomes unstable and undergoes disassembly, ultimately disrupting mitochondrial gene expression and energy metabolism. Collectively, our study introduces a tool for real-time monitoring of mtRNA G4s in cells and identifies the Wnt/β-catenin-GRSF1-mtRNA G4 axis as a previously unrecognized pathway coordinating MRG assembly and energy metabolism, providing new insights into phase separation within mitochondria.
    Keywords:  GRSF1; Wnt/β‐catenin pathway; mitochondrial RNA G‐quadruplex; mitochondrial RNA granule; molecular probe
    DOI:  https://doi.org/10.1002/advs.202523462
  7. Signal Transduct Target Ther. 2026 Feb 12. 11(1): 52
    RMzyme: regulations of RNA-modifying enzymes in humans.
    Ruihan Luo, Haixia Xu, Qingbo Zhou, Shanli Ding, Min Qiang, Jianguo Wen, Pora Kim, Xiaojuan Yang, Yunshi Cai, Kunlin Xie, Jiang Zhu, Yungang Xu, Tian Lan, Xiaobo Zhou, Hong Wu.
      RNA modifications represent a dynamic layer of gene expression regulation, RNA stability, and translation with profound implications for cellular function and disease. However, the critical regulation and functions of RNA-modifying proteins (RMPs) remain poorly understood. Here, we present a large-scale characterization of RMPs through 378 multiomics datasets encompassing genomics, bulk and single-cell transcriptomics, epitranscriptomics, proteomics, and posttranslational modifications (PTMs) across 63 human tissues. Our analysis of experimental perturbations of RMPs revealed dynamic differential modification peaks and expressed genes. We applied nonnegative matrix factorization to annotate RMP-mediated cell types in single-cell transcriptomes. Functional annotations in acute myeloid leukemia (AML) revealed RMPs such as ALKBH5 as critical mediators of m6A dynamics, influencing pathways involved in translation initiation, immune regulation, and tumorigenesis. We revealed cell type-specific modification patterns, including those in ALKBH5-enriched AML stem cells with special ligand‒receptor interactions and genetic variations modulated by m6A. We integrated proteogenomic data to uncover PTM-associated regulatory, mutation, and protein‒protein interaction networks linked to RMPs. We developed RMzyme, a platform that consolidates our findings and provides insights into RMPs and their downstream effects. This resource is expected to facilitate biomedical research into the molecular mechanisms of human diseases through the lens of RNA modifications and multiomics data integration.
    DOI:  https://doi.org/10.1038/s41392-025-02568-2
  8. STAR Protoc. 2026 Feb 06. pii: S2666-1667(26)00010-9. [Epub ahead of print]7(1): 104357
    Protocol for rapid tRNA enrichment and chemiluminescent northern blot detection of tRNA and tRNA-derived fragments.
    Pavlina Gregorova, Minna-Maria K Heinonen, Milla M Laarne, L Peter Sarin.
      Transfer RNA (tRNA), its post-transcriptional modifications, and tRNA-derived fragments (tRFs) play essential roles in cellular processes and gene regulation. Here, we present a fast and efficient tRNA enrichment protocol using silica spin columns. To analyze tRNA and tRFs, we describe steps for DNA probe labeling, tRNA separation on polyacrylamide (PAA) gels, and RNA transfer, UV crosslinking, and non-radioactive northern blotting. Additionally, this protocol describes the use of chemical affinity modifiers, enabling the detection of chemical modifications in specific tRNA isoacceptors.
    Keywords:  Cell Biology; Molecular Biology; Molecular/Chemical Probes
    DOI:  https://doi.org/10.1016/j.xpro.2026.104357
  9. bioRxiv. 2026 Feb 01. pii: 2026.02.01.703098. [Epub ahead of print]
    Ab initio prediction of RNA structure ensembles with RNAnneal.
    Lukas Herron, Yunrui Qiu, Anjali Verma, Venkata Sai Sreyas Adury, Richard John, Suemin Lee, Shams Mehdi, Disha Sanwal, John S Schneekloth, Pratyush Tiwary.
      RNA utilizes three-dimensional structure in addition to sequence to carry out diverse functions in gene expression and disease. Much like well-folded proteins, RNAs adopt specific three-dimensional structures to carry out their function. Yet comparatively few RNA structures have been solved by atomic resolution structural techniques, in part because unlike structured proteins, RNAs fold into heterogeneous ensembles of interconverting structures that pose a challenge for high-resolution structure probing methods. In this work, we introduce RNAnneal as a method for RNA structural ensemble prediction that seamlessly integrates generative deep learning with statistical physics and molecular dynamics modeling. Given the primary sequence, RNAnneal uses ab inito (i.e., first principles) modeling to sample an ensemble of 3D structures, which, in turn, are used to train an ensemble of unsupervised deep learning models. The RNAnneal score, representing the consensus of the deep learning models, is then used to evaluate the 3D structures. We evaluated RNAnneal structures against 16 experimentally-resolved conformations (ERCs) of riboswitch RNAs and found that pseudoknot-free (PK-free) ERCs were well-reproduced by RNAnneal, with clear avenues for improving performance even on PK-comprising structures. Furthermore, we found that the RNAnneal score outperforms the Rosetta score and a state-of-the-art RNA forcefield on the task of classifying ERCs from decoys. We then introduce the interaction entropy as a measure of conformational heterogeneity within an ensemble and use it to assess our predictions. RNAnneal thus provides a generalizable framework for predicting RNA structural ensembles that will accelerate RNA-targeted drug discovery and the design of functional RNA molecules.
    DOI:  https://doi.org/10.64898/2026.02.01.703098
  10. Mol Cell. 2026 Feb 06. pii: S1097-2765(26)00023-7. [Epub ahead of print]
    RBPscan: A quantitative in vivo tool for profiling RNA-binding protein interactions.
    Dmitry A Kretov, Owen Sanborn, Thora McIsaac, Elaine Park, Imrat Imrat, Samuel Wu, Marianne Régis, Louis-Mathieu Harvey, Daniel Cifuentes.
      RNA-binding proteins (RBPs) are essential regulators of gene expression at the post-transcriptional level, yet obtaining quantitative insights into RBP-RNA interactions in vivo remains challenging. Here, we developed RBP specificity and contextual analysis via nucleotide editing (RBPscan), which integrates RNA editing with massively parallel reporter assays to profile RBP binding in vivo. In RBPscan, fusion of an RBP to the adenosine deaminase acting on RNA (ADAR) catalytic domain induces RNA editing of a recorder mRNA carrying the tested RBP-binding site, serving as a readout of the RBP-RNA interaction. We demonstrate the utility of RBPscan in zebrafish embryos, human cells, and yeast, showing that it quantifies binding strength, resolves dissociation constants, identifies binding motifs for various RBPs, and links binding affinities to their impact on mRNA stability. RBPscan also provides positional mapping of Pumilio-binding sites in the long non-coding RNA NORAD. With its simplicity, scalability, and cross-system compatibility, RBPscan is a versatile tool for investigating protein-RNA interactions and complements established methods for studying post-transcriptional regulatory networks.
    Keywords:  ADAR; RBP-binding specificity; RBPs; RNA editing; RNA motif discovery; RNA-binding proteins; adenosine deaminase acting on RNA; dose-response analysis; massively parallel reporter assays; microRNAs; protein-RNA interactions
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.003
  11. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00036-7. [Epub ahead of print]45(2): 116958
    A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
    Ying Wang, Xinwan Su, Yu Chen, Yijian Chen, Chengyu Shi, Fangzhou Liu, Yuqi Ye, Panyi Sun, Manman Tan, Meng Yu, Ya Wang, Shanshan Xie, Jian Liu, Qingfeng Yan, Qiming Sun, Dante Neculai, Wei Liu, Jianzhong Shao, Yang Liu, Weiqiang Lin, Aifu Lin.
      Mitochondrial genetic diseases arise from mitochondrial DNA (mtDNA) defects, which gene therapy tools may rectify. However, delivering single-guide RNAs (sgRNAs) into mitochondria remains a challenge limiting CRISPR-mediated mtDNA therapy. Here, through network analysis of mitochondrion-localized long noncoding RNAs (lncRNAs) and RNA-binding proteins (RBPs), we found that lncRNA RP11-46H11.3 translocates into mitochondria via binding mitochondria-associated RBPs using its key RNA recognition motifs (RRMs); its derived 30 nt ST2-RNA mitochondrial targeting sequence (RMTS) showed the highest mitochondrial localization efficiency. We engineered the RMTS-CRISPR tool by fusing ST2-RMTS to sgRNA, verifying its ability to target and cleave mtDNA. Strikingly, our results demonstrated that RMTS-CRISPR could achieve heteroplasmic mtDNA shifting efficiencies of up to 26.37% in m.3243A>G mutant cell models and 26.79% in vivo, offering a technological approach for the correction of heterogeneous mtDNA mutations. Taken together, our findings reveal a CRISPR-based mitochondrial gene intervention strategy that may have applications in mitochondrial disorders.
    Keywords:  CP: genomics; CRISPR-Cas system; RNA recognition motif; mitochondrial DNA; mitochondrial disorder; organelle-associated RNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.116958
  12. bioRxiv. 2026 Feb 05. pii: 2026.02.03.703549. [Epub ahead of print]
    Cognate amino acid therapies provide preclinical benefit in 19 C. elegans models of ARS2 deficiency.
    Cristina Remes, Kelsey Keith, Rui Xiao, Vernon E Anderson, Donna M Iadarola, Eiko Nakamaru-Ogiso, Neal D Mathew, Marni J Falk.
      Mitochondrial aminoacyl-tRNA synthetases (mt-ARS) are essential mitochondrial translation machinery components that catalyze mitochondrial transfer RNAs (tRNAs) charging with their cognate amino acid. Although mt-ARS have a common biochemical function, patients with mt-ARS pathogenic variants commonly develop neurological disorders with varying phenotypes, severity spectrum, and age of onset. Cognate amino acid supplementation has shown reported benefits in select cases of both mt-ARS ( ARS2 ) and cytosolic ( ARS1 ) deficiencies, although the safety and potential benefits of this candidate therapy approach across the full spectrum of mt-ARS disorders remain unclear. Here, C. elegans models were systematically generated for all 19 mitochondrial mt-ARS genes by feeding RNAi knockdown for one or two generations. mt-ARS deficient animals at baseline and upon cognate amino acid treatment were studied at the level of linear growth, neuromuscular activity, lifespan, mitochondrial physiology, and fertility. Results demonstrated that cognate amino acid treatment in a dose-dependent fashion consistently improved worm linear growth and neuromuscular activity, and reduced mitochondrial unfolded protein response stress, in all 19 knockdown models. It further rescued impaired fertility of hars-1 and fars-2 knockdown strains. Collectively, these preclinical studies provide compelling evidence to warrant future cognate amino acid treatment study in rigorous clinical trials spanning all human mt-ARS deficiencies.
    DOI:  https://doi.org/10.64898/2026.02.03.703549
  13. bioRxiv. 2026 Feb 04. pii: 2026.02.02.703345. [Epub ahead of print]
    Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.
    Rachel L Doser, Thomas J LaRocca.
      Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation.
    Abstract Figure:
    DOI:  https://doi.org/10.64898/2026.02.02.703345
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