bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–05–31
twelve papers selected by
Hana Antonicka, McGill University
  1. Nanopore Sequencing Reveals rRNA Modification Changes in Human Cells Experiencing Oxidative or Inflammatory Stress.
  2. Mitochondrial ribosomal protein MRPL27 supports glioma malignancy through regulation of oxidative phosphorylation.
  3. Mitochondrial translocation of immunostimulatory RNA RN7SL1 suppresses innate immune responses.
  4. CSDE1 Associates with TOM20 and Mitochondrial Protein-Encoding mRNAs in Sensory Neurons.
  5. Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
  6. The Evolution of the First Code.
  7. Substrate selectivity of the human RNA m5C methyltransferase NSUN2.
  8. Unsupervised Reference Modeling of Nanopore Signals for DNA/RNA Modification Detection.
  9. Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.
  10. dsRADAR: Imaging and Quantifying Cellular dsRNA by Repurposing RNA Binding Proteins.
  11. An encyclopedic regulatory and functional atlas of RNA interactomes.
  12. Phenylalanyl-tRNA synthetase FARS-1/FARSA balances longevity and immunity by downregulating endogenous mitochondrial double-stranded RNAs.
  1. ACS Chem Biol. 2026 May 27.
    Nanopore Sequencing Reveals rRNA Modification Changes in Human Cells Experiencing Oxidative or Inflammatory Stress.
    Aaron M Fleming, Cynthia J Burrows.
      Ribosomal RNA (rRNA) modifications are tuned to regulate protein synthesis; however, their temporal dynamics during oxidative or inflammatory stress remain poorly understood. Nanopore direct RNA sequencing using Dorado v5.2.0 modification-aware models for the data analysis was employed to map human rRNA epitranscriptomic marks in a cell line undergoing oxidative stress, inflammatory stress, or ferroptosis. Oxidative stress triggered a global trend of decreased modification occupancy in which six modifications shifted significantly over 48 h, particularly, 18S Ψ573 and 18S m6A1832. Conversely, inflammatory stress induced a complex response involving an acute pulse of hypermodifications at 28S Um1773 and 28S Ψ1779, for example, and chronic hypomodification at specific target sites (e.g., 18S Gm1328 and 28S Gm4228). In this work, the pseudouridine modifications 28S Ψ4296 and 28S Ψ4353 were identified as "universal stress markers" that decreased under all stressors studied, including ferroptosis. Mapping these changes onto the ribosome structure revealed that they reside in functional regions such as the decoding center and A-site finger, supporting a role in functional ribosome reprogramming during stress. Analysis of mitochondrial rRNA (mt-rRNA) revealed modification shifts within the peptidyl transferase center, suggesting a mechanism to attenuate mitochondrial translation during chronic stress. This work demonstrates that oxidative and inflammatory stress drive distinct, time-resolved remodeling of the human rRNA epitranscriptome and provides a framework for using rRNA modifications as biomarkers of cellular health during oxidative or inflammatory stress exposure.
    DOI:  https://doi.org/10.1021/acschembio.6c00154
  2. Cell Mol Life Sci. 2026 May 25.
    Mitochondrial ribosomal protein MRPL27 supports glioma malignancy through regulation of oxidative phosphorylation.
    Jingyao Gu, Boya Zhou, Lin Ji, Haoyang Yuan, Haibo Ji, Mingxiao Zhu, Chunyan He, Xueping Gu, Suji Yan, Yin Wang.
      Glioma is a highly invasive primary brain tumor with a poor prognosis and currently lacks effective treatment methods. Increasing evidence indicates that mitochondrial oxidative phosphorylation (OXPHOS) is crucial for the development of glioma; however, the regulatory mechanisms controlling mitochondrial protein synthesis and energy metabolism are not yet fully understood. Analysis of the TCGA and CGGA databases reveals that MRPL27 is highly expressed in glioma tissues and is significantly associated with poor patient survival. Silencing MRPL27 significantly inhibits the proliferation, migration, and tumor growth of glioma cells, while inducing cell apoptosis. Mechanistically, the absence of MRPL27 impairs the mitochondrial oxidative phosphorylation process, reduces ATP production, disrupts redox balance, and increases oxidative stress. Notably, MRPL27 deficiency specifically reduces the protein content of mitochondrial-encoded oxidative phosphorylation components without altering their transcriptional levels, indicating its role in post-transcriptional regulation of mitochondrial protein expression. In summary, these findings suggest that MRPL27 is a key regulator of mitochondrial translation and energy metabolism in glioma, and emphasize the significance of mitochondrial ribosome regulation as a potential metabolic weakness for therapeutic intervention.
    Keywords:  Glioma progression; MRPL27; Mitochondrial translation; Oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s00018-026-06236-8
  3. Acta Biochim Biophys Sin (Shanghai). 2026 May 19. xx(xx): xx
    Mitochondrial translocation of immunostimulatory RNA RN7SL1 suppresses innate immune responses.
    Yuxin Liang, Lina Wang, Gege Qin, Xiaolong Liu, Hongwei Yang, Zhen Zhang, Jinghe Yuan, Wei Zhou, Xiaohong Fang.
      The significance of mitochondria in innate immunity is increasingly recognized. Mitochondrial immunostimulatory nucleic acids released into the cytosol can trigger an innate immune response. However, the possibility of translocating immunostimulatory nucleic acids from the cytosol to the mitochondria remains unexplored. In this study, we demonstrate that the nuclear-encoded immunostimulatory RNA RN7SL1 could be translocated into the mitochondria from the cytosol. Once inside the mitochondria, RN7SL1 is shielded by mitochondrial membranes, which prevents its recognition by cytosolic dsRNA sensors. The RNA-binding protein LRPPRC interacts with RN7SL1 directly and regulates its translocation. Inhibition of LRPPRC impairs this translocation, reduces RN7SL1 abundance in mitochondria, and activates the RIG-I-dependent innate immune response. Furthermore, in clinical human lung cancer specimens, elevated RN7SL1 expression is associated with a more pronounced negative correlation between the immune response and LRPPRC expression. These findings reveal a novel mitochondrial function in suppressing the immune response induced by immunostimulatory RNA.
    Keywords:  RNA transport; dsRNA; innate immunity; mitochondrion
    DOI:  https://doi.org/10.3724/abbs.2026079
  4. Antioxidants (Basel). 2026 May 11. pii: 608. [Epub ahead of print]15(5):
    CSDE1 Associates with TOM20 and Mitochondrial Protein-Encoding mRNAs in Sensory Neurons.
    Hoyong Jin, Eunsu Jang, Eunhye Park, Ju Yeon Lee, Ju Hwan Song, Yongcheol Cho.
      Mitochondrial proteostasis in neurons relies on the coordinated expression, targeting, and import of a predominantly nuclear-encoded proteome to meet high metabolic demands. Here, we identify the RNA-binding protein cold shock domain containing E1 (CSDE1) as a TOM20-associated factor linked to mitochondrial protein-encoding mRNAs in sensory neurons. CSDE1 immunoprecipitation followed by sequencing from naïve dorsal root ganglion tissue revealed association with nuclear-encoded mitochondrial mRNAs enriched for inner membrane/matrix and oxidative phosphorylation pathways. A subset of CSDE1 localized to mitochondria and associated with the outer mitochondrial membrane import receptor TOM20 via its N-terminal region in an RNA-independent manner. In cultured sensory neurons, CSDE1 depletion reduced the mitochondrial-fraction abundance of representative nuclear-encoded electron transport chain mRNAs and decreased the abundance of selected mitochondrial proteins in the mitochondrial fraction. CSDE1 depletion reduced TMRM-positive mitochondrial puncta density along sensory neurites, without significantly increasing MitoSOX-detectable mitochondrial superoxide signals under either basal or oxidative challenge conditions. These findings identify CSDE1 as a TOM20-associated RNA-binding protein linked to mitochondrial protein-encoding transcripts in sensory neurons and support a model in which CSDE1 contributes to mitochondria-associated post-transcriptional regulation.
    Keywords:  CSDE1; OXPHOS; RNA-binding proteins; TOM20; mitochondrial mRNA; mitochondrial proteostasis; oxidative stress; protein import; sensory neurons; translation-import coupling
    DOI:  https://doi.org/10.3390/antiox15050608
  5. Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2605194123
    Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
    Djamal Brahim Belhaouari, Anil Pant, Santiago Navarro-Forero, Fernando Cantu, Zhilong Yang.
      Induction of RNA degradation in infected cells is a strategy used by many viruses to promote efficient replication. Vaccinia virus, the prototype poxvirus and the vaccine platform for smallpox and mpox, encodes two decapping enzymes to accelerate mRNA and double-stranded RNA (dsRNA) degradation during infection, through functional coordination with host cell RNA exonuclease. Previous studies have largely focused on RNA degradation as a mechanism for regulating viral gene expression and evading innate immune sensing. Here, we show that impaired RNA degradation in vaccinia virus-infected cells, due to either depletion of viral decapping enzymes or cellular exonuclease, severely compromises mitochondrial respiration and integrity. We further demonstrated that accumulation of excess dsRNA and mRNA, including pseudouridine-modified RNAs, is sufficient to induce profound defects in mitochondrial respiration and integrity. Notably, this impairment occurs independently of interferon induction and dsRNA innate immune sensor Protein Kinase R. Moreover, excess RNA suppresses respiration in purified cell-free mitochondria and physically associates with mitochondria in cell-free and cellular contexts, supporting an immune-independent mechanism. Excess mRNA and dsRNA reduce mitochondrial membrane potential in both cells and purified mitochondria, indicating disruption of the proton gradient as the mechanism underlying impaired mitochondrial respiration and integrity. Together, these findings identify excess mRNA and dsRNA as perturbants of mitochondrial homeostasis in cells with dysfunctional RNA degradation during vaccinia virus infection, revealing a paradigm-shift concept linking RNA metabolism to mitochondrial function. The finding carries broad implications for understanding RNA and mitochondrial biology and RNA-based therapeutics and vaccines.
    Keywords:  RNA degradation; dsRNA; mRNA; mitochondrial respiration; poxvirus
    DOI:  https://doi.org/10.1073/pnas.2605194123
  6. Genes (Basel). 2026 May 02. pii: 544. [Epub ahead of print]17(5):
    The Evolution of the First Code.
    Lei Lei, Savio Torres de Farias, Zachary Frome Burton.
      Background/Objectives: tRNAs, tRNAomes, aminoacyl-tRNA synthetases (AARSs), the first proteins, ribosomes and the genetic code coevolved. We utilize sequence data to reconstruct key steps in establishing the first code on Earth. Methods: Networks were constructed to describe initial tRNAome and AARSome evolution. Results: tRNA-34 wobble and tRNA-37 modifications were necessary to evolve the code, as were additional tRNA modifications, so diverse tRNA modification enzymes (i.e., histidyl-tRNA -1 GTP synthase) are among the first proteins. tRNA-linked chemistry brought asparagine, glutamine, cysteine and possibly additional amino acids into the code. tRNA, tRNA modifications and tRNA-linked chemistry were core founding innovations for code evolution. Coevolution of AARSomes was also essential. Class II and class I AARSs have distinct folds but are nonetheless homologs by sequence. Early AARS enzymes folded around Zn motifs. Networks were generated for tRNAomes and AARSomes in ancient Archaea, because Archaea are the closest living organisms to the last universal common ancestor. Conclusions: The first code on Earth was surprisingly ordered, and the few apparent deviations from the regular order can yet be explained. Early in the evolution of the code, innovation was more strongly selected than accuracy. The code froze, however, because of evolving fidelity mechanisms. A historical record was documented in tRNA and in the genetic code structure and has been preserved in living organism sequences. AARSome structure describes the first code evolution more adequately than tRNAomes.
    Keywords:  abiogenesis; aminoacyl-tRNA synthetase; astrobiology; genetic code; last universal common (cellular) ancestor; network analyses; tRNA; tRNA modifications; tRNA-linked chemistry
    DOI:  https://doi.org/10.3390/genes17050544
  7. Nature. 2026 May 27.
    Substrate selectivity of the human RNA m5C methyltransferase NSUN2.
    Jacob Canepa, Victor M Ruiz-Arroyo, Netanya S Schlamowitz, Yunsun Nam.
      Specific deposition of RNA modifications is important for regulating gene expression1,2. 5-Methylcytosine (m5C) is a common epitranscriptomic modification, and NSUN2 is a key enzyme responsible for m5C methylation of various types of RNA. Dysregulation of NSUN2 is associated with numerous diseases, including cancers and neurological disorders3. The versatility of NSUN2 complicates our understanding of its substrate specificity and molecular roles in biology and disease. Here we show how NSUN2 interacts with RNA substrates at distinct stages of its catalytic cycle to modify cytidines. Furthermore, we show the role of RNA structure in facilitating NSUN2 activity at multiple tRNA positions. We identify RNA duplexes surrounding the m5C modification site as crucial recognition elements for methylation, which enabled us to derive a minimized substrate that captures the preferred features of an NSUN2 substrate-a dual-stem structure containing the CNNRR motif at the 5' end of the first stem. Insights into the mechanisms underlying substrate-specific NSUN2 enzymatic activity provide opportunities for understanding and therapeutically targeting NSUN2-dependent methylation. Overall, our work highlights the roles of RNA structure and sequence in defining substrate specificity and regulating RNA-modifying enzymes.
    DOI:  https://doi.org/10.1038/s41586-026-10582-9
  8. Genes (Basel). 2026 Apr 29. pii: 525. [Epub ahead of print]17(5):
    Unsupervised Reference Modeling of Nanopore Signals for DNA/RNA Modification Detection.
    Yongji Zou, Mian Umair Ahsan, Kai Wang.
       BACKGROUND: Nanopore sequencing produces ionic current signals that are sensitive to chemical modifications in DNA and RNA molecules. However, accurate modification detection remains challenging due to limited labeled data and variability across experimental conditions.
    METHODS: We present a scalable unsupervised framework for modification discovery that learns reference signal distributions from unmodified sequences using a CNN-Transformer variational autoencoder (VAE). The model is trained on large-scale data via streaming sampling and k-mer-aware soft balancing to ensure robust signal representation. At inference, candidate nucleotides are scored using the VAE reconstruction error, and read-level signals are aggregated to produce site-level modification evidence.
    RESULTS: On controlled DNA oligonucleotide datasets, models trained on unmodified sequences achieve strong discrimination when evaluated on modified oligos. In contrast, performance decreases in cell line samples when models trained on unmodified whole-genome-amplified (WGA) DNA and in vitro-transcribed (IVT) RNA are evaluated on natively modified (5mC/m6A) data, reflecting the impacts of biological noise and heterogeneity. Despite reduced classification accuracy, site-level anomaly score profiles exhibit peak-like patterns that correspond to known modification-enriched regions.
    CONCLUSIONS: These findings demonstrate the feasibility of large-scale unsupervised reference modeling for de novo modification detection, while underscoring the challenges in translating models built from synthetic oligo datasets into robust genome-wide modification detection.
    Keywords:  anomaly detection; base modification detection; nanopore sequencing; unsupervised learning; variational autoencoder
    DOI:  https://doi.org/10.3390/genes17050525
  9. Antioxidants (Basel). 2026 May 03. pii: 580. [Epub ahead of print]15(5):
    Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.
    Dong-Bin Back, Gen Hamanaka, Ji-Hyun Park, Shin Ishikane, Masayoshi Tanaka, Takafumi Nakano, Yoshihiko Nakamura, Kazuhide Hayakawa.
      Mitochondrial transplantation has been proposed as a strategy to restore cellular bioenergetics after oxidative injury, but the mechanisms governing ATP recovery remain unclear. Using placental mitochondria, we examined ATP restoration following H2O2-induced oxidative stress. Unmodified mitochondria modestly increased ATP under baseline conditions but failed to restore ATP after injury. In contrast, lipid-coated mitochondria (MitoCoat) and lipid-encapsulated mitochondria-associated mRNAs (MitoCoat-mRNA) significantly increased ATP levels in injured cells. Transcriptomic analyses revealed that ATP recovery occurred without the normalization of canonical glycolytic or oxidative phosphorylation (OXPHOS) gene programs. Instead, unmodified mitochondria induced broad transcriptional responses associated with immune activation and cellular stress, whereas MitoCoat elicited a more restricted transcriptional profile. Notably, mitochondria-associated mRNAs alone restored ATP without detectable changes in host transcriptional programs. The removal of mitochondrial surface-associated ribosomes or the inhibition of cytosolic but not mitochondrial translation attenuated ATP recovery. The restoration of key metabolic enzymes through cytosolic translation, including PFKP, pyruvate dehydrogenase, and ATP synthase subunit ATP5A suggests that mitochondria-associated mRNAs promote recovery by re-establishing coupling between glycolysis and mitochondrial OXPHOS. Together, these findings identify encapsulated mitochondria-associated mRNAs as a potential strategy to restore cellular bioenergetics under oxidative stress.
    Keywords:  MitoCoat; lipid modification; mRNA; mitochondria
    DOI:  https://doi.org/10.3390/antiox15050580
  10. bioRxiv. 2026 May 13. pii: 2026.05.12.724404. [Epub ahead of print]
    dsRADAR: Imaging and Quantifying Cellular dsRNA by Repurposing RNA Binding Proteins.
    Weina Cheng, Tyson D Todd, Harshad Ingle, Angela M Halstead, Megan T Baldridge, José B Sáenz, Jennifer M Heemstra.
      Double-stranded RNA (dsRNA) is recognized by cellular receptors as a sign of viral infection, triggering the innate immune response. Increasing evidence shows that cellular dysregulation, for example in immune disorders and neurodegenerative diseases, can also lead to accumulation of endogenously produced dsRNA that stimulates a viral-like immune response. Additionally, dsRNA contamination in RNA therapeutics can lead to harmful side effects via a similar pathway. Despite the clinical relevance of dsRNA, reliable tools for its detection remain limited. At present, dsRNA detection relies almost exclusively on the monoclonal antibodies J2 and K1, which suffer from sequence bias and low sensitivity, limiting their reliability. To address this challenge, we aimed to repurpose naturally occurring dsRNA-binding domains (dsRBDs) to produce reliable, pan-specific affinity reagents for dsRNA. We first systematically screened the dsRBDs of the three human adenosine deaminases acting on RNA (ADARs). This analysis identified ADAR3 dsRBDs as promising candidates due to their reduced sequence dependence compared to the dsRBDs of ADAR1 and ADAR2. We then engineered ADAR3-derived dsRBD constructs having varying linker lengths and domain combinations, allowing us to specifically vary the length cutoff of dsRNA detected, thus creating dsRNA accumulation detected by ADAR3 RBDs (dsRADAR) affinity reagents. Finally, we demonstrate the superior performance of dsRADAR over currently available dsRNA antibodies in a cell model of viral infection and a tissue model of gastric inflammation. Together, dsRADAR provides a sensitive and reliable approach for imaging and quantifying diverse dsRNA structures in a variety of biological contexts.
    Graphic Abstract:
    DOI:  https://doi.org/10.64898/2026.05.12.724404
  11. Nat Methods. 2026 May 25.
    An encyclopedic regulatory and functional atlas of RNA interactomes.
    Keren Zhou, Junhong Huang, Shurong Liu, Wujian Zheng, Shun Liu, Yinghao Xing, Yinan Cao, Yibo Chen, Xinping Hu, Li Cai, Jie Zhou, Penghui Lin, Jiajia Xuan, Fangzhou Xie, Lahong Xu, Junhao Li, Lingling Zheng, Lianghu Qu, Jianjun Chen, Bin Li, Jianhua Yang.
      RNA molecules interact extensively with each other and with RNA-binding proteins (RBPs) to regulate gene expression. To improve detection of RBP-RNA and RNA-RNA interactions, we developed the rbsSeeker and rriScan tools and integrated the interactions into the Encyclopedia of RNA Interactomes (ENCORI), providing web-based modules to explore RNA interactions. Using this resource, we identified and validated novel N6-methyladenosine (m6A)-associated proteins, an orphan small nucleolar RNA guiding rRNA pseudouridines and target-directed microRNA degradation events, establishing ENCORI as a framework for studying RNA interactomes.
    DOI:  https://doi.org/10.1038/s41592-026-03105-x
  12. Mol Cell. 2026 May 25. pii: S1097-2765(26)00284-4. [Epub ahead of print]
    Phenylalanyl-tRNA synthetase FARS-1/FARSA balances longevity and immunity by downregulating endogenous mitochondrial double-stranded RNAs.
    Jooyeon Sohn, Moonhyeon Jeon, Hanseul Lee, JinA Lim, Seokjin Ham, JiSoo Park, Jongsun Lee, Yoonji Jung, Gee-Yoon Lee, Hyemin Min, Eunseok Kang, Yerim Jang, Yunhee Kong, Dajeong Bong, Yoosik Kim, Seung-Jae V Lee.
      Endogenous double-stranded RNAs (dsRNAs) are immunogenic self-molecules that drive aberrant immune activation under pathological conditions. Here, we show that dsRNAs and their regulation by RNA-binding proteins are key determinants of the fine balance between aging and immunity in Caenorhabditis elegans and cultured human cells. We find elevated levels of dsRNAs with organismal aging and cellular senescence. We identify a moonlighting function for phenylalanyl-tRNA synthetase, FARS-1/FARSA, as a key factor necessary and sufficient for extending lifespan by downregulating dsRNAs, in particular, mitochondrial dsRNAs. FARS-1/FARSA possesses a previously unrecognized dsRNA-binding domain and mediates dsRNA downregulation with the RNA helicase, RHA-2/DHX37, independently of its canonical role in translation. Notably, increased dsRNA expression resulting from genetic inhibition of fars-1/FARSA upregulates immune response-related genes and enhances innate immunity against pathogens. Our study establishes that FARS-1/FARSA is an evolutionarily conserved dsRNA-binding protein that delays aging and promotes longevity by suppressing dsRNA accumulation.
    Keywords:  Caenorhabditis elegans; FARS-1/FARSA; RNA-binding protein; double-stranded RNA; immunity; longevity; mitochondria; senescence
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.030
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