bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–05–03
eleven papers selected by
Hana Antonicka, McGill University
  1. Investigation of TRMT61B methyltransferase activity on mRNA and its effects on translation.
  2. Enzyme-Mediated Covalent Labeling Enables In Situ Imaging of RNA Modification States.
  3. Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
  4. Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
  5. Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
  6. Augmented prediction of multi-species protein-RNA interactions using evolutionary conservation of RNA-binding proteins.
  7. Dissection of Mitochondrial Function via Chemical Perturbation and Single-Cell Profiling.
  8. Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics.
  9. Mitochondrial protein Mrpl13 regulates zebrafish liver development through the mTORC1-mitochondrial homeostasis pathway.
  10. RNAdetector: fast and accurate predictor of RNA type-specific binding residues in protein sequences.
  11. Orchestrating innate immunity through RNA editing and helicase activity: ADAR1, dsRNA sensors, and tumor immune evasion.
  1. Nucleic Acids Res. 2026 Apr 23. pii: gkag365. [Epub ahead of print]54(8):
    Investigation of TRMT61B methyltransferase activity on mRNA and its effects on translation.
    Dorthy Fang, John M Babich, Ryan Stanton, Isaac W Vock, Kyrillos Abdallah, Mingyi Zhu, Raj Letchuman, Richard Li, Matthew D Simon, Wendy V Gilbert, Sigrid Nachtergaele.
      Despite recent advances in technology to map RNA chemical modifications transcriptome-wide, the distribution of N1-methyladenosine (m1A) in messenger RNA (mRNA) remains contested, hindering a clear understanding of its function. Additionally, the enzyme(s) that installs the majority of reported mRNA m1A sites has yet to be identified. In this study, we characterized TRMT61B, an m1A methyltransferase known to methylate mitochondrial RNAs, but whose sequence preferences have been underexplored. By integrating cellular overexpression of TRMT61B and in vitro methylation of a synthetic pool of diverse human mRNA sequences, we identified a preference for a YMRA consensus motif in single-stranded RNA regions. In these experiments, TRMT61B methylated thousands of novel human mRNA sites, revealing activity on cytosolic mRNAs. We used these novel m1A-modifiable sequences to test the effects of m1A on translation of luciferase reporters and on ribosome recruitment to modified transcripts in the pool. We found that m1A addition can significantly affect translation and ribosome recruitment, but that these effects vary by transcript. Taken together, our results inform future studies of TRMT61B and mRNA modifications, and emphasize that studies of m1A regulation of mRNA must be carried out and interpreted in a highly context-aware manner.
    DOI:  https://doi.org/10.1093/nar/gkag365
  2. J Am Chem Soc. 2026 Apr 28.
    Enzyme-Mediated Covalent Labeling Enables In Situ Imaging of RNA Modification States.
    Andrew H Ryu, Neal K Devaraj.
      Post-transcriptional tRNA modifications are regulators of gene expression, yet their spatial organization and dynamic regulation remain poorly understood, because methods to track tRNA modification status inside cells are lacking. Sequencing and biochemical approaches provide population-level readouts but typically require RNA extraction, eliminating spatial information and obscuring cell-to-cell heterogeneity. Here, we report a chemoenzymatic RNA fluorescent labeling strategy that enables the imaging of a specific tRNA modification state in mammalian cells. Our method relies on the catalytic selectivity of the bacterial enzyme tRNA guanine transglycosylase (TGT) to covalently incorporate fluorophore-conjugated preQ1 analogues into q-cognate tRNAs only when they lack queuine, a unique hypermodified base that influences translation, stress responses, and mammalian physiology. Because queuine-modified tRNAs are not substrates for transglycosylation, fluorophore incorporation directly reports the hypomodification status. Queuine-hypomodified tRNAs are selectively visualized with subcellular resolution in fixed cells. Using this approach, we track queuine incorporation and loss kinetics across cell lines, analyze genetic factors that control modification, and resolve differences between cytosolic and mitochondrial tRNA populations. Beyond queuine, this work demonstrates a strategy for converting the endogenous RNA modification state into a covalent fluorescent readout, providing a chemical framework for spatial analysis of RNA modifications in intact cells.
    DOI:  https://doi.org/10.1021/jacs.6c03719
  3. Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):
    Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
    Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.
      Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication. In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.
    DOI:  https://doi.org/10.1093/nar/gkag233
  4. bioRxiv. 2026 Feb 06. pii: 2026.02.04.703776. [Epub ahead of print]
    Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
    Xiaojuan Fan, Markus Hafner.
      Subcellular RNA localization is a fundamental layer of gene regulation, yet its heterogeneity across individual cells remains poorly understood. Here, we introduce the RNA Localization Profiler (RLP), a proximity-based RNA-editing strategy that maps compartment-specific RNAs in living cells. Across the cytoplasm, endoplasmic reticulum (ER), and plasma membrane, RLP identifies robust and highly specific RNA localization programs linked to translation and membrane organization. Single-cell RLP (scRLP) reveals that individual cells harbor roughly 5,000-7,000 cytoplasmic RNAs, with <10% associated with the ER. These measurements uncover pervasive subcellular heterogeneity in RNA localization that is undetectable by bulk assays. Spatial RNA patterns define an orthogonal axis of cell-state identity that is independent of gene expression. For example, ZWINT mRNA relocalizes to the cytoplasm in a cell cycle-dependent manner. These findings establish heterogeneous levels of subcellular RNA localization as a variable dimension of intracellular organization and cell identity.
    DOI:  https://doi.org/10.64898/2026.02.04.703776
  5. Nat Commun. 2026 Apr 30.
    Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
    Eleonora Centanini, Oliver Pain, Patrick F Chinnery, Alan Hodgkinson.
      Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-72649-5
  6. Nat Commun. 2026 Apr 27.
    Augmented prediction of multi-species protein-RNA interactions using evolutionary conservation of RNA-binding proteins.
    Jiale He, Tong Zhou, Lu-Feng Hu, Yuhua Jiao, Junhao Wang, Shengwen Yan, Siyao Jia, Qiuzhen Chen, Wentao Zhu, Jilin Zhang, Mutian Jia, Yuanning Li, Xianwei Wang, Yangming Wang, Yucheng T Yang, Lei Sun.
      RNA-binding proteins (RBPs) play critical roles in the regulation of gene expression. Recent studies have begun to detail the RNA recognition mechanisms of diverse RBPs. However, given the array of RBPs studied so far, it is implausible to experimentally profile RBP-binding peaks for hundreds of RBPs in multiple non-model organisms. Here, we introduce MuSIC (Multi-Species RBP-RNA Interactions using Conservation), a deep learning-based framework for predicting cross-species RBP-RNA interactions by leveraging label smoothing and evolutionary conservation of RBPs across 11 phylogenetically diverse species ranging from human to yeast. MuSIC outperforms state-of-the-art computational methods, and achieves highly accurate prediction of RBP-binding peaks across species. The prediction confidence is higher in the metazoan species, partially reflecting differences in RBP conservation patterns. Finally, the effects of homologous genetic variants on RBP binding can be computationally quantified across species, followed by experimental validations. The target transcripts with disrupted binding events are enriched in the ubiquitination-associated pathways. To summarize, MuSIC provides a useful computational framework for predicting RBP-RNA interactions cross-species and quantifying the effects of genetic variants on RBP binding, offering insights into the RBP-mediated regulatory mechanisms implicated in human diseases.
    DOI:  https://doi.org/10.1038/s41467-026-72351-6
  7. Cell Prolif. 2026 Apr 27. e70216
    Dissection of Mitochondrial Function via Chemical Perturbation and Single-Cell Profiling.
    Hao Luo, Xiaona Yin, Hongxin He, Yaning Wang, Hongbo Zhang.
      Mitochondria play central roles in cellular energy metabolism and signal transduction, and maintenance of mitochondrial homeostasis is essential for proper cellular function. Rather than being regulated by individual genes alone, mitochondrial homeostasis is governed by coordinated functional modules, including glucose and lipid metabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), calcium handling, mitochondrial dynamics, mitochondrial reactive oxygen species (mtROS) regulation, and mitochondrial transcription and translation. However, how perturbation of these modules reshapes cellular states remains incompletely understood. Here, we combined targeted chemical perturbations with single-cell RNA sequencing (scRNA-seq) to systematically profile transcriptional responses to inhibition of core mitochondrial functional modules. Comparative analyses revealed both shared and module-specific transcriptional programs, including recurrent co-expression patterns across distinct perturbations. Analysis of mitochondrial gene expression across conditions implicated mtROS as an important regulator of mitochondrial respiratory chain (MRC) gene expression, potentially acting through activation of the mitochondrial integrated stress response (mtISR). Further comparative analysis of perturbations targeting individual MRC complexes uncovered distinct transcriptional and cellular consequences among complexes. Examination of cell-cycle dynamics showed that mitochondrial perturbations generally suppress cell proliferation; inhibition of most MRC complexes was associated with G1-phase arrest, whereas perturbation of complex III preferentially led to G2/M-phase arrest, potentially reflecting differential engagement of p53-associated signaling pathways. Finally, our analysis revealed both conserved and divergent transcriptional responses to mitochondrial perturbations between human and mouse cells. Together, these findings establish a systematic single-cell framework for dissecting mitochondrial functional modules and highlight both shared and function-specific principles by which mitochondrial perturbations influence cellular transcriptional states.
    Keywords:  cell‐cycle regulation; chemical perturbation; mitochondrial function; mitochondrial stress signaling; single‐cell transcriptomics
    DOI:  https://doi.org/10.1111/cpr.70216
  8. JIMD Rep. 2026 May;67 e70092
    Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics.
    MitoMDT Diagnostic Network for Genomics and Omics
      MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.
    Keywords:  MRPS22; corpus callosum; genomic autopsy; hydrops fetalis; mitochondrial disease; mitoribosome; proteomics
    DOI:  https://doi.org/10.1002/jmd2.70092
  9. Commun Biol. 2026 Apr 30.
    Mitochondrial protein Mrpl13 regulates zebrafish liver development through the mTORC1-mitochondrial homeostasis pathway.
    Xinkai Cheng, Lei Li, Shibo Fang, Lindong Yu, Chenglin Liu, Yaqi Jiao, Yang Fang, Libaijia Lin, Long Zhao, Ying Su.
      The liver is the largest metabolic organ in the human body, performing functions as metabolism, secretion, immunity, and detoxification. Due to the high energy demand, liver cells are rich in mitochondria. Mitochondrial homeostasis is crucial for liver development and function, yet the molecular pathways linking mitochondrial dysfunction to liver defects remain incompletely understood. In this study, using the zebrafish model, we show that loss of Mrpl13, a component of the mitochondrial ribosomal subunit, results in pronounced abnormalities in liver development. The deficiency of Mrpl13 disrupts mitochondrial homeostasis, as evidenced by fragmentated mitochondria, impaired energy metabolism, excessive reactive oxygen species, and lipid accumulation in liver cells. Notably, loss of Mrpl13 triggers mTORC1 signaling, and treatment with the mTORC1 inhibitor rapamycin significantly alleviates liver developmental defects, suggesting that mTORC1 signaling mediates the role of Mrpl13 in regulating mitochondrial homeostasis and liver development. Overall, our findings reveal a regulatory axis involving Mrpl13, mTORC1, and mitochondrial homeostasis during liver development, providing a theoretical basis for exploring therapeutic strategies for liver defects associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42003-026-10137-8
  10. Nucleic Acids Res. 2026 Apr 23. pii: gkag394. [Epub ahead of print]54(8):
    RNAdetector: fast and accurate predictor of RNA type-specific binding residues in protein sequences.
    Gang Hu, Kui Wang, Ajay Arya, Lukasz Kurgan.
      Proteins interact with several RNA types to facilitate a broad spectrum of cellular functions. However, the underlying interaction data are sparse, and existing methods for predicting RNA-binding residues (RBRs) in protein sequences are almost exclusively RNA type-agnostic, limiting their utility. To this end, we introduced RNAdetector, a sequence-based method that accurately predicts messenger RNA-, ribosomal RNA-, small nuclear RNA (snRNA)-, and transfer RNA-binding residues and type-agnostic RBRs. RNAdetector employs an innovative deep transformer network architecture and transfer learning, which together produce a large boost to predictive performance and minimize cross-predictions, defined as incorrectly predicting wrong types of RBRs. Moreover, our design has a low computational footprint and produces accurate predictions in about 9 s per protein, facilitating analysis of large collections of proteins. A comparative evaluation on a low-similarity test dataset showed that RNAdetector provided substantially more accurate RNA-type-specific predictions, a much shorter runtime, additionally covered snRNA, and significantly reduced cross-predictions compared to the only other RNA-type-specific predictor that is cross-prediction prone. Moreover, we empirically showed that RNAdetector's predictions of type-agnostic RBRs are modestly more accurate than those generated by several representative predictors of RNA-type-agnostic RBRs and RNA-binding proteins. RNAdetector is available as a convenient web server at http://biomine.cs.vcu.edu/servers/RNAdetector/.
    DOI:  https://doi.org/10.1093/nar/gkag394
  11. Front Cell Dev Biol. 2026 ;14 1788799
    Orchestrating innate immunity through RNA editing and helicase activity: ADAR1, dsRNA sensors, and tumor immune evasion.
    Moeko Minakuchi, Joseph M Salvino, Jessie Villanueva.
      Dysregulated dsRNA editing and RNA metabolism in cancer contribute to immune evasion, highlighting the critical role of RNA structural regulation in disease. Intracellular RNA structures regulate gene expression, innate immunity, genome stability, and cell fate. Among these, double-stranded RNA (dsRNA) is particularly important; exogenous dsRNA typically originates from viral infection, whereas endogenous dsRNA arises from repetitive elements or transcriptional errors, allowing cells to distinguish "self" from "non-self." The RNA-editing enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) prevents inappropriate innate immune activation by catalyzing adenosine-to-inosine (A-to-I) editing of endogenous dsRNA. RNA helicases complement this function by remodeling RNA structures and resolving nucleic acid hybrids, maintaining RNA homeostasis and immune surveillance. Recent studies have revealed an interplay between ADAR1 and RNA helicases that regulate dsRNA immunogenicity and R-loop dynamics, establishing this network as a key determinant of tumor immunity. Dysregulated RNA editing and structural regulation in cancer further underscore the potential of targeting these pathways therapeutically, providing strategies beyond conventional gene- or protein-centered approaches. In this review, we summarize current insights into how ADAR1 and RNA helicases control RNA structure, emphasize their roles in innate immune sensing, and discuss emerging approaches to modulate RNA editing and RNA architecture for therapeutic benefit. Taken together, research in this area positions RNA structural control as a central determinant of immune homeostasis and a promising frontier in cancer therapy.
    Keywords:  ADAR1; RNA editing; dsRNA sensors; helicase activity; tumor immune evasion
    DOI:  https://doi.org/10.3389/fcell.2026.1788799
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