bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–06–14
six papers selected by
Hana Antonicka, McGill University
  1. Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
  2. Expression of four mitochondrial tRNAs from only two loci.
  3. Expanding the MRPS34 Genotype-Phenotype Correlation: Two Novel Cases and a Cohort Review.
  4. RNA-binding protein transcripts reflect composition of target mRNAs.
  5. TRMT10C promotes mitochondrial fission through transferrin receptor m1A methylation modification and aggravates the progression of atrial fibrillation.
  6. Structure-driven RNA remodeling underlies broad substrate recognition by NSUN2.
  1. Biochim Biophys Acta Mol Cell Res. 2026 Jun 09. pii: S0167-4889(26)00069-8. [Epub ahead of print] 120171
    Folding the message: mRNA structure as a regulatory layer of human mitochondrial gene expression.
    Ahram Ahn, Seungwoo Hong, Michele Brischigliaro, Flavia Fontanesi, Antoni Barrientos.
      Mammalian mitochondrial gene expression operates within an unusually compact genomic architecture in which most regulatory information must be encoded within or immediately adjacent to protein-coding sequences. In this context, mitochondrial mRNAs function not merely as templates for translation but as structured molecules whose folding landscape contributes to multiple stages of gene expression. Recent advances in chemical probing, mutational profiling, and mitoribosome profiling have begun to disclose the human mitochondrial mRNA structurome in its native organellar context, revealing a transcriptome that is broadly accessible yet punctuated by localized structural elements and alternative conformational states. These studies indicate that RNA structure contributes to translation initiation on leaderless transcripts, elongation kinetics, translational coupling across bicistronic junctions, and dynamic remodeling during membrane protein synthesis. They also highlight the role of RNA-binding proteins, including LRPPRC-SLIRP and related factors, in maintaining a translation-competent folding environment. In this review, we discuss the structural organization of mitochondrial mRNAs, the experimental approaches that enabled its analysis, and emerging mechanistic links between RNA folding, translational regulation, and respiratory chain biogenesis. We further discuss how alterations in mt-mRNA structure may represent an underappreciated determinant of mitochondrial disease and consider implications for future diagnostic and therapeutic strategies.
    Keywords:  Bicistronic transcripts; Mitochondrial RNA folding; Mitochondrial RNA processing; Mitochondrial RNA structurome; Mitochondrial gene expression; Mitochondrial translation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120171
  2. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2534946123
    Expression of four mitochondrial tRNAs from only two loci.
    Jessica M Warren, Kasavajhala V S K Prasad, Anistynn M Mendez, Stephanie Temnyk, John P McCutcheon.
      Transfer RNAs (tRNAs) are among the few genes retained in animal mitochondrial genomes after more than a billion years of gene loss. These ancient bacterial vestiges are often structurally aberrant and less stable than their bacterial or cytosolic tRNA counterparts. In some lineages, mitochondrial tRNAs (mt-tRNAs) have become so truncated that the loss of one or both arms has expanded our understanding of what constitutes a functional tRNA. Here, we report another radical departure from canonical tRNA gene architecture: two overlapping tRNAs produced from opposite strands of the same locus. These "mirror" tRNA pairs eliminate the need to retain separate loci for all tRNA genes, as a single locus can produce tRNAs to decode two different amino acids. We show that these mirror tRNAs are aminoacylated and demonstrate their presence in mitoribosomes. Furthermore, mirror tRNAs display strand-specific patterns of nucleotide modification and RNA editing, reflecting specific posttranscriptional maturation that depends on transcriptional orientation. This demonstration of functional, bidirectional tRNA expression reveals an unexpected strategy by which mitochondrial genomes maintain a complete set of tRNAs in the face of unrelenting gene loss. The presence of mirror tRNAs has broad implications for the evolution of tRNA-interacting enzymes, mitochondrial biology, and even the origins of the protein synthesis machinery itself.
    Keywords:  bidirectional transcription; mitochondrial genome evolution; mitochondrial tRNAs
    DOI:  https://doi.org/10.1073/pnas.2534946123
  3. JIMD Rep. 2026 Jul;67(4): e70089
    Expanding the MRPS34 Genotype-Phenotype Correlation: Two Novel Cases and a Cohort Review.
    Alberte Aspaas Lundquist, Sumit Parikh, Thomas van Overeem Hansen, Flemming Wibrand, Elsebet Østergaard.
      MRPS34 encodes a mitoribosomal protein essential for mitochondrial translation. Biallelic pathogenic variants in MRPS34 cause Combined Oxidative Phosphorylation Deficiency 32 (COXPD32), a rare mitochondrial disorder within the Leigh syndrome spectrum (LSS), ranging from fatal in infancy to adult survival. The objective is to describe two new individuals with MRPS34-related disease and expand the clinical, genetic, and phenotypic spectrum of COXPD32. Clinical, radiological, biochemical, and molecular evaluations were conducted in two individuals with Leigh Syndrome (LS). Exome and genome sequencing identified presumed biallelic MRPS34 variants. A systematic review of all previously reported cases was performed to assess possible genotype-phenotype correlations (n = 11). Individual 1, who died in infancy with LS, was presumed compound heterozygous for a novel splice-site variant (c.364 + 2 T>C, p.(?)) and a nonsense variant (c.94C>T, p.(Gln32*)). Individual 2 survived into mid childhood and was homozygous for the hypomorphic variant c.322-10G>A, p.(?). Among 11 individuals, key features included developmental delay (100%), lactic acidosis (91%), brainstem lesions (91%), and metabolic acidosis (83%). Homozygosity for c.322-10G>A, p.(?) correlated with longer survival. MRPS34-related disease presents with multisystemic features and genotype-dependent severity. Accurate genetic diagnosis is essential for prognosis and therapeutic strategies.
    Keywords:  MRPS34; combined oxidative phosphorylation deficiency 32; genotype–phenotype correlation; hypomorphic splice variant; leigh syndrome spectrum; mitochondrial disease
    DOI:  https://doi.org/10.1002/jmd2.70089
  4. Nucleic Acids Res. 2026 Jun 08. pii: gkag540. [Epub ahead of print]54(11):
    RNA-binding protein transcripts reflect composition of target mRNAs.
    Thomas H Kapral, Bojan Žagrović.
      RNA-protein interactions are central to gene regulation, yet the large-scale organization of RNA-protein networks remains incompletely understood. Using a comprehensive human eCLIP dataset encompassing interactions between 150 RNA-binding proteins (RBPs) and >11 000 mRNAs, we identify a robust organizing principle underlying the RNA-protein network structure: mRNAs preferentially associate with RBPs whose own encoding transcripts share similar nucleotide composition. In other words, mRNAs enriched in a given nucleotide tend to be targeted by RBPs whose own transcripts are likewise enriched in that nucleotide and vice versa. This global pattern holds for all four RNA nucleotides, remains statistically significant after controlling for transcript length, expression levels and sequence-motif-driven interactions, and is confirmed by in vitro HTR-SELEX data. We use the observed relationship to rationalize the spatial organization of mRNAs in the nucleus i.e. the known G/C gradient towards nuclear speckles. Notably, an mRNA's propensity toward RBPs rich in arginine, which is predominantly encoded by and preferentially binds guanine, is a strong predictor of its speckle enrichment. Our findings highlight a fundamental link between coding and binding in biology and suggest that mRNA composition biases provide a fundamental layer of specificity in shaping the global RNA-protein interaction network.
    DOI:  https://doi.org/10.1093/nar/gkag540
  5. J Cell Commun Signal. 2026 Jun;20(2): e70059
    TRMT10C promotes mitochondrial fission through transferrin receptor m1A methylation modification and aggravates the progression of atrial fibrillation.
    Nijina Li, Hao Zhang.
      Atrial fibrillation (AF) is a common cardiac arrhythmia often accompanied by structural remodeling of the atria, particularly fibrosis, and disruption of normal mitochondrial function. N(1)-methyladenosine (m1A), a methylation of RNA, is gaining attention for its role in diverse biological processes. This study aimed to explore the role of the m1A methyltransferase tRNA methyltransferase 10C (TRMT10C) in AF pathogenesis. In the study, TRMT10C and m1A methylation levels were upregulated in AF rats, accompanied by excessive mitochondrial fission and myocardial fibrosis. Knockdown of TRMT10C inhibited the expression levels of mitochondrial fission-related proteins Drp1 and Fis1, reduced collagen deposition (collagen I, Postn, collagen III, and fibronectin), and AF progression. In vitro results showed that TRMT10C knockdown inhibited TGF-β1-induced cardiac fibroblasts proliferation and migration, whereas overexpression of transferrin receptor (TFRC) reversed this effect. Mechanistically, TRMT10C enhanced the stability of TFRC mRNA by promoting m1A methylation, driving mitochondrial fission and fibrosis. Collectively, our findings elucidate a novel TRMT10C-TFRC m1A axis driving pathological mitochondrial dynamics and fibrosis in AF, offering new insight into cell-signaling pathways underlying atrial disease and potential therapeutic targets.
    Keywords:  TRMT10C; atrial fibrillation; atrial fibrosis; m1A methylation; mitochondrial fission
    DOI:  https://doi.org/10.1002/ccs3.70059
  6. Sci China Life Sci. 2026 May 26.
    Structure-driven RNA remodeling underlies broad substrate recognition by NSUN2.
    Qian Hu, Wen Yang, Yunyun Yu, Ran Yi, Yutong Zhang, Leyuan Duan, Fudong Li, Kaiming Zhang, Qingguo Gong, Shanshan Li.
      The human RNA m5C methyltransferase NSUN2 catalyzes site-specific cytosine methylation across diverse RNA substrates and thereby regulates a wide range of biological and physiological processes. However, the molecular basis by which NSUN2 achieves broad substrate recognition while maintaining catalytic specificity has remained unclear. Here, we determine structures of human NSUN2 in both substrate-free and substrate-bound states using X-ray crystallography and cryo-electron microscopy. Structures of NSUN2 in complex with multiple tRNA substrates reveal a structure-first, sequence-tolerant strategy in which NSUN2 actively remodels tRNA architecture, exposing the buried target cytosine and positioning it within the catalytic pocket for methyl transfer. This recognition strategy enables NSUN2 to accommodate diverse tRNA substrates through a largely conserved interaction interface. Together, our findings define the molecular principles underlying NSUN2-mediated RNA m5C modification.
    Keywords:  NSUN2; conformational remodeling; cryo-EM; m5C modification; substrate recognition; tRNA methyltransferase
    DOI:  https://doi.org/10.1007/s11427-026-3373-3
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