bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–03–22
seven papers selected by
Hana Antonicka, McGill University
  1. Functional characterization of dynamic nascent RNA folding ensembles in real time.
  2. Human Endonuclease G Preferentially Cleaves Oxidatively Damaged DNA.
  3. RNA modifications in gene regulation: Functions and pathways.
  4. RNA modifications: disease biomarkers and signaling molecules.
  5. Characterization of mitochondrial double-stranded RNA levels in Non-Small Cell Lung Carcinoma.
  6. Epigenetic and mitoepigenetic regulation in cancer and therapeutic perspectives.
  7. Structural insights into RNase H catalytic mechanism from room-temperature X-ray and neutron crystallography of apo- and RNA/DNA hybrid-bound enzyme.
  1. Sci Adv. 2026 Mar 20. 12(12): eaec4037
    Functional characterization of dynamic nascent RNA folding ensembles in real time.
    Kavan Gor, Eva Maria Geissen, Olivier Duss.
      RNA structure starts forming cotranscriptionally as the nascent RNA emerges from the RNA polymerase and is dynamically modulated by cellular factors. How individual RNA conformations, out of an ensemble of RNA molecules, relate to function is not well understood. Here, developing multicolor single-molecule fluorescence microscopy experiments, we track in real time nascent RNA structure formation, functionally characterizing up to eight different types of RNA molecules. We find that ribosomal proteins, RNA modification enzymes or antisense oligonucleotides specifically modulate a subset of the RNA folding classes. For example, we provide direct evidence that increased local RNA accessibility at specific sites correlates with the chaperoning activity of ribosomal proteins during ribosome assembly. These experiments provide a general framework to study how dynamic RNA folding, and misfolding, relates to function.
    DOI:  https://doi.org/10.1126/sciadv.aec4037
  2. Biochemistry. 2026 Mar 19.
    Human Endonuclease G Preferentially Cleaves Oxidatively Damaged DNA.
    Wen-Ting Lu, Yi-Ping Chen, Wei-Zen Yang, Hanna S Yuan, Jason L J Lin.
      Endonuclease G (EndoG) is a conserved endonuclease implicated in mitochondrial DNA (mtDNA) replication, maintenance of mtDNA integrity under oxidative stress, and the removal of nuclear and paternal mtDNA during apoptosis and early embryogenesis. Despite its biological significance, the substrates targeted by EndoG and its cleavage preferences remain unclear. Here, we characterize human EndoG (hEndoG) across diverse nucleic acid substrates, including single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), nicked and gapped dsDNA, modified dsDNA containing 8-oxoguanine (oxoG-DNA) and hydroxymethylated cytosine (5hmC-DNA), single-stranded RNA (ssRNA), and RNA/DNA hybrids. We show that hEndoG binds most of these substrates with only modest differences in affinity (∼10-fold), yet displays a particularly strong preference for cleaving oxidatively damaged DNA, including nicked and gapped dsDNA, and oxoG-DNA. Notably, hEndoG preferentially cleaves the strand opposite the gapped or nicked site, and it targets the complementary strand to the modified base in oxoG-DNA and 5hmC-DNA. Our structural modeling of hEndoG bound to ssDNA and dsDNA indicates that ssDNA is a favored substrate because its flexibility allows kinked conformations that position the scissile phosphate near the catalytic Mg2+ in the His-Me finger motif. Together, these findings support a critical role for hEndoG in preserving mitochondrial genome integrity under conditions of oxidative stress by selectively targeting and removing oxidatively damaged DNA.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00669
  3. Cell. 2026 Mar 19. pii: S0092-8674(26)00053-X. [Epub ahead of print]189(6): 1591-1619
    RNA modifications in gene regulation: Functions and pathways.
    Jiangbo Wei, Chuan He.
      RNA is frequently chemically modified, with over 170 types of chemical modifications identified to date in cellular RNAs. These modifications, along with their effector proteins, constitute new layers of gene expression regulation by controlling either the fate of modified RNAs at nearly every stage of their life cycle or local transcription through modulating the nearby chromatin state and transcriptional complexes. This is especially evident in dynamic biological contexts such as cellular state transitions, signaling, immune responses, and stress adaptation. In this review, we discuss recent breakthroughs and promising avenues for future exploration. Particular attention is given to the functional significance of mRNA modifications, the emerging roles of modifications on chromatin-associated regulatory RNAs in chromatin and transcriptional regulation, and mechanistic insights that will guide future scientific interrogation of RNA modifications in gene expression regulation. We also highlight how these fundamental understandings are beginning to catalyze the development of novel therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.01.006
  4. Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00004-4. [Epub ahead of print]
    RNA modifications: disease biomarkers and signaling molecules.
    Shijia Pan, Liwen Zhang, Yunfang Zhang, Junchao Shi, Ying Zhang.
      RNA modifications constitute a dynamic regulatory code governing RNA structure, fate, and translation. Modified nucleosides, long dismissed as metabolic waste, are now recognized as stable biomarkers and active signaling messengers involved in metabolic and reproductive regulation. Advances in methods for detecting modified nucleosides could accelerate translation toward clinical diagnostics and monitoring.
    Keywords:  LC–MS/MS; RNA modification; biomarkers; diagnostics
    DOI:  https://doi.org/10.1016/j.tem.2026.01.004
  5. Cancer Res Commun. 2026 Mar 17.
    Characterization of mitochondrial double-stranded RNA levels in Non-Small Cell Lung Carcinoma.
    Matthew R Krieger, Sandy Che-Eun S Lee, Ting Fu, Maya Cielo Cornejo, Kevin L He, Ryan Howe, Vanessa Saldivar, Angela L Zhang, Guillaume F Chanfreau, Michael A Teitell, Xinshu Xiao, David B Shackelford, Carla M Koehler.
      Mitochondrial double-stranded RNA (mtdsRNA) is exported to the cytoplasm when mitochondrial RNA degradation is impaired, serving as a novel damage-associated molecular pattern (DAMP) for mitochondrial stress. Whereas mtdsRNA has been detected in certain cancers, its prevalence and functional role remain largely underexplored. Moreover, mtdsRNA is not readily detectable in large-scale computational datasets, reflecting technical limitations in the detection of structured mitochondrial transcripts. Here, we used comprehensive computational characterization of non-small cell lung cancer (NSCLC) cell lines and identified elevated light-strand transcripts in a subset of cell lines, suggesting a potential for mtdsRNA formation. We stratify NSCLC lines into groups with high and low mtdsRNA abundance. Despite high cytoplasmic mtdsRNA levels in select NSCLC cell lines, we did not identify significant correlation with mtdsRNA abundance and Type-I interferon (IFN-l) response. RT-qPCR analysis revealed that only USP18 transcripts amongst the IFN-l transcripts probed were significantly regulated in select NSCLC lines, indicating a partial or suppressed IFN-I response. Strand-specific RT-qPCR also revealed no bias in mitochondrial gene expression. These findings indicate that basal mtdsRNA accumulation alone is insufficient to trigger IFN-I signaling and may be tolerated in NSCLC, indicating adaptive mechanisms. Our findings suggest that mtdsRNAs could serve alternative non-immunogenic roles in tumor biology. Importantly, our work reports that mtdsRNA is upregulated in a subset of NSCLC cell lines and in other cancer cell types, suggesting that mtdsRNA may serve as a new marker of mitochondrial dysfunction in cancer.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0656
  6. Front Pharmacol. 2026 ;17 1760013
    Epigenetic and mitoepigenetic regulation in cancer and therapeutic perspectives.
    Selcen Celik-Uzuner, Ihsan Nalkiran, Ugur Uzuner, Hatice Sevim Nalkiran.
      Epigenetic modifications on nuclear and mitochondrial DNA constitute key regulatory layers influencing the transcriptional, metabolic, and phenotypic adaptability of cancer cells. The canonical principles of epigenetic control encompass DNA methylation, histone modification, and non-coding RNA-mediated regulation, which collectively contribute to the silencing of tumor suppressor genes, the activation of oncogenes, and chromatin remodeling. Therefore, epigenetic drugs (epi-drugs) are of great interest in the development of new-generation therapeutics and holistic treatment approaches. Accordingly, this work presents a narrative review that integrates current evidence on the molecular mechanisms, therapeutic developments, and translational relevance of epigenetic and mitoepigenetic regulation in cancer. RNA-mediated regulation collectively contributes to the silencing of tumor suppressor genes and to the activation of oncogenes. The field of mitoepigenetics encompasses mitochondrial DNA (mtDNA) methylation, RNA modifications, and post-translational regulation of mitochondrial proteins such as TFAM, DNMT1, and sirtuins, which influence oxidative phosphorylation, redox balance, and apoptotic pathways, thereby affecting tumor initiation, progression, and treatment response. Recent advances in epigenetic drug development include FDA-approved DNMT and HDAC inhibitors and newer agents targeting EZH2, IDH1/2, and DOT1L, which broaden the scope of precision oncology. In addition, modulation of mitochondrial epigenetic mechanisms has been identified as a potential approach for addressing metabolic reprogramming and therapeutic resistance in cancer. The convergence of nuclear and mitochondrial regulatory frameworks reveals the critical need for biomarker-informed, combinatory, and organelle-targeted therapeutic approaches to sustain treatment efficacy. Comprehensive characterization and pharmacological targeting of epigenetic and mitoepigenetic networks provide a structured basis for developing personalized and metabolism-informed interventions in cancer therapy.
    Keywords:  DNA methylation; cancer therapy; epigenetics; histone modification; mitoepigenetics
    DOI:  https://doi.org/10.3389/fphar.2026.1760013
  7. Curr Res Struct Biol. 2026 Jun;11 100188
    Structural insights into RNase H catalytic mechanism from room-temperature X-ray and neutron crystallography of apo- and RNA/DNA hybrid-bound enzyme.
    Oksana Gerlits, Aliyah Collins, Andrey Kovalevsky.
      RNase H enzymes are sequence-nonspecific endonucleases that cleave RNA strands in RNA/DNA hybrid duplexes, an enzymatic process essential in DNA replication and repair in both prokaryotes and eukaryotes. Also, RNase H activity of the reverse transcriptase in human immunodeficiency viruses (HIV-1 and HIV-2) is indispensable for the viral replication cycle. RNase H enzymes play an central role in the development of gene therapies and are targets for novel antivirals. It is therefore of great importance to gain a detailed understanding of the RNase H catalytic mechanism to improve drug design. We utilized Bacillus halodurans RNase H1 (BhRNase H1) to shed light on its function and catalytic mechanism. Room-temperature neutron crystallography of the wild-type and inactive D132N mutant enzymes revealed that E109, belonging to the catalytic DEDD motif, can change its protonation state, allowing us to propose its role in the protonation of the leaving O3' hydroxyl group of RNA. X-ray crystallography has demonstrated the ability of the RNA/DNA duplex to slide along the protein surface upon metal ion binding at site MA, transforming a product mimic into a Michaelis-like complex, which confirms an essential role of the MA metal ion in catalysis.
    Keywords:  Enzyme mechanisms; Enzyme-nucleic acid complex; Neutron diffraction; Protonation state; RNA/DNA hybrid duplex; RNase H; Room temperature crystallography
    DOI:  https://doi.org/10.1016/j.crstbi.2026.100188
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