bims-mitran Biomed News
on Mitochondrial translation
Issue of 2026–09–06
six papers selected by
Andreas Kohler, Umeå University
  1. Guanosine 10 methylation by TRMT11-TRMT112 optimizes human mitochondrial tRNAs for efficient translation.
  2. SLIRP differentially modulates RNA binding of pathogenic LRPPRC variants.
  3. Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
  4. Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.
  5. Rewiring the ribosome to translate proteins encoded in its own RNA.
  6. Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
  1. Nucleic Acids Res. 2026 Aug 24. pii: gkag859. [Epub ahead of print]54(16):
    Guanosine 10 methylation by TRMT11-TRMT112 optimizes human mitochondrial tRNAs for efficient translation.
    Jonny Petrosyan, Mehmet Yilmaz, Carolin P M Scheitl, Nicolas Lemus-Diaz, Angela Boshnakovska, Laurianne L E Tay, Wanwan Hu, Olga Beine-Golovchuk, David Touboul, Ricarda Richter-Dennerlein, Claudia Höbartner, Marc Graille, Peter Rehling, Katherine E Bohnsack.
      Modified nucleotides are essential determinants of RNA function, and identifying the enzymes that install them is fundamental to understanding their cellular roles. Here, we show that the human RNA methyltransferase TRMT11 and its cofactor TRMT112 are imported into mitochondria via N-terminal targeting signals. Using a recently developed N2-methylguanosine (m2G)-sensitive DNAzyme, we demonstrate that TRMT11 catalytic activity and interaction with TRMT112 are required for installation of m2G at position 10 in 13 mitochondrial (mt-)tRNAs. The crosslinking profile of TRMT11 on mt-tRNAs experimentally supports a model of the TRMT11-TRMT112-mt-tRNATrp complex in which the THUMP domain contacts the 3' end of the acceptor stem, and G10 is flipped into the S-adenosylmethionine binding pocket for methylation. Transcriptome-wide mapping reveals that TRMT11 interacts with most nuclear-encoded and mt-tRNAs, but only methylates a subset. In vitro reconstitution of TRMT11-TRM112-mediated methylation defines key structural requirements for m2G10 installation across different mt-tRNAs, and reveals how pathogenic mutations influence this modification. TRMT11-TRMT112 recognizes folded mt-tRNAs, and in the degenerate mt-tRNALys, m1A9 strongly enhances m2G10 methylation efficiency. Loss of m2G10 modifications alters the conformation of numerous mt-tRNAs, perturbs mitochondrial protein synthesis, and impairs oxidative phosphorylation, highlighting an essential role of this modification in maintaining mitochondrial function.
    DOI:  https://doi.org/10.1093/nar/gkag859
  2. NAR Mol Med. 2026 Jul;3(3): ugag040
    SLIRP differentially modulates RNA binding of pathogenic LRPPRC variants.
    Louise Lambert, Urška Rovšnik, Amandine Moretton, Katarina Johansson, Mãdãlina Sãcultanu, Mathilde Chéron, Adèle Porcan, Bertil Macao, Siet van den Wildenberg, Xuefeng Zhu, Maria Falkenberg, Géraldine Farge.
      The LRPPRC/SLIRP complex is a key post-transcriptional regulator of mitochondrial gene expression, stabilizing mitochondrial mRNAs and promoting their polyadenylation and translation. Mutations in LRPPRC cause mitochondrial disorders, including Leigh syndrome French-Canadian type (LSFC), primarily affecting oxidative phosphorylation. Here, we examined the RNA-binding properties of wild-type LRPPRC and three pathogenic variants (A354V, K909del, and R1276_K1300del) using electrophoretic mobility shift assays, acoustic force spectroscopy, and AlphaFold 3 modeling. All three mutations reduced intrinsic RNA binding, with R1276_K1300del showing no detectable interaction in the absence of SLIRP. Remarkably, SLIRP restored RNA binding of this mutant to near wild-type levels, likely through conformational stabilization, as supported by single-molecule and structural analyses. These findings highlight SLIRP's critical role in modulating LRPPRC function and suggest that enhancing SLIRP activity represents a potential therapeutic strategy for LRPPRC-related mitochondrial disorders.
    DOI:  https://doi.org/10.1093/narmme/ugag040
  3. Sci Adv. 2026 Sep 04. 12(36): eaec8606
    Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
    Kristina Bubb, Giovanni Rigoni, Polyxeni Papadea, Gianluigi Pironti, Jelena Misic, Shan Jiang, David Alsina, Diana Rubalcava-Gracia, Daniel C Andersson, Roberta Filograna, Camilla Koolmeister, Patrick Giavalisco, Anna Wredenberg, Matthias Mann, Florian A Rosenberger, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8606
  4. FEBS Open Bio. 2026 Sep 01.
    Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.
    Lishen Wang, Mingqiang Deng, Dongmei He, Diqin Lai, Dongjun Liu, Dengyong Zhu, Zhenhua Zhang, Peng Tang, Chuanman Zhou, Menghui Yin, Xichen Bao.
      The Warburg effect has long suggested that oxidative phosphorylation (OXPHOS) is dispensable for tumor growth. However, recent studies have shown that the mitochondrial RNA polymerase inhibitors IMT1 and IMT1b, which impair OXPHOS, are potent anticancer agents. Here, we demonstrate that ionomycin, a selective ionophore known to modulate mitochondrial homeostasis, similarly inhibits mitochondrial gene expression across cancer cell lines. Specifically, gene expression and nascent RNA profiling revealed a global downregulation of mitochondrial gene transcription in Jurkat T, THP-1, HeLa, and NCI-H441 cells. Thus, we conclude that ionomycin suppressed mitochondrial gene transcription, impaired OXPHOS, and thereby inhibited cancer cell proliferation and growth, providing a novel insight into the function of ionomycin.
    Keywords:  OXPHOS; cell proliferation; ionomycin; mitochondrial gene transcription
    DOI:  https://doi.org/10.1002/2211-5463.70297
  5. Nature. 2026 Sep 02.
    Rewiring the ribosome to translate proteins encoded in its own RNA.
    Kasra Alizadeh, Dorota Klepacki, Nora Vázquez-Laslop, Alexander S Mankin.
      Cellular protein synthesis relies on random encounters between ribosomes and mRNAs, limiting optimization of the translation machinery for production of a single protein-a key need in biotechnology. One potential solution is integrating the protein-coding sequence into the ribosome itself, thereby committing the ribosome to synthesis of a single polypeptide. The feasibility of such integration could also address a long-standing challenge in RNA world models: explaining how early protein synthesis could function reliably despite the scarcity and poor organization of its components1. Whether a ribosome can translate its own ribosomal RNA (rRNA) has remained unclear. Here we show that bacterial ribosomes can synthesize proteins encoded within their own RNA. We engineered a chimeric messenger-ribosomal RNA (mrRNA) by appending a protein-coding sequence to 16S rRNA. The hybrid mrRNA assembles into a small ribosomal subunit that binds to the large subunit to form Ribo-M, a ribosome capable of translating mrRNA-encoded proteins. Translation is abolished by mutations or antibiotics that impair the function of the small subunit, demonstrating that mrRNA translation is carried out in cis by ribosomes assembled on the chimeric mrRNA. Incorporating mrRNA into a ribosome with tethered subunits yielded Ribo-TM, in which encoding, decoding and peptide synthesis are united within a single RNA scaffold. These findings establish the mechanistic feasibility of a ribosome translating its own rRNA in vivo and in vitro, offering a versatile platform for orthogonal protein production and insights into the origin of translation.
    DOI:  https://doi.org/10.1038/s41586-026-10962-1
  6. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123
    Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
    Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.
      Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.
    Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell
    DOI:  https://doi.org/10.1073/pnas.2531151123
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