bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–02–08
thirteen papers selected by
Hana Antonicka, McGill University
  1. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  2. Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
  3. Suppression of interferon signaling via small-molecule modulation of TFAM.
  4. The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
  5. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  6. PCLIPtools: a robust framework for identifying RNA-protein interaction sites from PAR-CLIP experiments.
  7. Mitochondrial specialization and signaling shape neuronal function.
  8. Ribosomal Protein bL27 Protects Translating Ribosomes from tmRNA-SmpB.
  9. SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
  10. Application progress of tRNA modification in gynecological tumors: A review.
  11. Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
  12. Taurine Restores Oocyte Quality by Enhancing Mitochondrial Function in Mice Exposed to Dibutyl Phthalate during Adolescence.
  13. Mechanisms of microRNA trafficking to mitochondria in the heart.
  1. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  2. bioRxiv. 2026 Jan 25. pii: 2026.01.25.701366. [Epub ahead of print]
    Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
    Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.
      Accurate replication of mitochondrial genome (mtDNA) integrity, which is essential for cellular metabolism and energy supply, relies primarily on DNA polymerase gamma (Pol γ), Twinkle helicase, and mitochondrial single-stranded DNA binding protein (mtSSB). Twinkle alone exhibits little helicase activity while reports indicate that Pol γ displays from modest to limited unwinding activity. This led us to dissect Pol γ strand displacement activity using structural, biochemical and in silico approaches. Here, we show that human Pol γ carries out robust strand displacement synthesis at physiological concentrations of divalent metal ions which reveals that distinct metal-binding sites can independently regulate DNA synthesis and unwinding activities. We further showed that Pol γ can displace RNA/DNA hybrid with comparable efficiency as DNA/DNA duplex, representing a key implication on RNA primer removal to preserve mtDNA integrity. Our cryo-electron microscopy structures of Pol γ complexed with a template containing downstream dsDNA and an incoming nucleotide revealed the structural mechanism for the strand displacement activity. We identified four conformational states that represent successive stages of DNA unwinding, accompanied by coordinated rearrangement of the downstream DNA and Pol γ elements that mediate strand displacement. This work establishes biochemical and structural mechanisms of Pol γ strand displacement activity, providing fundamental insight into human mitochondrial DNA replication and integrity.
    Graphical abstract:
    DOI:  https://doi.org/10.64898/2026.01.25.701366
  3. Elife. 2026 Feb 06. pii: RP108742. [Epub ahead of print]14
    Suppression of interferon signaling via small-molecule modulation of TFAM.
    Dionisia Sideris, Husan Lee, Lyndsay Olson, Kalyan Nallaparaju, Keiichiro Okuyama, Jeffrey Ciavarri, Robert Lafyatis, Mads Larsen, Bo Lin, Irene Alfaras, Jason Kennerdell, Toren Finkel, Yuan Liu, Bill Chen, Lin Lyu.
      The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.
    Keywords:  TFAM; cGAS-STING pathway; cell biology; human; interferon sinaling; mitochondria; mitochondrial DNA; small molecule
    DOI:  https://doi.org/10.7554/eLife.108742
  4. Curr Biol. 2026 Feb 03. pii: S0960-9822(26)00006-0. [Epub ahead of print]
    The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
    Ryan R Cupo, Eunice Domínguez-Martín, Richard Youle.
      Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.
    Keywords:  Atg1; Atg32; Drp1; NUMT; STING; autophagy; fission; lysosome; nucleoid; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.01.006
  5. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699287. [Epub ahead of print]
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfam fl/fl Ub Cre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2026.01.13.699287
  6. Nucleic Acids Res. 2026 Jan 22. pii: gkag062. [Epub ahead of print]54(3):
    PCLIPtools: a robust framework for identifying RNA-protein interaction sites from PAR-CLIP experiments.
    Ahsan H Polash, Markus Hafner.
      PAR-CLIP is a widely used method for identifying binding sites of RNA-binding proteins (RBPs) transcriptome-wide. A characteristic T-to-C transition in the sequenced complementary DNA pinpoints the site of RBP-RNA crosslinking and is induced by the use of a photoreactive uridine analogue, 4-thiouridine (4SU). As with other system-wide methods, PAR-CLIP, too, is prone to false discoveries, as the T-to-C signal might result from systematic noise, pre-existing SNPs, and polymerase chain reaction errors. Therefore, rigorous statistical methods are required for analyzing PAR-CLIP data. The few existing tools to analyze PAR-CLIP data lack updates and sufficient documentation, and often fail to process current higher-depth sequencing data. Here, we report PCLIPtools, a lightweight, customizable suite for analyzing PAR-CLIP data. PCLIPtools considers the read depth, T-to-C transitions, and the other mutations to statistically estimate high-confidence interaction sites. Benchmarking shows that PCLIPtools identifies more functionally significant targets than the current standard tool, PARalyzer, without losing high-confidence sites and outperforming it in runtime. Exploratory analyses show PCLIPtools' specific targets are enriched for read depth and T-to-C conversion, supporting their validity. With simplicity, robustness, and speed, PCLIPtools improves the precision of PAR-CLIP data analysis while being accessible to experimental RNA biologists.
    DOI:  https://doi.org/10.1093/nar/gkag062
  7. Trends Neurosci. 2026 Feb 03. pii: S0166-2236(25)00263-2. [Epub ahead of print]
    Mitochondrial specialization and signaling shape neuronal function.
    Benjamin Chun-Kit Tong, Francesco Gubinelli, Lena F Burbulla, Angelika B Harbauer.
      Neurons are specialized cells designed to process information and transmit it, often across long distances. In many neurons, the axonal volume far exceeds the somato-dendritic volume, creating a need for long-range transport and local polarization mechanisms. In addition, action potential firing and restoration of ionic gradients, as well as dynamic changes in synaptic plasticity, further increase the energetic demands of neurons. In this review, we highlight the roles mitochondria play in vertebrate neuronal biology and how mitochondrial functionality is tuned to support the unique demands of neurons. We cover the influence of mitochondrial positioning, ATP generation and Ca2+ buffering on neuronal function, and explore the role of mitochondria in neurotransmitter metabolism and local protein translation.
    Keywords:  Ca(2+) signaling; local translation; neuronal cell biology; neurotransmitter metabolism; respiration; transport
    DOI:  https://doi.org/10.1016/j.tins.2025.12.006
  8. bioRxiv. 2026 Jan 19. pii: 2026.01.19.700400. [Epub ahead of print]
    Ribosomal Protein bL27 Protects Translating Ribosomes from tmRNA-SmpB.
    Divyasorubini Seerpatham, George Wanes, Chathuri Pathirage, Mynthia Cabrera, Edu Usoro, Kristin Koutmou, Christine M Dunham, Paul C Whitford, Kenneth C Keiler.
      Bacterial ribosomal protein bL27 is universally conserved and its amino terminus is adjacent to the peptidyl transfer center, yet its role in translation remains unclear. Combining genetics, biochemistry and molecular dynamics, we show that bL27 has an unexpected role in preventing trans -translation, the bacterial ribosome rescue mechanism, from interfering with protein synthesis. Deletion of the bL27 gene causes a 10,000-fold decrease in viability and this defect is partially rescued by deletion of the gene encoding tmRNA, a critical molecule for trans -translation. Molecular dynamics simulations also indicate that bL27 can slow the movement of tmRNA on the ribosome. These data link trans -translation and bL27, and support a model in which the amino terminus of bL27 acts as a gatekeeper to prevent tmRNA from sterically interfering with tRNA on the ribosome.
    DOI:  https://doi.org/10.64898/2026.01.19.700400
  9. Nat Metab. 2026 Feb 06.
    SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
    Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.
      Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.
    DOI:  https://doi.org/10.1038/s42255-026-01455-6
  10. Int J Biol Macromol. 2026 Feb 03. pii: S0141-8130(26)00653-7. [Epub ahead of print] 150727
    Application progress of tRNA modification in gynecological tumors: A review.
    Pengfei Wang, Xiaofei Chen, Lujiadai Xue, Yapeng Huang, Xiaoyu Wang, Weidong Ji, Hu Li.
      The conventional role of tRNA as a pivotal molecule in protein synthesis is well-established. However, recent studies have unveiled a previously underappreciated function of tRNA chemical modifications in tumor biology, particularly in tumor initiation, progression, and metastasis. Gynecological malignancies represent a significant threat to women's health. Despite advances in medical technology, gynecological malignancies remain difficult to manage, partly due to limited treatment options. Delayed diagnosis and high tumor heterogeneity further contribute to poor prognosis. This review focuses on tRNA modifications in gynecological cancers, including ovarian, cervical, and endometrial cancers. It systematically elucidates the expression profiles and regulatory mechanisms of various tRNA modifications. Additionally, it explores their correlation with malignant characteristics-such as enhanced tumor cell proliferation, drug resistance, invasion, and metastasis. Furthermore, it explores the translational potential of these modifications as biomarkers, therapeutic targets, and prognostic indicators, and the potential links in the TME, metabolic reprogramming, and Immunotherapeutic Response, offering a novel perspective for the precise diagnosis and management of gynecological tumors.
    Keywords:  Gynecological tumor; Methylation; Pseudouridylation; Queuosine; tRNA modification
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150727
  11. Brain. 2026 Feb 02. pii: awag037. [Epub ahead of print]
    Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
    Marton Szabo, Daniel Lagos, Emily Cross, Jack Collier, Rita Horvath.
      Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.
    Keywords:  mitochondria derived vesicles (MDVs); mtDNA; mtDNA release, primary mitochondrial diseases (PMD); pathogen-associated molecular patterns (PAMPs); sterile-inflammation
    DOI:  https://doi.org/10.1093/brain/awag037
  12. Free Radic Biol Med. 2026 Feb 04. pii: S0891-5849(26)00066-3. [Epub ahead of print]
    Taurine Restores Oocyte Quality by Enhancing Mitochondrial Function in Mice Exposed to Dibutyl Phthalate during Adolescence.
    Yidan Ma, Liping Yan, Yan Zhang, Yanqing Geng, Xin Yin, Rufei Gao, Xinyi Mu, Xiaoqing Liu, Junlin He.
      Adolescence represents a vulnerable window for ovarian development, during which oocytes rely heavily on mitochondrial bioenergetics and redox homeostasis. Dibutyl phthalate (DBP) is a widely used plasticizer recognized for its endocrine-disrupting properties. It can compromise oocyte integrity during these sensitive developmental stages. We found that adolescent DBP exposure impairs oocyte quality in mice, causing fragmentation, meiotic arrest, spindle disorganization, and chromosome misalignment. Smart RNA-seq analysis of DBP-exposed oocytes revealed that these defects are associated with mitochondrial dysfunction, particularly impairment of respiratory chain complex I. Consistently, DBP exposure induced mitochondrial clustering, excessive ROS production, loss of membrane potential, ATP depletion, and suppression of complex I activity, which could be recapitulated by in vitro administration of MBP, a bioactive DBP metabolite. Inhibition of complex I with rotenone reduced oocyte maturation and mitochondrial membrane potential, supporting complex I as a primary target of DBP-induced injury. Mechanistically, DBP reduced 5-taurinomethyluridine (τm5U) modification of mitochondrial tRNAs and decreased the protein level of the mitochondrially encoded complex I subunit MT-ND1, leading to impaired complex I activity. Systemic taurine availability was also reduced. Notably, taurine supplementation restored τm5U modification and enhanced MT-ND1 translation, thereby rescuing complex I activity and reestablishing mitochondrial function. These improvements mitigated DNA damage and apoptosis, corrected meiotic defects, and rescued oocyte maturation, embryonic development, and fertility. Together, our findings indicate that DBP disrupts oocyte development by impairing mitochondrial redox homeostasis in mice, and suggest that taurine supplementation can restore mitochondrial function and preserve female fertility under environmental insults.
    Keywords:  Dbutyl phthalate; Mitochondrial function; Oocyte; Taurine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.046
  13. Curr Opin Physiol. 2025 Sep;pii: 100848. [Epub ahead of print]45
    Mechanisms of microRNA trafficking to mitochondria in the heart.
    Diego Quiroga, Rachel Daniel, Samarjit Das.
      MicroRNAs (miRNAs) are essential post-transcriptional regulators of gene expression, and accumulating evidence supports their presence and function within mitochondria. These mitochondrial microRNAs (MitomiRs) modulate key processes such as oxidative phosphorylation, ATP production, calcium homeostasis, and reactive oxygen species balance in cardiac tissue. Despite growing recognition of their importance, the mechanisms governing miRNA trafficking to mitochondria remain incompletely understood. This review explores the current knowledge on miRNA biogenesis, mitochondrial import pathways - including the roles of Argonaute 2 (AGO2), the Translocase of the Outer/Inner Mitochondrial Membrane (TOM/TIM) complexes, and Polynucleotide Phosphorylase (PNPase) - and the regulatory impact of specific MitomiRs, such as miR-181c, miR-210, miR-378, let-7b, and miR-1. Understanding how these molecules influence mitochondrial function provides insight into their therapeutic potential in cardiovascular disease.
    DOI:  https://doi.org/10.1016/j.cophys.2025.100848
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒09 at 20:00.