bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2025–11–09
eighteen papers selected by
Hana Antonicka, McGill University
  1. Regulation of RNA-binding proteins by small biomolecules.
  2. Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
  3. Biomolecular condensates: molecular structure, biological functions, diseases, and therapeutic targets.
  4. Exploiting nanopore sequencing advances for tRNA sequencing of human cancer models.
  5. RNACOREX - RNA coregulatory network explorer and classifier.
  6. Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.
  7. Antimycin A: From mitochondrial poison to multifaceted biological probe and therapeutic agent.
  8. HemK class methyltransferase, a protein translation regulator: role in growth, development and phenotypic diversity.
  9. RNA binding of GAPDH controls transcript stability and protein translation in acute myeloid leukemia.
  10. Kinetoplast DNA structure, RNA editing patterns and small respiratory Complex I in Trypanosoma musculi.
  11. G-quadruplex ligand RHPS4 compromises cellular radioresistance by inhibiting the mitochondrial adaptive response induced by ionizing irradiation.
  12. Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
  13. 3S-DB identifies an RNA repository facilitating stop codon readthrough for selenocysteine insertion and selenoproteome expansion.
  14. Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
  15. The RNA-binding protein HNRNPA2B1 regulates neurite RNA abundance and motor-dependent cargo transport.
  16. Mitochondrial Leigh syndrome: the state of the art.
  17. Meta-analysis of mRNA dysregulation associated with Parkinson's disease and other neurological disorders.
  18. 18S and 25S Exonuclease Resistant Ribosomal RNA Molecules Are Produced by 5'-End Modification During TOR Inhibition.
  1. Nat Rev Mol Cell Biol. 2025 Nov 06.
    Regulation of RNA-binding proteins by small biomolecules.
    Weili Miao, Douglas F Porter, Vanessa Lopez-Pajares, Paul A Khavari.
      RNA-binding proteins (RBPs) are essential for post-transcriptional gene regulation, including for RNA modification such as N6-methyladenosine (m6A), splicing, polyadenylation, localization, translation and decay. Dysregulation of RBPs has been causally linked to a wide array of human diseases, including cancer, neurodegenerative diseases, metabolic disorders and tissue differentiation abnormalities. Although RBPs have traditionally been studied through their RNA, protein and post-translational interactions, growing evidence shows that small biomolecules (SBMs) such as sugars, nucleotides, metabolites such as S-adenosylmethionine (SAM) and NAD(P)H, and drugs can directly bind RBPs and modulate their structure, localization and RNA-binding activity. These context-dependent and concentration-dependent interactions link RBP regulation to cellular metabolism and are a key focus of current research. In this Review, we discuss the expanding landscape of SBM-binding RBPs and the functions of these RBPs in condensate formation, RNA localization, processing and translation. We highlight the molecular principles that underlie these interactions and their functional relevance to human diseases. We also examine recent advances in the identification of SBM-RBP interactions and the innovative methodologies that are driving discoveries in this rapidly advancing field. Together, these insights underscore the potential of SBMs to modulate RBPs and inform novel therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41580-025-00914-4
  2. Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):
    Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
    Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.
      The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.
    DOI:  https://doi.org/10.1093/nar/gkaf1140
  3. Mol Biomed. 2025 Nov 05. 6(1): 99
    Biomolecular condensates: molecular structure, biological functions, diseases, and therapeutic targets.
    Sunkyung Choi, Jung-Min Lee, Kee K Kim.
      Cells constantly encounter environmental and physiological fluctuations that challenge homeostasis and threaten viability. In response to these cues, specific proteins and nucleic acids engage in multivalent interactions and undergo phase separation to form membraneless assemblies known as biomolecular condensates. Nuclear condensates include paraspeckles, nuclear speckles, and Cajal bodies, while cytoplasmic condensates include stress granules, processing bodies, RNA transport granules, U-bodies, and Balbiani bodies. These assemblies regulate transcription, splicing fidelity, RNA stability, translational reprogramming, and integration of signaling pathways, thereby serving as dynamic platforms for metabolic regulation and physiological adaptation. However, dysregulation of these condensates has been increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases, cancers, and viral infections, contributing to toxic protein aggregation, nucleic acid dysregulation, and aberrant cell survival signaling. This review provides a comprehensive synthesis of the molecular mechanisms governing condensation, delineates the diverse types and functions of major biomolecular condensates, and examines therapeutic approaches based on their pathophysiological relevance to disease development and progression. Furthermore, we highlight the cutting-edge technologies, including CRISPR/Cas-based imaging, optogenetic manipulation, and AI-driven phase separation prediction tools, which enable the real-time monitoring and precision targeting of cytoplasmic biomolecular condensates. These insights underscore the emerging potential of biomolecular condensates as both biomarkers and therapeutic targets, paving the way for precision medicine approaches in condensate-associated diseases.
    Keywords:  Biomolecular condensate; Nuclear speckle; Paraspeckle; Phase separation; Stress granule
    DOI:  https://doi.org/10.1186/s43556-025-00350-y
  4. NAR Cancer. 2025 Dec;7(4): zcaf044
    Exploiting nanopore sequencing advances for tRNA sequencing of human cancer models.
    Adva Kochavi, Arno Velds, Maya Suzuki, Shinichiro Akichika, Tsutomu Suzuki, Roderick L Beijersbergen, Reuven Agami.
      Transfer RNAs (tRNAs) are essential regulators of protein synthesis, and dysregulation of their abundance and modification status is involved in many human diseases including cancer. Despite the rapid development of novel tRNA sequencing approaches, due to tRNAs' stable secondary structure and abundant modification sites, the human tRNA landscape has remained mostly unexplored. Here, we evaluated the new RNA004 chemistry of Oxford Nanopore Technologies, that is integrated with updated Dorado base-caller models, for tRNA quantification and modification annotation in human cancer models. We demonstrated that this technology identifies variations in tRNA expression across cancer cell lines and in response to external stress conditions, with highly reproducible results. We also show that analysis of base-calling error rate can indicate the presence of known modifications, including the cancer-associated tRNAPhe-Wybutosine modification. Furthermore, implementing the updated Dorado modification-calling feature, we showed the potential of RNA004 tRNA-seq in predicting common tRNA modifications. We also pinpointed possible limitations and challenges associated with both modification calling methods. Overall, RNA004 tRNA-seq can potentially enhance our understanding of the human tRNAome by simultaneously analyzing both tRNA abundance and modifications.
    DOI:  https://doi.org/10.1093/narcan/zcaf044
  5. PLoS Comput Biol. 2025 Nov;21(11): e1013660
    RNACOREX - RNA coregulatory network explorer and classifier.
    Aitor Oviedo-Madrid, José González-Gomariz, Ruben Armañanzas.
      Micro-RNAs (miRNA) and their relationship with messenger RNAs (mRNA) have been widely associated with disease development and progression. Post-transcriptional coregulatory networks are sets of miRNA-mRNA interactions that regulate specific genetic behaviors through their combined activity. However, identifying reliable sets of such interactions associated with specific diseases remains challenging, partly due to the high rate of false positives and the lack of user-friendly tools developed for this purpose. In this work, we introduce a new Python package called RNACOREX (RNA CORegulatory network EXplorer and classifier). RNACOREX is a new, easy-to-use tool that allows researchers to find disease associated post-transcriptional coregulatory networks and use them to classify new unseen observations of miRNA and mRNA quantifications. RNACOREX combines structural information from curated databases with expression data analysis, using conditional mutual information to infer reliable sets of miRNA-mRNA interactions. These sets are then used to build probabilistic models based on Conditional Linear Gaussian (CLG) classifiers, which allow both prediction on new samples and validation of the inferred networks. To demonstrate its capabilities, we tested RNACOREX in 13 different databases from the The Cancer Genome Atlas Program, generating the associated post-transcriptional coregulatory networks and extracting classification performance metrics for each tumor type. Specifically, we used RNACOREX to classify patients according to their survival time in each cancer type, highlighting miRNA-mRNA interactions that consistently appeared across different cancer types. The results show that RNACOREX achieves competitive predictive performance compared to widely used classification algorithms, while offering the added benefit of interpretability through its graph-based modeling framework.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013660
  6. Front Cell Infect Microbiol. 2025 ;15 1686785
    Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.
    Tracy Okine, Eleanor Hill, Kate Sheran, Talia H Swartz.
      Antiretroviral therapy (ART) has transformed HIV into a chronic, manageable condition, yet people living with HIV (PLWH) continue to experience persistent immune activation and systemic inflammation that drive long-term comorbidities, including neurocognitive impairment and cardiovascular disease. This residual inflammation requires new mechanistic explanations and targeted therapeutic approaches. Increasing evidence highlights mitochondria as central hubs in the regulation of cellular metabolism and immune responses. In PLWH, both HIV and ART disrupt mitochondrial function, leading to the release of proinflammatory mediators such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These signals activate the NLRP3 inflammasome, resulting in secretion of IL-1β and other cytokines. In parallel, excess mitochondrial ATP engages purinergic receptors such as P2X1 and P2X7, propagating inflammatory signaling to surrounding immune cells. This review examines the mito-immune axis in HIV, focusing on OxPhos dysregulation, inflammasome activation, and purinergic receptor signaling, and explores potential interventions-including purinergic antagonists-that aim not only to suppress viral replication but also to restore immunometabolic balance. By recognizing mitochondria as dynamic regulators of immune function, we outline a paradigm shift in HIV treatment that addresses the underlying drivers of chronic inflammation.
    Keywords:  ATP; HIV; OxPhos; inflammasome; inflammation; mitochondria
    DOI:  https://doi.org/10.3389/fcimb.2025.1686785
  7. Chem Biol Interact. 2025 Nov 03. pii: S0009-2797(25)00435-1. [Epub ahead of print]422 111805
    Antimycin A: From mitochondrial poison to multifaceted biological probe and therapeutic agent.
    Woo Hyun Park.
      Antimycin A is a member of a large family of depsipeptide natural products produced primarily by Streptomyces bacteria. First identified for its potent antifungal properties, it has become one of the most widely used and best-characterized inhibitors of cellular respiration. The canonical mechanism of Antimycin A involves high-affinity binding to the Qi site of the cytochrome bc1 complex (Complex III) in the mitochondrial electron transport chain, effectively blocking electron flow and halting ATP synthesis via oxidative phosphorylation. This inhibition leads to a cascade of profound cellular consequences, most notably the massive production of superoxide radicals from the Complex III Qo site, induction of oxidative stress, and the initiation of cell death pathways such as apoptosis. However, decades of research have revealed that the biological activities of Antimycin A extend far beyond its role as a simple mitochondrial poison. It is a key modulator of complex cellular processes including autophagy and mitophagy, and a molecule with a surprisingly diverse and potent range of bioactivities. Recent studies have highlighted its potential as an anticancer agent that selectively targets tumor cells, a potential antifungal and antiviral therapy, and an indispensable chemical probe for investigating mitochondrial function and retrograde signaling. This review synthesizes the current understanding of Antimycin A, covering its biosynthesis and chemical diversity, its detailed molecular mechanism of action, its multifaceted impacts on cellular physiology in organisms from yeast to humans, and its expanding applications in both basic research and as a potential therapeutic agent.
    Keywords:  Antimycin A; Biosynthesis; Mitochondrial complex III; Oxidative stress; Therapeutic potential
    DOI:  https://doi.org/10.1016/j.cbi.2025.111805
  8. Mol Biol Rep. 2025 Nov 06. 53(1): 58
    HemK class methyltransferase, a protein translation regulator: role in growth, development and phenotypic diversity.
    Swapnaneel Pal, Surjit Singh.
      Across eukaryotic and prokaryotic life forms, translation termination occurs followed by disassembly of ribosomal subunits and release of the nascent polypeptide. This process is governed by the presence of Release factors or translation termination factors, which render polypeptide hydrolysis from the peptidyl t-RNA by interacting with its conserved GGQ motif. Studies have shown that methylation of Release Factors by Methyltransferases at this highly conserved motif is necessary for efficient translation termination; failure to do so leads to the accumulation of polyribosomes and subsequently altered protein synthesis, ultimately resulting in an undesired phenotype. HemK class methyltransferases are a widely conserved class of enzymes involved in the methylation of Glutamine. Due to methylation of release factors by HemK at the GGQ motif, faithful translation termination occurs. Its absence leads to reduced stress tolerance as well as developmental abnormalities and other detrimental effects. Studies have suggested HemK to be associated with DNA methylation as well as chromatin remodelling activities. This review provides a brief overview of the role of HemK as a translational as well as transcriptional regulator, and its function in prokaryotic and eukaryotic systems.
    Keywords:  Growth and development; HemK; Methyltransferase; Protein translation; Ribosomal release factor
    DOI:  https://doi.org/10.1007/s11033-025-11233-4
  9. RNA Biol. 2025 Dec;22(1): 1-23
    RNA binding of GAPDH controls transcript stability and protein translation in acute myeloid leukemia.
    Sama Shamloo, Jeffrey L Schloßhauer, Shashank Tiwari, Kim Denise Fischer, Omar Almolla, Yohana Ghebrechristos, Lisa Kratzenberg, Aathma Merin Bejoy, Ioannis Aifantis, Francesco Boccalatte, Eric Wang, Jochen Imig.
      Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukaemia (AML) RBPs are key regulators of tumour proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear. Given the inherent complexity of targeting AML broadly, our goal was to uncover potential ncRBP candidates critical for AML survival using a CRISPR/Cas-based screening. We identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a pro-proliferative factor in AML cells. Based on cross-linking and immunoprecipitation (CLIP), we are defining the global targetome, detecting novel RNA targets mainly located within 5'UTRs, including GAPDH, RPL13a, and PKM. The knockdown of GAPDH unveiled genetic pathways related to ribosome biogenesis, translation initiation, and regulation. Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML.
    Keywords:  AML; Glyceraldehyde-3-phosphate dehydrogenase; RNA binding protein; mRNA stabilization; ribosome-nascent chain complex; translation
    DOI:  https://doi.org/10.1080/15476286.2025.2580180
  10. Commun Biol. 2025 Nov 07. 8(1): 1544
    Kinetoplast DNA structure, RNA editing patterns and small respiratory Complex I in Trypanosoma musculi.
    Ju-Feng Wang, Ying-Xin Bi, Michael Hammond, Julius Lukeš, De-Hua Lai, Zhao-Rong Lun.
      Kinetoplast (k) DNA, a specialized form of mitochondrial DNA in trypanosomes, is composed of catenated maxicircles and minicircles, and is essential for the survival of these parasitic protists. In this study, we provide a detailed description of the near-complete minicircle complement of Trypanosoma musculi, a globally distributed, mouse-specific haemoflagellate. We have identified 39 minicircle classes, which can be grouped via their structural organization into five distinct categories. Using RNA-seq, we have reconstructed mitochondrial transcripts of ATP6, RPS12, CYTB, COX2 and COX3, all of which undergo canonical editing that renders them translatable, as well as abnormally edited transcripts of four respiratory Complex I subunits. Additionally, through a combined analysis of the kDNA minicircles, edited mRNAs and small RNAs, we identified 108 guide (g)RNA genes and further categorized their conservation in comparison with Trypanosoma lewisi, an opportunistic human parasite. Moreover, we demonstrate a small respiratory Complex I in T. musculi, highlighting the functional consequences of missing gRNAs. Finally, we propose a model for the evolutionary maintenance of gRNAs, contributing to our understanding of kDNA dynamics in trypanosomes and other kinetoplastid flagellates.
    DOI:  https://doi.org/10.1038/s42003-025-08883-2
  11. NAR Cancer. 2025 Dec;7(4): zcaf033
    G-quadruplex ligand RHPS4 compromises cellular radioresistance by inhibiting the mitochondrial adaptive response induced by ionizing irradiation.
    Sabine Tricot, Capucine Siberchicot, Isaline Bontemps, Chantal Desmaze, Gueorgui Kratassiouk, Marie Vandamme, Guillaume Pinna, Ivan Nemazanyy, J Pablo Radicella, Guy Lenaers, Xavier Renaudin, Jérome Lebeau, Anna Campalans.
      A major challenge in radiotherapy is to enhance tumour cell sensitivity to radiation while minimizing damage to healthy tissues. Enhancing the effectiveness of radiotherapy can be achieved by combining irradiation with small radiosensitizing molecules, which promote cancer cell death and allow for reduced radiation doses, thereby limiting harm to surrounding healthy tissues. Since mitochondria play a key role in tumour cell proliferation, they represent a promising therapeutic target for cancer treatment. In this study, we characterized the impact of irradiation on mitochondrial function in radioresistant cancer cells. Our findings revealed several adaptive responses that may contribute to radioresistance, including increased mitochondrial DNA (mtDNA) content, mitochondrial mass, enhanced activity, and hyperfusion of the mitochondrial network. Notably, the use of mitochondrial-targeted G-quadruplex (G4) ligands, which block mtDNA replication and transcription, disrupted these responses, reducing cancer cell survival in a mtDNA-dependent manner. These results demonstrate that mitochondrial adaptations contribute to radioresistance and highlight mitochondria as a novel target for the radiosensitizing effects of G4 ligands.
    DOI:  https://doi.org/10.1093/narcan/zcaf033
  12. Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]
    Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
    Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.
      Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.
    Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
  13. Redox Biol. 2025 Nov;pii: S2213-2317(25)00401-X. [Epub ahead of print]87 103888
    3S-DB identifies an RNA repository facilitating stop codon readthrough for selenocysteine insertion and selenoproteome expansion.
    Chenfang Si, Lu Zhang, Jing Gao, Kongyan Niu, Yunxia Li, Nan Liu, Bing Shan, Yaoyang Zhang.
      Selenoproteins contain the selenocysteine (Sec, U), which is essential for redox regulation due to its reactive selenol group. The current set of 25 human selenoproteins was defined by the presence of SECIS elements in the 3' UTR coupled with in-frame UGA codons through a stop codon readthrough mechanism. However, the discovery of novel selenoproteins and SECIS elements remains limited by the constraints of SECIS prediction methods. In this study, we focus on SECISBP2, the core SECIS-binding protein, to analyze its binding RNAs using RNA immunoprecipitation sequencing (RIP-Seq) technology. We constructed the 3S-DB, a database of 1,333 SECISBP2-bound RNAs with potential SECIS functions for UGA recoding, including most known selenoprotein transcripts. Importantly, we validate that the 3' UTRs of PDF and ATP5MJ exhibit SECIS activity using luciferase assays and by fusing them to known selenoprotein RNAs. In summary, our results provide a valuable resource of mRNAs with potential for UGA recoding and previously unrecognized SECIS elements, with the potential to expand the known selenoproteome and advance our understanding of their roles in redox biology and beyond. Furthermore, this work offers new insights into non-canonical stop codon readthrough and the broader mechanisms governing translational regulation of the genetic code.
    Keywords:  Redox biology; SECIS; SecMS; Selenoprotein; Stop codon readthrough
    DOI:  https://doi.org/10.1016/j.redox.2025.103888
  14. J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]
    Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
    Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.
      Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.
    Keywords:  Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone
    DOI:  https://doi.org/10.1093/jb/mvaf062
  15. Mol Biol Cell. 2025 Nov 05. mbcE25080383
    The RNA-binding protein HNRNPA2B1 regulates neurite RNA abundance and motor-dependent cargo transport.
    Joelle Lo, Levi B Gifford, Katherine F Vaeth, Amber Baldwin, Gurprit Bhardwaj, Camille E A Goo, Neelanjan Mukherjee, Holger A Russ, Jeffrey K Moore, J Matthew Taliaferro.
      RNA molecules are localized to subcellular regions through interactions between localization-regulatory cis-elements and trans-acting RNA binding proteins (RBPs). However, the identities of RNAs whose localization is regulated by a specific RBP as well as the impacts of that RNA localization on cell function have generally remained unknown. Here, we demonstrate that the RBP HNRNPA2B1 acts to keep specific RNAs out of neuronal projections. Using subcellular fractionation, high-throughput sequencing, and single molecule RNA FISH, we find that hundreds of RNAs demonstrate markedly increased abundance in neurites in HNRNPA2B1 knockout cells. These RNAs often encode motor proteins and are enriched for known HNRNPA2B1 binding sites and motifs in their 3' UTRs. The speed and processivity of microtubule-based transport is impaired in these cells. HNRNPA2B1 point mutations that increase its cytoplasmic abundance relative to wildtype lead to stronger suppression of RNA mislocalization defects than seen with wildtype HNRNPA2B1. We further find that the subcellular localizations of HNRNPA2B1 target RNAs are sensitive to perturbations of RNA decay machinery, suggesting that HNRNPA2B1's known role in regulating cytoplasmic RNA stability may explain these observations. These findings establish HNRNPA2B1 as a negative regulator of neurite RNA abundance and a necessary factor for efficient motor-dependent cargo transport. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-08-0383
  16. Arch Pediatr. 2025 Nov 05. pii: S0929-693X(25)00182-4. [Epub ahead of print]
    Mitochondrial Leigh syndrome: the state of the art.
    Gauthier Toutain, Célia Hoebeke, Marguerite Gastaldi, Mathieu Milh, Brigitte Chabrol.
       BACKGROUND: Leigh syndrome or subacute necrotizing encephalomyelopathy was first recognized as a neuropathological entity in 1951. It is a progressive neurological disease characterized by neuroradiological lesions, particularly in the brainstem and basal ganglia. Leigh's syndrome is a pan-ethnic disorder with onset usually in infancy or early childhood. Over the last six decades, this complex neurodegenerative disorder has been shown to comprise >100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This article reviews clinical, radiological, biochemical and genetic aspects of the disorder.
    OBJECTIVES: this overview provides a better understanding of this rare mitochondrial disease by identifying its clinical, radiological and genetic manifestations in order to improve early diagnosis, patient follow-up and genetic counseling.
    METHODOLOGY: systematic literature review RESULTS: Leigh syndromes present with childhood developmental regression, a loss of previously achieved developmental milestones. Numerous non-neurological manifestations of Leigh syndrome have been reported, many of which are related to the underlying genetic defects. These include cardiomyopathy, renal tubulopathy, gastrointestinal and endocrine dysfunction, and liver disease. Known genetic causes, including defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon CONCLUSION: Management of mitochondrial diseases must be multidisciplinary, and in collaboration with a center of reference (CRMR) or a center of competence (CCMR) with expertise in mitochondrial diseases.
    Keywords:  Central nervous system; Genetic; Itochondrial DNA; Leigh syndrome; Metabolic disease; Mitochondrial disease; Neurodegeneration; Neuroimaging; Nuclear DNA; OXPHOS; Treatment
    DOI:  https://doi.org/10.1016/j.arcped.2025.04.007
  17. Biomed Phys Eng Express. 2025 Nov 03.
    Meta-analysis of mRNA dysregulation associated with Parkinson's disease and other neurological disorders.
    Tun Lin Aung, Ye Win Aung, Xiaoran Shi.
      Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, characterized by both motor and non-motor symptoms. In this study, we conducted a meta-analysis of gene expression profiles from four GEO datasets (comprising 59 PD patients and 41 participants control) to identify consistently differentially expressed messenger ribonucleic acids (DEmRNAs). We identified 5,495 down-regulated and 9,850 up-regulated DEmRNAs, of which 64 and 25, respectively, were common across all datasets. Functional enrichment analysis revealed that down-regulated DEmRNAs were primarily enriched in pathways related to neurotransmitter transport, dopamine biosynthesis, and dopaminergic synapse function, while up-regulated DEmRNAs were linked to cell cycle regulation and PI3K-Akt signaling. Notably, dysregulation of key genes, including SNCA (encoding α-synuclein), SLC6A3, TUBB, TUBB3, TUBB4B, and NDUFA9, were associated with PD as well as other neurodegenerative disorders, such as Alzheimer's, Huntington's, and Prion diseases. These DEmRNAs and pathways may offer potential biomarkers and therapeutic targets for PD and related neurological disorders.
    Keywords:  Differentially Expressed Genes; Functional Enrichment and Pathway Analysis; Meta-Analysis; Neurodegeneration; Parkinson ’s disease; Transcriptomics
    DOI:  https://doi.org/10.1088/2057-1976/ae1a8a
  18. Yeast. 2025 Nov 06.
    18S and 25S Exonuclease Resistant Ribosomal RNA Molecules Are Produced by 5'-End Modification During TOR Inhibition.
    Miguel A Rocha, Gowda Bhavani, Jacob Fleischmann.
      Saccharomyces cerevisiae yeast cells have been shown to produce 18S and 25S ribosomal RNA molecules that are resistant to degradation by exonucleases, which require a 5' monophosphate for activity. These resistant RNA species accumulate during the diauxic shift, a phase marked by reduced TOR signaling. To further investigate the link between TOR activity and the accumulation of resistant rRNA, we examined the effects of pharmacological TOR inhibition. Treatment with rapamycin, an active TOR suppressor, led to increased levels of resistant 18S and 25S RNA. Importantly, this accumulation was also observed in cells with constitutively active RNA polymerase I (CARA), indicating that the resistant RNA species arise independently of RNA Pol I transcriptional regulation. Similarly, a TOR1-deleted mutant of Saccharomyces cerevisiae produces resistant 18S and 25S rRNA species in a sustained manner. Thiouracil labeling revealed that rRNA molecules generated during the logarithmic growth phase can be converted into the resistant form, suggesting a posttranscriptional modification process. Furthermore, thiouracil uptake assays demonstrated that overall rRNA synthesis decreases during the diauxic phase. Notably, decapping of the resistant rRNAs restored their sensitivity to exonucleases, indicating that the resistance is conferred by 5' end modifications, likely involving the addition of one or more phosphate groups.
    DOI:  https://doi.org/10.1002/yea.70007
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒09 at 4:44.