bims-mirnam 2026-06-21 papers

Issue of 2026–06–21
four papers selected by
Hana Antonicka, McGill University

Biochem Soc Trans. 2026 Jun 24. 54(6): 755-767

The impact of psuedouridine modification on human tRNA.

Yasmin Stone, Ethan Morgan, Yong-Han Su, Ching-Ying Kuo, Ting-Yu Lin.

Transfer RNA (tRNA) is an important RNA in cells that decodes messenger RNA (mRNA) codons during protein translation to ensure correct amino acid sequences. The biogenesis of tRNA involves multiple processing steps to produce mature and functional molecules. Pseudouridine (Ψ), a derivative of uridine, is an abundant RNA modification and occurs at multiple positions within tRNAs. These modified sites are highly conserved across organisms. Classical biochemical studies have established that Ψ stabilises RNA-RNA interactions, but structural characterisations and molecular dynamics simulations reveal that Ψ can locally remodel tRNA architecture in ways that are dictated by where it is within tRNAs. Advances in transcriptome-wide Ψ mapping have uncovered additional modified sites beyond those previously described, with several novel sites appearing to be regulated in a cellular context-dependent manner. Furthermore, dysregulated pseudouridylation has been implicated in conditions ranging from cancer to inherited genetic disorders. Together, these developments reframe our understanding of Ψ from a well-established RNA stabiliser to a modification with roles far more dynamic, context-dependent, and clinically relevant than previously appreciated. The present review summarises and discusses the up-to-date developments in the impacts of pseudouridylation on human tRNA biogenesis, tRNA functions, and human health. More mechanistic questions remain open and will require further investigation. As pseudouridylation can also happen in mRNA and rRNA, exploring the interplay between these RNAs will be crucial for fundamental biology and advancing Ψ applications in biotechnology and biomedical uses.

Keywords: Pseudouridine; Pseudouridine synthases; RNA modifications; cancer; neurodevelopmental disorders; tRNA

DOI: https://doi.org/10.1042/BST20250258

Protein Sci. 2026 Jul;35(7): e70682

Co-translational protein targeting to mitochondria in the context of co-translational protein maturation.

Nikita A Kvasov, Yury S Bykov.

Mitochondria import the majority of their proteins from the cytosol, creating a fundamental challenge: precursor proteins must be synthesized, maintained in an import-competent state, and delivered to mitochondrial translocases without premature folding or aggregation. While mitochondrial protein import has been considered a post-translational process, growing evidence shows that a subset of mitochondrial proteins is synthesized in proximity to the organelle. We term this process co-translational targeting, or local translation. It may lead to direct structural coupling of protein synthesis and import, which we term co-translational translocation. New approaches, including selective ribosome profiling, proximity labeling, and RNA imaging, reveal that mitochondrial mRNA localization is highly dynamic and can be driven by both RNA-based and translation-dependent mechanisms. In contrast to the well-defined signal recognition particle pathway at the endoplasmic reticulum, mitochondrial targeting appears to rely on more flexible mechanisms shaped by nascent-chain properties, translation elongation, and coding-sequence features beyond the targeting signal. We discuss how these processes may support mitochondrial biogenesis and proteostasis while also creating vulnerabilities associated with ribosome stalling and precursor quality control. Together, recent findings position mitochondrial protein targeting as an integral part of cellular protein biogenesis and highlight key open questions in the coordination of translation and organelle function.

Keywords: NAC; chaperones; co‐translational import; mRNA localization; mitochondria; protein targeting; translation

DOI: https://doi.org/10.1002/pro.70682

Sci Adv. 2026 Jun 19. 12(25): eaec3505

NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.

Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.

DOI: https://doi.org/10.1126/sciadv.aec3505

Signal Transduct Target Ther. 2026 Jun 18. pii: 240. [Epub ahead of print]11(1):

Targeting N1-methyladenosine modification in osteoblasts through tRNA methyltransferase 10C reverses mitochondrial dysfunction and ameliorates osteoporosis.

Haijian Sun, Wei Wang, Chi Zhang, Tehan Zhang, Xiaoli Yang, Yanbin Feng, Liying Shan, Zheng Yang, Yan Zhang, Shenghou Liu, Wenzhao Wang, Juncheng Wang, Xuben Hou, Shiqing Feng.

Osteoporosis is among the most common degenerative systemic bone diseases and is accompanied by abnormally downregulated oxidative phosphorylation (OXPHOS) in osteoblasts. While mutations in the tRNA methyltransferase (TRMT10C) gene in humans are known to cause OXPHOS dysfunction and early mortality, its role in bone homeostasis remains unknown. Here, we observed markedly reduced expression of TRMT10C, which is encoded by the nuclear genome, and OXPHOS subunits, which are encoded by the mitochondrial (mt) genome, in osteoblasts from both age-related and estrogen deficiency-induced osteoporosis mice. Conditional knockout of Trmt10c in osterix-expressing osteoprogenitor cells resulted in growth retardation, bone loss, and spontaneous fractures. Critically, through a multistage in silico screening approach, we identified a novel small-molecule compound as a TRMT10C agonist for the first time. Pharmacological activation of TRMT10C by this compound significantly promoted bone formation and ameliorated osteoporotic phenotypes in both aged and ovariectomized mice. Mechanistically, this study provides the first evidence that TRMT10C can bind to and catalyze the N1-methyladenosine (m1A) modification of mt-rRNA, in addition to its known role in catalyzing the m1A modification of mt-tRNA and mt-mRNA. This study reveals a previously unknown role for TRMT10C in bone metabolism and identifies it as a promising therapeutic target for osteoporosis.

DOI: https://doi.org/10.1038/s41392-026-02740-2