bims-mirnam 2026-04-05 papers

Issue of 2026–04–05
nine papers selected by
Hana Antonicka, McGill University

Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00167-X. [Epub ahead of print]86(7): 1195-1196

A splicing factor's unexpected detour to the mitochondrial surface.

In this issue of Molecular Cell, Garcia et al.1 reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.

DOI: https://doi.org/10.1016/j.molcel.2026.03.011

bioRxiv. 2026 Mar 27. pii: 2026.03.25.714317. [Epub ahead of print]

Pathogenic human mitochondrial tRNA variants impair RNA processing by compromising 5' leader removal.

Jubilee H Muñozvilla, Avery Ontiveros, Tatiana V Mishanina.

Human mitochondrial genome (mtDNA) encodes multiple proteins in the oxidative phosphorylation complexes as well as the ribosomal and transfer RNAs (tRNAs) needed for in situ translation. These genes are transcribed from only three promoters, producing polycistronic transcripts that are co-transcriptionally cleaved by mitochondrial RNase enzymes to release majority of individual gene products. tRNAs separate many of these genes and are thought to serve as "punctuation" marks that enable RNase recognition, binding, and hydrolysis of the 5' "leader" and 3' "trailer" sequences flanking the tRNA. Mutations in the tRNA genes dominate the mtDNA-linked mitochondrial pathologies; yet a systematic study of the impact of tRNA sequence variation on the RNase-catalyzed processing is lacking. Here, we employed human mitochondrial tRNA Tyr as a model system to dissect the effect of tRNA variants on the in vitro 5' leader and 3' trailer hydrolysis. We found that nucleotide variations located near the catalytic interfaces - particularly within or near the tRNA acceptor stem - showed the strongest defects in 5' processing and prevented release of the downstream tRNA in a tRNA cluster where multiple tRNAs are transcribed in tandem. This work provides mechanistic insight into how mutations disrupt coordinated mitochondrial tRNA processing and establish a framework for predicting variant effects based on their structural position relative to the processing enzymes.

DOI: https://doi.org/10.64898/2026.03.25.714317

Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00162-0. [Epub ahead of print]86(7): 1293-1310.e14

U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.

Gloria R Garcia, Murali Palangat, Josquin Moraly, Benjamin T Donovan, Bixuan Wang, Ira Phadke, David Sturgill, Jiji Chen, Guofeng Zhang, Ronald J Holewinski, Brittney Short, Gustavo A Rivero, David M Swoboda, Naomi Taylor, Kathy McGraw, Daniel R Larson.

The mechanisms underlying molecular targeting to mitochondria remain enigmatic, yet this process is crucial for normal cellular function. The RNA-binding proteins U2AF1 and U2AF2 form a heterodimer (U2AF) that shuttles between the nucleus and cytoplasm, regulating splicing in the nucleus and translation in the cytoplasm. Our study in human bronchial epithelial cells (HBECs) identifies an unexpected role for U2AF in mitochondrial function. We demonstrate that U2AF interacts with nuclear-encoded mitochondrial (NE-mt) mRNAs and proteins, inhibits translation, localizes to the mitochondria, and regulates mRNA localization to mitochondria. Moreover, an oncogenic point mutation in U2AF1(S34F) disrupts this regulation, leading to altered mitochondrial structure, increased translation, large changes in the mitochondria proteome, and oxidative phosphorylation (OXPHOS)-dependent metabolic rewiring, recapitulating changes observed in bone marrow progenitors from patients with myelodysplastic syndromes. These findings reveal a non-canonical role for U2AF, where it modulates multiple aspects of mitochondrial function by regulating the translation and mitochondrial localization of nuclear-encoded mRNAs.

Keywords: U2AF1; cancer; mRNA localization; metabolism; mitochondria; myeloid leukemia; translation

DOI: https://doi.org/10.1016/j.molcel.2026.03.006

Acta Pharm Sin B. 2026 Mar;16(3): 1292-1335

Targeting RNA binding proteins with small-molecule inhibitors: Advances, challenges, and therapeutic opportunities.

Yuning Shi, Dazhi Feng, Jieya Zhou, Lihua Liu, Xinnan Li, Zhenwei Yuan, Jianbing Wu, Hong Yao.

RNA-binding proteins (RBPs) constitute central regulators of post-transcriptional gene expression and have been increasingly recognized as critical contributors to the pathogenesis of cancer, neurodegenerative disorders, and autoimmune diseases. However, in contrast to well-established drug targets such as kinases and G protein-coupled receptors, RBPs remain largely underexploited owing to their intrinsic structural heterogeneity, dynamic RNA interactions, and paucity of canonical ligand-binding pockets. In this review, we synthesize current knowledge on the roles of RBPs in disease, outline recent advances in the design of small-molecule modulators, and highlight innovative applications of high-throughput screening and chemical biology approaches for target identification and validation. We further discuss emerging concepts and challenges in translating RBP modulators into therapeutics, providing a forward-looking perspective on how these efforts may reshape small-molecule drug discovery in this evolving field.

Keywords: Chemical biology approaches; Disease; Drug discovery; High-throughput screening; Post-transcriptional gene expression; RNA binding proteins; Small-molecule modulators; Target identification

DOI: https://doi.org/10.1016/j.apsb.2025.12.010

Noncoding RNA Res. 2026 Aug;19 28-39

A conserved mammalian mecciRNA, mecciATP6, regulates mitochondrial homeostasis through interaction with HNRNPA3.

Xiaoyang Cao, Juzheng Sui, Ge Shan, Xu Liu.

Circular RNAs (circRNAs) are covalently closed, single-stranded RNA molecules generated from both nuclear and mitochondrial genomes. Several nuclear-encoded circRNAs have been reported to be conserved in sequence and function across animals. However, the evolutionary conservation and physiological significance of mitochondria-encoded circRNAs (mecciRNAs) remain largely unexplored. Here, by analyzing mitochondrial RNA sequencing data from human and mouse cells, we identify a conserved mecciRNA derived from the MT-ATP6 locus, termed mecciATP6. We show that mecciATP6 modulates mitochondrial homeostasis by binding and regulating the protein abundance of an evolutionarily conserved RNA-binding protein (RBP) HNRNPA3. Our data provide a conceptual framework for defining mecciRNA conservation across mammals and uncover a conserved mecciRNA-protein regulatory mechanism linked to mitochondrial homeostasis.

Keywords: HNRNPA3; Mitochondria-encoded circRNA; Mitochondrial homeostasis; RNA stability; circRNA

DOI: https://doi.org/10.1016/j.ncrna.2026.03.002

bioRxiv. 2026 Mar 26. pii: 2026.03.23.712647. [Epub ahead of print]

Mitochondrial protein translation is a heightened dependence and therapeutic vulnerability of chemo-refractory triple negative breast cancer.

Mariah J Berner, Steven W Wall, Mokryun L Baek, Audra Lane, Allison S Greer, Karen Wang, Lacey E Dobrolecki, Ivy Strope, Qian Zhu, Bing Zhang, Jonathan T Lei, Michael T Lewis, Gloria V Echeverria.

Triple negative breast cancer (TNBC) patients harboring residual cancer burden following completion of conventional neoadjuvant chemo-immunotherapy regimens have poor relapse-free and overall survival rates despite recent advances in immunotherapies and antibody drug conjugates. We and others have demonstrated the requirement of mitochondrial function for survival of chemo-refractory TNBC, as well as its pervasive association with chemoresistance in human and patient-derived xenograft (PDX) cohorts. We sought to gain new mechanistic insights into the mitochondrial vulnerability of TNBC. Analyses of human and PDX mass spectrometry proteomics datasets revealed that mitochondrial protein translation-related signatures were among the top significantly associated with chemoresistance. Those signatures encompassed many core mitoribosome components as well as the mitoribosome accessory protein, Oxidase (Cytochrome C) Assembly 1-Like (OXA1L), which was consistently enriched in chemoresistant versus chemosensitive TNBCs across datasets. OXA1L, while not yet characterized in cancer, has been reported to be crucial for the termination of translation of the 13 mtDNA-encoded electron transport chain (ETC) proteins and for the insertion of those proteins, as well as nDNA-encoded ETC proteins, into the inner mitochondrial membrane. Together, those functions are crucial for the proper formation and function of the ETC. Therefore, we hypothesized that mitochondrial translation supported by OXA1L supports mitochondrial dependence and chemoresistance in TNBC. Knockdown (KD) of OXA1L in human TNBC cells reduced ETC protein levels, mitochondrial 'respirasome' supercomplex levels, ATP production, and oxidative phosphorylation (oxphos). Of note, OXA1L was required for the characteristic oxphos elevation induced by carboplatin (CRB), and KD significantly enhanced CRB sensitivity. To explore the translational potential of targeting the mitoribosome in TNBC, we leveraged the bacterial ancestry of mitochondria to repurpose the FDA-approved antibiotic tigecycline (TIG) as a chemo-sensitizing drug based on its mitoribosome inhibitory function. Direct measurement of mitochondrial nascent peptide levels revealed that, while CRB elevated mitochondrial translation, TIG potently diminished mitochondrial translation as monotherapy and when combined with CRB or docetaxel (DTX). Further, TIG abolished CRB-induced oxphos, decreased oxphos in combination with DTX, and significantly improved sensitivity to chemotherapies in human TNBC cell lines, PDX-derived spheroids, and in an in vivo PDX trial. These findings identify OXA1L-dependent mitochondrial translation and ETC formation as critical determinants of mitochondrial function that support TNBC chemoresistance, justifying further exploration of the clinical potential of repurposed antibiotics for TNBC.
DISCLOSURES: GVE is co-founder, Chief Scientific Officer, and an equity stakeholder of Nemea Therapeutics. G.V.E. formerly received sponsored research funding from Chimerix Inc. G.V.E. receives experimental compounds from the Lead Discovery Center of Germany and from Jazz Pharmaceuticals. MLB is a co-inventor at Nemea Therapeutics. MTL is a founder and limited partner in StemMed Ltd. and a manager in StemMed Holdings, its general partner. He is a founder and equity stakeholder in Tvardi Therapeutics Inc. Some PDX models, including BCM-4272 and BCM-7649, are exclusively licensed to StemMed Ltd., resulting in royalty income to MTL when used for commercial purposes. LED is a compensated employee of StemMed Ltd. Some PDX models, none of which are included in this study, are exclusively licensed to StemMed Ltd., resulting in royalty income to LED. All other authors have nothing to disclose.

DOI: https://doi.org/10.64898/2026.03.23.712647

J Radiat Res. 2026 Apr 01. pii: rrag021. [Epub ahead of print]

Inhibition of mitochondrial RNA polymerase sensitizes cancer cells to radiation by inhibiting mitochondrial respiration.

Sachiko Tsunoda, Yukina Osawa, Noriko Hosoya.

Radiotherapy is a cornerstone of cancer treatment, but its efficacy is limited by tumor radioresistance and toxicity to normal cells. Thus, radiosensitizing agents that selectively target cancer-specific pathways are needed. Mitochondria contain their own deoxyribonucleic acid (DNA) that encodes proteins essential for oxidative phosphorylation (OXPHOS), the primary energy source for cell growth and survival. Recently, IMT1, a specific inhibitor of mitochondrial transcription targeting mitochondrial RNA polymerase (POLRMT), was developed and shown to suppress tumor growth in several cancers overexpressing POLRMT. However, the effect of combining IMT1 with radiation remains uncharacterized. Here, we show that IMT1 enhances radiosensitivity in cancer cells by inhibiting mitochondrial respiration. We inhibited POLRMT by administrating sublethal dose of IMT1 in OXPHOS-dependent cancer cell lines HeLa, A549, MDA-MB-468, HCT116, A431 and AN3CA, and observed increased radiosensitivity. While radiation alone upregulated mitochondrial respiration, IMT1 abolished this capacity when combined with radiation, showing very low oxygen consumption rates in all respiratory states. IMT1 enhanced radiation-induced apoptosis, but did not affect DNA damage repair and cell cycle regulation. Supplementation with galactose rescued hyper-radiosensitivity induced by IMT1. These findings support the mechanistic link between impaired mitochondrial respiration and radiosensitization induced by POLRMT inhibition. The radiosensitizing effect of IMT1 was not observed in normal cell lines RPE1 and HME1 and the glycolysis-dominant cancer cell line HT1080, suggesting that OXPHOS-dominant cancers would profit most from POLRMT inhibition. Thus, this study presents a novel therapeutic strategy that may improve the efficacy of radiotherapy in OXPHOS-dependent cancer cells while minimizing damage to normal cells.

Keywords: IMT1; mitochondrial RNA polymerase; mitochondrial respiration; mitochondrial transcription; radiosensitization

DOI: https://doi.org/10.1093/jrr/rrag021

Acta Crystallogr F Struct Biol Commun. 2026 Apr 01. 82(Pt 4): 101-113

Structures of pentatricopeptide repeat proteins.

Anuradha Pullakhandam, Crystal Cooper, Ian D Small, Charles S Bond.

Pentatricopeptide repeat (PPR) proteins constitute the largest family of RNA-binding proteins in land plants, playing crucial roles in organellar gene expression through sequence-specific RNA recognition. Including the first PPR crystal structure in 2013, 30 PPR and 83 ribosomal PPR crystal or cryo-EM structures have been deposited in the Protein Data Bank, encompassing both native and designer proteins in apo and RNA-bound states. This comprehensive survey catalogues all PPR crystal structures, analysing their crystallographic properties, structural features and contributions to understanding PPR function. Key insights include the elucidation of the PPR recognition code, the characterization of dramatic conformational changes upon RNA binding and the structural basis for the modular architecture that enables programmable RNA targeting. Designer PPR structures have validated and extended principles derived from native proteins, demonstrating their utility as synthetic biology tools. This structural catalogue provides crystallographers and plant biologists with a comprehensive resource for understanding PPR protein architecture and function.

Keywords: RNA recognition; organellar gene expression; pentatricopeptide repeat proteins; protein crystallography; synthetic biology

DOI: https://doi.org/10.1107/S2053230X26002311

Curr Opin Struct Biol. 2026 Apr 01. pii: S0959-440X(26)00037-0. [Epub ahead of print]98 103255

Single-molecule approaches to study G-quadruplex, R-loop, and protein interactions.

Sunghyun Cho, Sua Myong.

G-quadruplexes (G4) are non-canonical nucleic acid structures formed by stacked Hoogsteen base-paired guanine (G) quartets, stabilized by monovalent cations. Due to the inherent propensity of G-rich sequences to fold into G4 structures, both DNA and RNA G4s are widely detected in cells. Previous studies have demonstrated that the unique structure and exceptional stability of G4s can act as physical barriers to translocating enzymes and modulate nucleic acid topology. In addition, G4-binding proteins (G4BPs), including G4 helicases, interact with G4 structures and modulate their stability, thereby contributing to the regulation of transcription and translation. This review highlights single-molecule approaches for probing G4-G4BP interactions and recent advances elucidating G4 functions in the R-loop and transcription.

DOI: https://doi.org/10.1016/j.sbi.2026.103255