bims-mirnam 2026-07-05 papers

Issue of 2026–07–05
six papers selected by
Hana Antonicka, McGill University

Bone Res. 2026 Jun 29. pii: 68. [Epub ahead of print]14(1):

Angiogenin mediates cell-cell fusion as a mitochondrial RNA processing enzyme.

Ke Shen, Yixiang Zeng, Jiekang Wang, Kangping Song, Surendra Kumar, Peisong Gao, Guo-Fu Hu, Xu Cao, Mei Wan.

Cell-cell fusion, essential for diverse physiological events, requires high ATP levels. While mitochondrial activity increases in fusing cells, the mechanism driving mitochondrial ribosome (mitoribosome) biogenesis to support these energy demands remains unclear. Here, we identify angiogenin (ANG) as a mitochondrial tRNA (mt-tRNA) processing enzyme critical for mitoribosome biogenesis during myoblast and osteoclast fusion. Upon fusion initiation, ANG translocates to mitochondria, promoting mitoribosome biogenesis to support translation of respiratory complex proteins for ATP production. Using transcriptome-wide PARE and 5' RACE analyses, we show that ANG cleaves the tRNA 3'-end in mitochondrial pre-RNA transcripts bordering rRNAs and mRNAs, enabling their release for translation. Loss of ANG or disruption of its ribonucleolytic activity impairs osteoclast and myoblast fusion, disrupting bone and muscle homeostasis and skeletal muscle regeneration post-injury. Our findings establish ANG as an essential mitoribosome biogenesis regulator and highlight a novel mechanism of mitochondria energy regulation in high-energy-demand biological processes.

DOI: https://doi.org/10.1038/s41413-026-00545-1

Nat Commun. 2026 Jun 30. pii: 5552. [Epub ahead of print]17(1):

Gravitational and mechanical forces shape mitochondrial translation.

Taisei Wakigawa, Yusuke Kimura, Mari Mito, Toshiya Tsubaki, Muhoon Lee, Koki Nakamura, Abdul Haseeb Khan, Hironori Saito, Tohru Yamamori, Tomokazu Yamazaki, Akira Higashibata, Tatsuhisa Tsuboi, Yusuke Hirabayashi, Nono Takeuchi-Tomita, Taku Saito, Atsushi Higashitani, Yuichi Shichino, Shintaro Iwasaki.

Life on Earth has evolved in a form suitable for the gravitational force. Although the pivotal role of gravity in gene expression has been suggested, the molecular details remain unclear. Here, we show that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling reveals reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under microgravity. We found that attenuation of cell adhesion through laminin-integrin interactions caused the phenotype. Mitochondrial translation is activated by a signal relayed by FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and the mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix. Consumption of mitochondrial malonyl-CoA by mtFAS reduces the malonylation of the translational machinery and accelerates the rates of translational initiation and elongation. Physiologically, this system operates in mechano-response of skeletal muscles. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in mitochondria.

DOI: https://doi.org/10.1038/s41467-026-74493-z

Front Bioinform. 2026 ;6 1857218

RNApedia: a database of structural protein-RNA interactions.

Luana Luiza Bastos, Diego Mariano, Pedro M Martins, Rafael Pereira Lemos, Rafael Eduardo Oliveira Rocha, Leandro Morais de Oliveira, Sheila Cruz Araújo, Tatiane Senna Bialves, Raquel C de Melo-Minardi.

The interaction between RNAs and RNA-binding proteins (RBPs) is fundamental for gene expression and regulation of cellular homeostasis. The growing interest in understanding protein-RNA complexes and their use in developing biotechnological solutions has highlighted the need for computational resources to enable detailed structural analysis of these interactions. Despite the availability of structural databases, there is still a significant gap in specialized databases that integrate, in a curated, systematic, and up-to-date manner, structural information on these complexes. Here, we propose RNApedia, a specialized, curated database of protein-RNA complexes accessible via an interactive and user-friendly web interface. The database brings together systematic analyses of 56,133 protein-RNA pairs. It integrates structural descriptors, including accessible and hidden surface areas, atomic contacts and interaction types, RNA classification, protein domains, RNA modifications, and, when available, affinity data. RNApedia is a scalable and integrative platform for exploring protein-RNA interactions, serving as a promising resource for structural bioinformatics and data-driven approaches, including applications in artificial intelligence. All data are freely available for download at: https://bioinfo.dcc.ufmg.br/rnapedia.

Keywords: PDB-derived data; curated dataset; machine learning dataset; molecular interfaces; protein-RNA interactions; structural bioinformatics

DOI: https://doi.org/10.3389/fbinf.2026.1857218

JIMD Rep. 2026 Jul;67(4): e70096

JAK Inhibition in PNPT1-Related Mitochondrial Interferonopathy: A Case Report and Review of Mitochondrial-Immune Crosstalk.

Dan Ross Brooks, Hyun Yong Koh, Taylor Martin Kerrins, Steven Lang, Emily Bland, Rui Yang, Sarah Kogan Nicholas, Stephanie Jean Sikkink, Stephen Kralik, Christine Eng, Chaya Nautiyal Murali, Seema Lalani, Pilar Lenglet Magoulas, Lisa Emrick, Kristen Sydney Fisher, Fernando Scaglia.

Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double-stranded RNA (mt-dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi-Goutières syndrome (AGS). We describe a 7-month-old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off-label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN-driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment-limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a "mitochondrial interferonopathy" and suggests that IFN-signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.

Keywords: COXPD13; JAK inhibitor; PNPT1; mitochondrial interferonopathy; polynucleotide phosphorylase (PNPase); tofacitinib; type I interferon

DOI: https://doi.org/10.1002/jmd2.70096

iScience. 2026 Jul 17. 29(7): 116425

Mitochondrial-generated G-quadruplex-forming lncRNAs regulate heme homeostasis.

Vinodh J Sahayasheela, Ryohei Noizumi, Manendra B Lankadasari, Takumi Terada, Mitsuharu Ooga, Atharv Kulkarni, Shinjiro Suzuki, Takuya Hidaka, Li Cai, Ganesh N Pandian, Toshikazu Bando, Amit R Reddi, Hiroshi Sugiyama.

Heme is an essential but potentially toxic prosthetic group synthesized in mitochondria. Maintaining mitochondrial heme homeostasis requires precise regulation of labile heme availability. Here, we show that mitochondria-generated long non-coding RNAs (mt-lncRNAs) are enriched in G-quadruplex-forming sequences and that these RNA G-quadruplex (rG4) structures bind and buffer heme. Using G4-specific pull-down and bio-orthogonal imaging, we demonstrate rG4 formation in mt-lncRNAs inside cells and show that mt-lncRNA rG4s bind hemin in vitro. Using orthogonal chemical perturbations-a mitochondria-targeted pyrrole-imidazole polyamide (MITO-PIP), which depletes mt-lncRNAs by inhibiting L-strand transcription, and MITO-pyridostatin derivative (MITO-PyPDS), which competitively displaces heme from rG4 structures-combined with genetically encoded heme sensors and ρ0 cells, disrupting mt-lncRNA rG4s increased labile mitochondrial heme, elevated nuclear and cytoplasmic heme, induced reactive oxygen species, and upregulated heme oxygenase 1 (HMOX-1). These findings establish an RNA structure-based mechanism for organellar metabolite buffering, with implications for heme-related disorders and mitochondrial disease.

Keywords: biochemistry; biophysics; molecular biology

DOI: https://doi.org/10.1016/j.isci.2026.116425

Front Neurosci. 2026 ;20 1854892

The exercise-microbiota-queuine-tRNA axis in Parkinson's disease: evidence, uncertainties, and experimental priorities.

Yang Zhou, Tao Jiang.

Parkinson's disease (PD) is a multisystem neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic degeneration, α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammatory remodeling. Although these mechanisms have been extensively investigated, how systemic metabolic and microbiota-derived signals intersect with neuronal translational control remains incompletely understood. Queuosine (Q) modification of tRNAs is a distinctive RNA modification because its precursor, queuine, is not synthesized de novo by mammalian cells but is acquired from diet and gut microbial metabolism. Emerging evidence indicates that Q-tRNA modification can influence codon decoding, translational speed, proteostasis, oxidative stress responses, and mitochondrial function, but direct evidence linking Q-tRNA dysregulation to PD remains limited. In this narrative review, we propose a conceptual and hypothesis-generating framework in which the microbiota-queuine-Q-tRNA modification axis may contribute to neuronal translational buffering and stress adaptation in PD. We distinguish established mechanisms, emerging evidence, and speculative links, emphasizing that the complete causal chain from exercise-induced microbiota remodeling to altered queuine availability, Q-tRNA modification, mitochondrial translational recalibration, and dopaminergic neuroprotection has not yet been experimentally demonstrated. We further discuss tRNA-derived fragments (tRFs) as candidate biomarkers and potential effector molecules in PD-associated translational stress, neuroinflammation, and intercellular RNA communication. Finally, we outline experimental priorities for validating this model, including direct Q-tRNA profiling in PD tissues and biofluids, exercise-intervention studies in PD models, microbiota/queuine manipulation, and mechanistic testing of circulating RNA carrier transport across the blood-brain barrier. This framework does not establish a new pathogenic pathway, but provides a structured roadmap for investigating how exercise, microbial metabolism, and RNA modification biology may converge on selective neuronal vulnerability in PD.

Keywords: Parkinson's disease; Q-tRNA modification; evidence hierarchy; exercise; gut microbiota; mitochondrial translational stress; precision medicine; queuine

DOI: https://doi.org/10.3389/fnins.2026.1854892