bims-mirnam 2026-07-12 papers

Issue of 2026–07–12
four papers selected by
Hana Antonicka, McGill University

NAR Genom Bioinform. 2026 Sep;8(3): lqag065

QutRNA2: robust tRNA modification discovery from Nanopore direct tRNA sequencing.

Michael Piechotta, Wei Guo, Isabel S Naarmann-de Vries, Felix Kallenborn, Swastik Mishra, Francesca Tuorto, Bertil Schmidt, Christoph Dieterich.

Transfer RNAs (tRNAs) are essential for protein synthesis and are extensively modified to ensure their structure and function. Direct RNA sequencing with Oxford Nanopore Technologies enables positional modification analysis but is challenged by tRNAs' short length, redundancy, and dense modifications. We present QutRNA2, a scalable workflow that includes GPU-accelerated local alignment, statistical filtering, pairwise error profile comparison, and customizable visualization. Achieving up to 25-fold speed gains over CPU methods, QutRNA2 identifies enzyme-dependent modifications in nuclear- and mitochondrial-encoded tRNAs, demonstrated in high-volume human and mouse samples. This open-source solution provides a comprehensive, multiplexing-compatible framework for tRNA analysis, addressing a key gap in current tools. QutRNA2 is released under Apache-2.0 license and is available at https://github.com/dieterich-lab/QutRNA2.

DOI: https://doi.org/10.1093/nargab/lqag065

Aging Cell. 2026 Jul;25(7): e70616

Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease.

Rachel L Doser, Thomas J LaRocca.

Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt-dsRNA signatures increased after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration and identify mt-dsRNA as a potential driver of chronic inflammation in the brain.

Keywords: Alzheimer's disease; aging; brain; double‐stranded RNA; inflammation; mitochondrial RNA

DOI: https://doi.org/10.1111/acel.70616

Biogerontology. 2026 Jul 07. pii: 124. [Epub ahead of print]27(4):

Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.

Antero Salminen, Kai Kaarniranta, Anu Kauppinen.

About 1.5-2 billion years ago, an endosymbiosis between aerobic α-proteobacteria and anaerobic archaeal cells generated mitochondria, i.e., organelles capable of producing oxidative energy. The bacterial genome was fundamentally reduced and a circular mitochondrial genome evolved containing mainly the genes coding for the subunits of the electron transport chain. Before the symbiotic event, there existed a virus-host co-evolution which involved the development of sensors for detecting dangerous viral DNA/RNA molecules. Endosymbiosis supplied eukaryotic cells not only with an oxidative powerhouse to allow the evolution of more complex multicellular organisms but it also meant that cells now housed an organelle which was able to generate reactive oxygen species (ROS) and to leak mitochondrial DNA (mtDNA) and double-stranded RNA (dsRNA) into the cytoplasm. There is now abundant evidence that during aging and age-related diseases mitochondria are prone to release both mtDNA and dsRNA. In the cytoplasm, mtDNA/dsRNA molecules activate a number of cytosolic nucleic acid sensors leading to the secretion of type-1 interferons (IFN) and many other cytokines which promote an age-related proinflammatory state. Currently, it is known that mtDNA can activate the cGAS-STING pathway, AIM2 inflammasomes, IFI16 receptors, and ZBP1 sensors and in addition mitochondrial dsRNA stimulates RIG-1/MDA5 signaling. Interestingly, there is abundant evidence that all these receptors are drivers of cellular senescence and inflammaging. For decades, there has been mounting evidence that mitochondria have a crucial role in the aging process. We will examine this question from the perspective of evolution and propose that mitochondrial evolution created an endogenic source for the leakage of dangerous mtDNA/dsRNA which subsequently stimulated cytosolic DNA/RNA sensors, an evolutionarily conserved viral defence mechanism. It seems that these two evolutionary events provided not only the basis for the inevitable process of aging but also ensuring the death of parental organisms.

Keywords: Ageing; Bacterial origin; CGAS-STING; DNA/RNA sensors; Endosymbiosis; Evolution

DOI: https://doi.org/10.1007/s10522-026-10470-9

FEBS J. 2026 Jul 08.

TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.

Dóra Varga, Zsolt Ráduly, Beáta Boros-Oláh, Éva Nagy, Zsolt Karányi, László Halász, Bálint László Bálint, György Vámosi, Emese Tóth, Péter Bai, Serena Santangelo, Patrizia Bossolasco, Antonia Ratti, Vincent Géli, Yves Pommier, Lóránt Székvölgyi.

Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA : DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.

Keywords: Amyotrophic Lateral Sclerosis (ALS); DRIP‐seq; R‐loop; TOP1MT; mitochondrion; rs2293925; topoisomerase

DOI: https://doi.org/10.1111/febs.70649