bims-mirnam 2026-09-27 papers

Issue of 2026–09–27
four papers selected by
Hana Antonicka, McGill University

Genes (Basel). 2026 Sep 11. pii: 1101. [Epub ahead of print]17(9):

Characterization of the Mitochondrial Genome Landscape in MSCs, iPSCs and iMSCs from Osteoarthritis Patients and Healthy Donors.

Vasileios Konteles, Ioanna Papathanasiou, Maria Tzetis, Eugenios Goussetis, Kostantinos Malizos, Aspasia Tsezou.

Background/Objectives: Osteoarthritis (OA) is strongly associated with mitochondrial dysfunction, oxidative stress, and the accumulation of mitochondrial DNA (mtDNA) alterations in several joint-associated cell types, including chondrocytes, synoviocytes, and mesenchymal stromal cells (MSCs). These alterations contribute to impaired cellular homeostasis and reduced regenerative potential. In this study, we systematically characterized mtDNA heteroplasmy and variant distribution across bone marrow MSCs, induced pluripotent stem cells (iPSCs) and induced MSCs (iMSCs) derived from OA patients and healthy donors. Methods: Ultra-deep mitochondrial genome sequencing was integrated with transcriptomic and miRNome analyses to investigate mitochondrial remodeling during cellular reprogramming, encompassing changes in mtDNA heteroplasmy, variant distribution, mtDNA copy number and associated transcriptomic adaptations of nuclear-encoded mitochondrial pathways. Results: OA-derived MSCs exhibited a markedly increased heteroplasmic burden, followed by decrease in mtDNA copy number and accumulation of non-synonymous variants, particularly within OXPHOS-related genes, including MT-ND1-5, MT-ATP8, MT-CO1, and MT-RNR1/2. Reprogramming into iPSCs and subsequent differentiation into iMSCs were associated with an increase in mtDNA copy number and a progressive reduction in heteroplasmic variants predicted to have pathogenic potential, including m.7913C>T and m.7821G>A, as well as substantial reduction in heteroplasmic variant burden within several mitochondrial genes, suggesting mitochondrial genome remodeling during cellular reprogramming. Multiomic analysis further revealed coordinated deregulation of mitochondrial-associated nuclear genes and ceRNA regulatory networks involving lncRNAs MEG3 and SNHG14, along with multiple mitochondria-related miRNAs. These findings suggest post-transcriptional regulations associated with mitochondrial adaptation in iMSCs Conclusion: Collectively, our findings suggest that cellular reprogramming is associated with mitochondrial genomic reorganization in the donor-matched cell populations examined. These exploratory observations support the utility of iMSCs as a relevant model for studying OA-associated mitochondrial alterations and as a potential tool for regenerative approaches in OA.

Keywords: iMSCs; mitochondrial SNVs; ncRNAs; osteoarthritis; transcriptome

DOI: https://doi.org/10.3390/genes17091101

Mol Biol Rep. 2026 Sep 25. pii: 1622. [Epub ahead of print]53(1):

Stress granules and RNA-binding proteins in cellular senescence: a modular perspective on stress adaptation and inflammation.

Maryam Bahraminasab, Janan Saleh Al-Rashdi, Mahmoud Darweesh, Saeed Mohammadi, Issa Sulaiman Al-Amri, Ahmed Al-Harrasi, Maha Rashid Al-Roshdi.

Cellular senescence is a complex stress response characterized not only by stable growth arrest but also by chromatin remodeling, altered proteostasis, metabolic adaptation, innate immune activation, and the senescence-associated secretory phenotype. Stress granules (SGs) are dynamic membraneless ribonucleoprotein condensates that form during translational stress and regulate mRNA triage, signaling and recovery. While both senescence and SGs represent important features of cellular stress response, the mechanisms underlying their intersection remain poorly defined. This review examines how the biology of SGs and RNA-binding proteins (RBPs) regulate senescence, with particular emphasis on stress granule-induced inflammation associated with SASP, activation of cGAS-STING, induction of NF- κB signaling, and interferon response. We discuss the differential ability of senescence inducers to generate canonical SGs and why SG formation does not necessarily result in global translational shutdown. In addition, we examine the potential roles of SG-associated RBPs, including G3BP1/2, TIA1/TIAR, CAPRIN1, USP10, HuR, ZFP36 family, FXR1, and TDP-43 together with methodological standards for identifying SGs in senescence. We present a stage-resolved modular framework describing the context-dependent functions of SG-associated RBPs throughout senescence progression and discuss therapeutic opportunities. Overall, this review suggests that stress granules and associated RNA-binding proteins should be considered context-dependent components in inflammation-driven senescence, rather than universal inducers of senescence onset.

Keywords: Biomolecular condensates; Cellular senescence; Inflammatory remodeling; Integrated stress response; RNA binding proteins; Stress granules

DOI: https://doi.org/10.1007/s11033-026-12735-5

bioRxiv. 2026 Sep 17. pii: 2026.09.14.751483. [Epub ahead of print]

Systematic Engineering of Loss-of-Function Alleles in the Zebrafish Mitochondrial Proteome.

Ankit Sabharwal, Md Roushan Ali, Kyler S Mitra, Jun Morisue, Jace Klein, Rishav Sarkar, Kaila Savage, Lucy Rai Thulung, Amanda Zumbrock, Cassidy Petree, Santiago Restrepo Castillo, Mireya Mota, Gaurav K Varshney, Karl J Clark, Eiko Nakamuru-Ogiso, Stephen C Ekker.

Pathogenic variants in the 13 protein-coding genes of the mitochondrial genome underlie clinically and biochemically heterogeneous disorders. Most mtDNA-encoded genes lack defined loss-of-function (LOF) models in vivo . To address this gap, we have generated Z-Terminator, a systematic in vivo atlas of loss-of-function alleles covering all the mtDNA-encoded OXPHOS subunits in zebrafish ( Danio rerio ). We used mitochondrial TALE base editors to introduce premature termination codon (PTC) alleles via C-to-T transitions across Complexes I, III, IV, and V. Larvae harboring PTC alleles displayed bioenergetic defects and elevated lactate. While mtDNA mutations are associated with sensorineural hearing loss, the cellular basis has remained unclear. We show that engineered mtDNA LOF alleles directly impair hair cell function in proportion to heteroplasmy in a living vertebrate. We investigated the germline transmission and tissue-specific heteroplasmy of these LOF alleles and observed that a subset of variants was transmitted to the F1 generation and displayed distinct mutant loads across organs. These findings establish Z-Terminator as a vertebrate platform for interrogating the role of mtDNA protein-coding genes in cellular dysfunction and for elucidating the pathophysiology of mitochondrial disorders.

DOI: https://doi.org/10.64898/2026.09.14.751483