bims-mirnam 2026-08-23 papers

Issue of 2026–08–23
four papers selected by
Hana Antonicka, McGill University

Sci Adv. 2026 Aug 21. 12(34): eaed6318

Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.

Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.

Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.

DOI: https://doi.org/10.1126/sciadv.aed6318

Curr Opin Struct Biol. 2026 Aug 18. pii: S0959-440X(26)00144-2. [Epub ahead of print]101 103362

A new dimension in protein-RNA interface prediction: Integrating protein language models and geometric deep learning.

Rozeena Arif, Alfredo Castello.

RNA-binding proteins (RBPs) are essential across biology, from viruses to complex multicellular organisms. They regulate gene expression and cellular responses, making RNA recognition central to understanding health and disease. Biochemical, biophysical, and structural studies have defined core principles of RNA binding, but recent RNA interactome surveys have expanded the RBP repertoire and revealed many noncanonical RNA-binding regions. This diversity demands highly scalable predictive methods. Here, we review machine learning predictors built on protein language models and structure-aware representations. These approaches improve generalisability, reduce reliance on deep evolutionary information, and enable proteome-scale prediction of RNA-binding residues, providing a route to map and interpret the molecular logic of protein-RNA interactions.

DOI: https://doi.org/10.1016/j.sbi.2026.103362

Mol Neurobiol. 2026 Aug 17. pii: 840. [Epub ahead of print]63(1):

Distinct Mitochondrial Central Dogma Gene Expression in the Buffalo Brain: A Comparative Transcriptomic Study with Metabolically Active Organs.

E M Sadeesh, Madhuri S Lahamge, A N Ampadi, Sweta Kumari, Roshan Mohiddin.

In long-lived neurons, precise control of mitochondrial gene expression is critical for maintaining bioenergetic capacity and preventing dysfunction linked to neurodegeneration. This control is executed by nuclear-encoded mitochondrial central dogma (NEM-CD) genes, yet their tissue-specific regulation, particularly in large mammalian brains, remains poorly defined. We conducted a comparative transcriptomic analysis of 214 NEM-CD genes across four buffalo tissues (brain/cerebellum, heart, kidney, and ovary) to elucidate organ-specific regulatory strategies. RNA sequencing and differential expression analysis revealed a definitive quantitative hierarchy (kidney > heart > brain > ovary), with tissue identity explaining 46.36% of intra-species transcriptomic variance (PC1). While the heart and kidney upregulated structural oxidative phosphorylation (OXPHOS) and translational machinery to meet high-throughput demands, the brain uniquely enriched genes governing transcriptional elongation (e.g., TEFM), RNA surveillance (e.g., PNPT1), and DNA repair (OGG1, POLG). Crucially, these findings were anchored by targeted LC-MS/MS proteomic screening, identifying brain-exclusive mitochondrial specialists such as SFXN3 and SLC25A14 (UCP5). Intra-species analysis revealed that the buffalo neuronal program participates in a robust body-wide regulatory plan (systemic coherence; median ρ = 0.8027), a synchronized architecture also observed in humans (median ρ = 0.9264). Subsequent cross-species compression identified a core set of highly conserved mitochondrial regulatory genes (e.g., ANGEL2, AARS2, RECQL4, MTFMT) that maintain strict evolutionary stability between humans and buffalo. Collectively, this study identifies a conserved "Precision-over-Throughput" neuroprotective strategy in mammalian brains, prioritizing transcriptional fidelity and genome maintenance over biogenic volume. This shared regulatory framework provides a stable comparative foundation for understanding mitochondrial dysregulation in both humans and large farm animals, offering a high-fidelity roadmap for neurodegenerative research.

Keywords: Bubalus bubalis ; Mitochondrial gene expression; Neurodegeneration; RNA processing; Tissue-specific regulation; Transcriptional fidelity

DOI: https://doi.org/10.1007/s12035-026-06134-x

Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 853-859

Novel Variants in Mitochondrial Ribosomal RNA Genes MT-RNR1 and MT-RNR2 Identified in Hereditary Optic Neuropathy Initially Presenting as Normal Tension Glaucoma: A Case Report.

Amanda Tran, Jonathan Micieli.

Introduction: Hereditary optic neuropathy may be caused by various mitochondrial or nuclear DNA mutations affecting the mitochondrial function. A growing body of evidence shows that mutations in non-classical mitochondrial genes, including the ribosomal RNA genes MT-RNR1 and MT-RNR2, have been reported in patients with hereditary optic neuropathy, although their pathogenicity remains uncertain. Herein, we report a case initially diagnosed as normal tension glaucoma in which whole mtDNA sequencing identified 2 novel variants in MT-RNR1 and MT-RNR2.
Case Presentation: A 36-year-old man was referred for glaucoma assessment but was found to have bilateral symmetric temporal optic disc pallor and retinal nerve fibre layer thinning that was inconsistent with a glaucomatous pattern. Intraocular pressure (IOP), Humphrey visual fields, colour vision, and pupillary responses were normal. Genetic testing was negative for the 3 primary Leber's hereditary optic neuropathy (LHON) mutations but identified MT-RNR1:m.990T>C and MT-RNR2:m.2619A>G, both at 99.5% heteroplasmy and classified as ACMG class 3. Visual function remained stable at 6-month follow-up.
Conclusion: Neither MT-RNR1 and MT-RNR2 variants could be definitively linked to the hereditary optic neuropathy in this patient, and they are best regarded as findings of uncertain significance. This case highlights a diagnostic pitfall as non-glaucomatous optic disc pallor can be mistaken for normal tension glaucoma and underscores the diagnostic value of whole mtDNA sequencing when primary LHON screening is negative.

Keywords: Hereditary optic neuropathy; MT-RNR1; MT-RNR2; m.2619A>G; m.990T>C

DOI: https://doi.org/10.1159/000553606