bims-mirnam 2026-04-26 papers

bims-mirnam

Biomed News

on Mitochondrial RNA metabolism

Issue of 2026–04–26
five papers selected by
Hana Antonicka, McGill University

Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
Multi-site DMS probing reveals higher-order structure of RNA-protein complexes in living cells.
Structural Basis of Mitochondrial Transcription Regulation via Interactions of PolRMT and TFAM with Upstream Promoter DNA.
Membranes arrest the coarsening of mitochondrial condensates in human cells.
Comprehensive RNA-binding protein analyses and deep learning uncover genetic constraints and disease associations in protein-RNA interfaces.

J Biol Chem. 2026 Apr 16. pii: S0021-9258(26)00327-3. [Epub ahead of print] 111455

Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.

Swarnali Basu, Rukshar Khan, Shiva Sharma, Priyanka Prajapati, Veena Ammanathan, Sumit Rungta, Amit Lahiri.

Mitochondrial translation is crucial for maintaining cellular respiration, energy balance, calcium signaling, apoptosis, immune surveillance, and the regulation of inflammatory responses. This specialized process, involving mitochondrial rRNAs, tRNAs, mitoribosomes, and nuclear-encoded translation factors, ensures the synthesis of mitochondrially encoded proteins that support oxidative phosphorylation. The mitochondrial translation cycle is tightly regulated by RNA-binding proteins, mitochondrial unfolded protein response, and stress-responsive pathways such as mTOR, particularly during metabolic shifts and immune activation. Emerging evidence highlights mitochondrial translation as a critical modulator of inflammation. In this review, we describe the alteration in mitochondrial-specific translation dynamics in immune cells, its adaptation to stress, and its interplay with organelle-wide signaling via mito-nuclear and mito-cytosolic communication. We focus on the alterations in mitochondrial translation machinery including mitoribosomal proteins, rRNA, tRNA synthetases or other regulatory factors linked to inflammatory diseases, including neurodegeneration, IBD, metabolic and cardiovascular disorders. We further examine how mitochondrial translation influences immune responses through mitochondrial DNA/RNA release, activation of mitochondrial damage-associated molecular patterns, and inflammasomes such as NLRP3. Collectively, mitochondrial translation functions as an immune centric-checkpoint that presents promising therapeutic target for intervention in inflammation-driven diseases.

DOI: https://doi.org/10.1016/j.jbc.2026.111455
Mol Cell. 2026 Apr 21. pii: S1097-2765(26)00205-4. [Epub ahead of print]

Multi-site DMS probing reveals higher-order structure of RNA-protein complexes in living cells.

Irfana Saleem, Thomas Miller, Lucas Kearns, Anthony Hoang, Joshua Meehan, Ritwika Bose, David Mitchell, David H Price, Calla M Olson, Chase A Weidmann, Anthony M Mustoe.

  Identifying tertiary structures and protein binding sites in RNA molecules remains a key challenge in RNA biology. We describe multi-site dimethyl sulfate (DMS)-mutational profiling (MaP) (msDMS-MaP), a strategy that enables simultaneous measurement of RNA secondary, tertiary, and quaternary structures via a single DMS chemical probing experiment. Optimized reverse transcription decodes typically invisible DMS N7-methylguanine (N7-G) modifications via a tautomer-induced mutational signature concurrent with N1 and N3 modifications. We show that N7-G reactivity reports on higher-order RNA structures, revealing key functional motifs such as pseudoknots and protein binding sites. Using msDMS-MaP, we find that E. coli ribosomal RNAs encode numerous independently folding tertiary structures that coincide with binding sites for primary assembly proteins. We further apply msDMS-MaP to define the quaternary structural ensemble of the 7SK small nuclear ribonucleoprotein particle (snRNP), revealing that each of the three 7SK structural isoforms possesses distinct protein binding profiles in cells. msDMS-MaP represents a broadly applicable strategy for enhanced RNA functional motif discovery and characterization.

Keywords:  7SK; RNA binding proteins; RNA folding; RNA motif discovery; RNA structure; RNA tertiary structure; RNP; ribosome assembly; structure modeling

DOI:  https://doi.org/10.1016/j.molcel.2026.03.029
bioRxiv. 2026 Apr 11. pii: 2026.04.09.717523. [Epub ahead of print]

Structural Basis of Mitochondrial Transcription Regulation via Interactions of PolRMT and TFAM with Upstream Promoter DNA.

Rory E Shakey, Caitlin Schroeder, Xiangyu Deng, Jamie Smith, Alfredo J Hernandez, Yang Gao.

Mitochondrial DNA (mtDNA) transcription is essential for cellular energy production and is carried out by a streamlined transcription system in which transcription factor A (TFAM), transcription factor B2 (TFB2M), and the mitochondrial RNA polymerase (PolRMT) assemble at defined promoters to initiate transcription. Previous structural studies elucidated the core initiation mechanism but relied on truncated promoter templates that excluded upstream regulatory DNA interactions. Here, we present two conformations of mitochondrial transcription initiation complexes assembled on the heavy-strand promoter (HSP): a TFAM-bound complex with extended upstream DNA and a TFAM-free complex containing short linear DNA. The TFAM-bound structure reveals a transcription-stimulatory interface between PolRMT and the upstream promoter region (UPR) enabled by TFAM-induced promoter bending. Consistent with this structural observation, UPR truncation reduces transcription from all mtDNA promoters, an effect abolished by mutation of the PolRMT interface. In contrast, the TFAM-free structure reveals a transcription-inhibitory interaction of linear upstream DNA with the PolRMT tether helix, which would sterically clash with TFAM binding. Deletion of the tether helix increases off-target transcription, supporting an autoinhibitory role that enhances promoter specificity. Together, these findings reveal how TFAM-shaped promoter architecture and PolRMT regulatory elements coordinate mitochondrial transcription initiation and regulation.

DOI: https://doi.org/10.64898/2026.04.09.717523
Commun Biol. 2026 Apr 23.

Membranes arrest the coarsening of mitochondrial condensates in human cells.

Sanjaya V B D Aththawala Gedara, Surya Teja Penna, Marina Feric.

Mitochondria contain double membranes that enclose their contents. Within their interior, the mitochondrial genome and its RNA products are condensed into ~100 nm sized (ribo)nucleoprotein complexes. How these endogenous condensates maintain their roughly uniform size and spatial distributions within mitochondria remains unclear. Here, we engineer optogenetic tools (mt-optoIDR) that enable controlled formation of synthetic condensates within live mitochondria upon light activation in HeLa cells. Using high-resolution microscopy, we visualize the nucleation of small, yet elongated condensates (mt-opto-condensates), which recapitulate the morphologies of endogenous mt-condensates. These narrow size distributions are independent of mt-optoIDR sequence features, suggesting the mitochondrial environment influences condensate formation. Consistently, mt-opto-condensates fluctuate within voids in between cristae in tubular mitochondria. To directly isolate the contribution of the mitochondrial membranes, we overexpress the dominant negative membrane fusion mutant (Drp1K38A), which results in the formation of bulbous mitochondria with restructured cristae. Based on quantitative particle tracking, bulbous mitochondria support significantly increased dynamics and rapid coarsening of mt-opto-condensates into a single, prominent droplet-in contrast to the membrane confinement observed in tubular mitochondria. Together, these observations inform how membranes can constrain the growth and dynamics of the condensates they enclose, without the need for additional regulatory mechanisms.

DOI: https://doi.org/10.1038/s42003-026-10085-3
Cell Syst. 2026 Apr 22. pii: S2405-4712(26)00070-0. [Epub ahead of print] 101588

Comprehensive RNA-binding protein analyses and deep learning uncover genetic constraints and disease associations in protein-RNA interfaces.

Hsuan-Lin Her, Brian A Yee, Shuhao Xu, Evan A Boyle, Katherine L Rothamel, Zia Z Zhao, Steven M Blue, Jasmine R Mueller, Samuel S Park, Grady G Nguyen, Jack T Naritomi, Adam Klie, Xintao Wei, Sara Olson, Lijun Zhan, Stefan Aigner, Brenton R Graveley, Gene W Yeo.

  RNA-binding proteins (RBPs) orchestrate post-transcriptional processes, including splicing, cleavage and polyadenylation, and translation. Our updated RBP resource integrates data from 92 additional RBPs (286 in total) profiled by enhanced CLIP (eCLIP), enabling comprehensive characterization of RNA elements within human K562 and HepG2 cells. To interrogate RBP-binding syntax, we trained deep-learning models on eCLIP profiles, allowing us to score genetic variants and quantify constraints on RBP-binding sites. We observed opposing selective-constraint profiles at splicing enhancers versus silencers, including an unexpected enrichment of strengthening mutations in ELAVL1- and HNRNPC-binding sites. Finally, our model prioritizes disease variants, exposing unexpected RBP-related mechanisms of pathogenesis, exemplified by the enrichment of weakening mutations in spliceosomal protein-binding sites among retinal disease variants. The complete eCLIP resource offers an integrated platform for exploring RBP-RNA interactomes.

Keywords:  RNA-binding protein; deep learning; eCLIP; negative selection; splicing; variant interpretation

DOI:  https://doi.org/10.1016/j.cels.2026.101588