bims-mirnam 2026-08-02 papers

bims-mirnam

Biomed News

on Mitochondrial RNA metabolism

Issue of 2026–08–02
ten papers selected by
Hana Antonicka, McGill University

MTERF1 loss buffers against pathogenic mtDNA deletions through transcriptional regulation.
PUS7 mRNA pseudouridylation is driven by RNA sequence, structure, and cell-type-specific features.
Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes.
Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.
Dual and opposing roles of the EXD2 exonuclease in the resolution of RNA-DNA hybrids.
Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody.
Sucralose promotes cardiac redox-metabolic remodeling through MRPL12-associated mitoribosomal stress.
Harmonized nucleoside mass spectrometry enables reproducible cross-platform RNA modification quantification.
Decoding Protein-Methylating METTLs in Humans: Structural, Functional, and Disease Insights over the Past Decade.

bioRxiv. 2026 Jul 17. pii: 2026.07.16.738964. [Epub ahead of print]

MTERF1 loss buffers against pathogenic mtDNA deletions through transcriptional regulation.

Tamar Kavlashvili, Elim Choi, Ruobing Cui, Juan C Landoni, Simon Zhang, Stefan Isaac, Stirling Churchman, Suliana Manley, Craig Thompson, Agnel Sfeir.

Large-scale mitochondrial DNA (mtDNA) deletions cripple oxidative phosphorylation once they exceed a critical heteroplasmy threshold, causing incurable mitochondrial pathologies. Using a genome-wide CRISPR/Cas9 screen in an engineered human cell line carrying a large-scale mtDNA deletion at high heteroplasmy, we identified mitochondrial transcription termination factor 1 (MTERF1) as a suppressor of the heteroplasmy burden. Loss of MTERF1 restored mitochondrial function and increased cellular proliferation in cells with a mtDNA deletion burden exceeding the pathogenic threshold, without altering heteroplasmy or mtDNA copy number. MTERF1 binds wild-type and deletion-bearing mitochondrial genomes indiscriminately at a site downstream of the ribosomal RNA genes and curbs transcription. Relieving this constraint broadly increased OXPHOS transcripts, thereby eliciting more respiratory output from the residual wild-type genomes. Notably, the buffering effect of MTERF1 loss extended beyond mtDNA deletions. In a counter-screen, MTERF1 loss could also restore respiratory growth in cells depleted of nuclear-encoded mitochondrial genes such as OPA1 and COX5A . Together, these findings indicate that by relieving a transcriptional constraint, MTERF1 loss compensates for reduced genome dosage, defining a strategy to enhance residual mitochondrial function in mtDNA deletion disorders and related conditions.

DOI: https://doi.org/10.64898/2026.07.16.738964
Cell Genom. 2026 Jul 30. pii: S2666-979X(26)00194-1. [Epub ahead of print] 101332

PUS7 mRNA pseudouridylation is driven by RNA sequence, structure, and cell-type-specific features.

Rebecca Rodell, Ronit Jain, Hossein Shenasa, Matias Montes, Nicolas Robalin, Stefan Prodic, Eduardo Eyras, Nicole M Martinez.

  PUS7 is a major mRNA pseudouridine synthase that influences gene expression and is dysregulated in neurodevelopmental disorders and cancer. PUS7 recognizes a prevalent and degenerate UNUAR sequence, but the mechanisms underlying PUS7's specificity remain unknown. We developed Nano-Mod-Amp, a targeted Nanopore high-throughput pseudouridine detection method, to interrogate PUS7 regulatory features. We established that USUAG, accessibility of the target uridine, and RNA structure are drivers of mRNA modification by PUS7. Perturbing structure through mutations or antisense oligos modulates pseudouridine levels. In cells, pseudouridines are responsive to PUS7 levels, demonstrating the regulatory potential of varying PUS7 levels across cell states. Conversely, PUS7 activity varies across cell types independently of expression levels, suggesting a potential regulatory role for RNA-binding proteins, RNA structure, or other cellular factors. We uncovered principles guiding PUS7 activity, enabling site-specific modulation of pseudouridines. These epitranscriptomic mechanisms provide molecular insight into the regulation and dysregulation of PUS7.

Keywords:  PUS7; RNA modification; RNA structure; antisense oligo; cell type regulation; epitranscriptome; nanopore sequencing; pseudouridine

DOI:  https://doi.org/10.1016/j.xgen.2026.101332
Front Immunol. 2026 ;17 1758569

Deoxyguanosine kinase deficiency couples purine metabolism to innate immune activation and lipid accumulation in hepatocytes.

Maija Corey, Mahati Rayadurgam, Mousa Vatanmakanian, Alicia Gibbons, Carolina Altbaum, Jeamin Jung, Neha Reddy, Priyanka Saminathan, Kiyokazu Kakugawa, Sonia Sharma.

   Introduction: Mitochondrial DNA depletion syndromes (MDS) caused by deoxyguanosine kinase (DGUOK) deficiency are classically attributed to impaired mitochondrial DNA (mtDNA) maintenance. However, many patients develop hepatic steatosis and inflammation despite preserved mtDNA content, suggesting that additional pathogenic mechanisms contribute to disease. DGUOK is a key enzyme in the mitochondrial purine salvage pathway, but its role in coordinating purine metabolism with lipid homeostasis and innate immune signaling remains poorly understood.
Methods: Acute DGUOK deficiency was induced in human hepatocellular carcinoma (HepG2) hepatocytes by siRNA-mediated knockdown. Mitochondrial integrity was assessed by mtDNA quantification, mitochondrial morphology, and oxidative phosphorylation (OXPHOS) protein expression. Lipid accumulation was evaluated by BODIPY staining, and transcriptomic changes were analyzed by bulk RNA sequencing. Purine imbalance was modeled by treatment of wild-type cells with 2'-deoxyadenosine, followed by assessment of DNA methylation, interferon signaling, and lipid accumulation.
Results: Acute DGUOK depletion induced a 2.9-fold increase in intracellular lipid droplet accumulation and activation of a type I interferon (IFN) transcriptional program despite preserved mtDNA copy number, mitochondrial morphology, and OXPHOS complex expression. Bulk RNA sequencing revealed induction of human endogenous retroviruses (HERVs) and interferon-stimulated genes (ISGs), together with suppression of lipid metabolic pathways and remodeling of purine-, methionine-, and methylation-associated networks. Consistent with these transcriptional changes, DGUOK-deficient cells exhibited an approximately 40% reduction in global DNA methylation, accompanied by hypomethylation of CpG-rich region within the ISG15 and ISG20 promoters. Perturbation of purine homeostasis with exogenous 2'-deoxyadenosine phenocopied DGUOK deficiency, driving DNA hypomethylation, activation of viral mimicry pathways, and lipid accumulation.a.
Discussion: These findings demonstrate that acute DGUOK deficiency promotes innate immune activation and metabolic reprogramming through a purine-dependent mechanism that precedes mtDNA depletion and overt mitochondrial dysfunction. By linking disrupted mitochondrial purine salvage to HERV and ISG derepression, interferon signaling, epigenetic remodeling, and steatosis, this study provides a mechanistic framework for the immunometabolic pathology of DGUOK deficiency and identifies mitochondrial purine metabolism as an important regulator of hepatic immune and metabolic homeostasis.

Keywords:  deoxyguanosine kinase deficiency; hepatic steatosis; human endogenous retroviral elements; immunometabolism; purine metabolism; type I interferon

DOI:  https://doi.org/10.3389/fimmu.2026.1758569
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2608102123

Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.

Jingwen Chen, Lili Su, Bangze Pan, Junhao Sang, Linlin Li, Junsong Huang, Zhao-Lan Hu, Lixin Wang, Xiaojie Zhang, Jun Jin.

  Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8+ T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.

Keywords:  T cell aging; cryo-electron tomography; mitoribosome

DOI:  https://doi.org/10.1073/pnas.2608102123
Nucleic Acids Res. 2026 Jul 17. pii: gkag762. [Epub ahead of print]54(14):

Dual and opposing roles of the EXD2 exonuclease in the resolution of RNA-DNA hybrids.

Meng Hu, Yinghong Chen, Yanan Li, Xia Zhang, Yi Zhao, Xiaoxuan Song, Lishuang Chen, Zhiyun Ren, Yuting Zhang, Yali Mi, Cong Liu, Wei Li, Chao Liu, Bo Sun.

Nucleases are specialized enzymes known for degrading nucleic acids in diverse cellular processes. Among them, EXD2 contributes to genome maintenance by digesting a broad range of nucleic acid substrates, including non-canonical RNA-DNA hybrids (RDHs). However, the molecular mechanism underlying the interplay of EXD2 with these hybrid structures has remained elusive. Here, using an optical tweezers-based single-molecule approach, we unveil that EXD2 cooperatively binds to and slowly digests mechanically tensioned RDHs. On the other hand, the cooperative binding of a high amount of EXD2 onto a relaxed RDH drives their co-condensation. Moreover, EXD2 is capable of recognizing damage sites along RDHs and inducing damaged RDH condensation even at low protein concentrations. Surprisingly, this co-condensation, in contrast, protects RDHs from timely degradation by other nucleases. Consistently, we unveil that overexpressed EXD2 colocalizes with mitochondrial RDHs and, rather than cleavage, prevents them from fast degradation. Therefore, EXD2 is a promiscuous moonlighting enzyme that can exert opposing activities toward RDHs. Our findings provide a mechanistic understanding of the functional roles of EXD2 in cells.

DOI: https://doi.org/10.1093/nar/gkag762
Curr Issues Mol Biol. 2026 Jun 23. pii: 645. [Epub ahead of print]48(7):

Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.

Xiaobing Zhang, Huiyu Li, Jiaxin Zhao, Jiawen Tang, Xiaoqing Li, Pengjing Li, Qingyun Zhao, Qi Wang, Wei Zou.

  The second most prevalent neurodegenerative illness in the world, Parkinson's disease (PD), currently has no viable treatments. Although it is yet unknown if mitochondrial dysfunction is an initial event or evolves as a result of neurodegeneration, it is thought to be a crucial component of Parkinson's disease etiology. From the perspective of mitochondrial quality control (MQC), which includes PINK1/Parkin-mediated mitophagy, mitochondrial dynamics, and mitochondrial proteostasis, this article examines mitochondrial dysfunction. Together, these processes preserve mitochondrial homeostasis and prevent the buildup of damaged mitochondria. Dysfunctional mitochondria gradually build up and cause oxidative stress and aberrant cellular signaling when mitochondrial quality control is compromised. According to available data, mitochondrial reactive oxygen species (mtROS) primarily worsen pre-existing mitochondrial damage by encouraging α-synuclein aggregation, cardiolipin remodeling, and dopamine oxidation. In addition, innate immune pathways like cGAS-STING and TLR9 signaling can be triggered by mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial DNA, which can lead to long-term neuroinflammatory reactions in PD. While new research suggests that m6A RNA modification may be involved in the regulation of mitochondrial stress, the PINK1/Parkin pathway is crucial for maintaining mitochondrial homeostasis. Therapeutic approaches that target mitophagy augmentation, neuroinflammatory signaling, and mitochondrial protection have garnered increasing attention. In an attempt to improve mitochondrial function and lessen persistent neuroinflammatory activation, future research will probably need to concentrate on combination treatment techniques.

Keywords:  PINK1/Parkin pathway; Parkinson’s disease; m6A modification; mitochondrial malfunction; neuroinflammation; oxidative stress; therapeutic target

DOI:  https://doi.org/10.3390/cimb48070645
FEBS J. 2026 Jul 29.

Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody.

Gabriele Casagrande Raffi, Jian Chen, Elsemieke Passchier, Cor Lieftink, Chrysa Papagianni, Jeanette H W Leusen, Roderick L Beijersbergen, Liqin Wang, Rene Bernards.

  While many antagonistic antibodies are in routine clinical use, only a single agonistic antibody has received regulatory approval to date. While antibodies that activate Death Receptor 5 (DR5) were thought to have utility in the treatment of cancer by enhancing extrinsic apoptosis signaling, to date all clinical studies with these DR5 agonists have failed to deliver significant clinical benefit. A notable example of this is the DR5 agonistic antibody conatumumab. Here, we provide two potential avenues to improve the activity of DR5 agonists. First, we show that a dimeric IgA version (dIgA2) of the conatumumab antibody has a higher toxicity to cancer cells and a shorter half-life in vivo compared to the original IgG version of the antibody. Moreover, we conducted a genome-wide CRISPR screen to identify genes for which inactivation enhances the sensitivity of cancer cells to the dIgA2 DR5 antibody. We found that inhibition of mitochondrial protein translation synergizes with DR5 agonists. Consequently, antibiotics that inhibit mitochondrial protein translation also synergize with DR5 agonists. Finally, we show that these antibiotics activate the Integrated Stress Response (ISR) and upregulate DR5 through the EIF2a-ATF4 axis, which sensitizes cancer cells to DR5 activation. These data suggest a potential combination strategy for the effective use of DR5 agonistic antibodies.

Keywords:  CRISPR screening; apoptosis; dimeric IgA; integrated stress response; mitochondria

DOI:  https://doi.org/10.1111/febs.70669
Free Radic Biol Med. 2026 Jul 29. pii: S0891-5849(26)00979-2. [Epub ahead of print]

Sucralose promotes cardiac redox-metabolic remodeling through MRPL12-associated mitoribosomal stress.

Ying Sun, Hualing Zhai, Junxue Wang, Yuefeng Yu, Yuying Wang, Yingli Lu, Fangzhen Xia, Kun Zhang, Ningjian Wang.

  Mitochondrial redox imbalance and defective oxidative phosphorylation are central features of lipotoxic cardiac injury, but whether diet-related chemical exposures perturb cardiomyocyte mitochondrial gene-expression machinery remains unclear. Here, we investigated whether sucralose promotes cardiac redox-metabolic remodeling and lipid accumulation involving MRPL12-associated mitoribosomal impairment. Male C57BL/6J mice were exposed to sucralose in drinking water for 28 weeks; hiPSC-derived cardiomyocytes were used for mechanistic assays, and hiPSC-derived cardiomyocytes and H9c2 cardiomyoblast-like cells were used for lipid-accumulation assays under palmitic acid/oleic acid-induced lipid-loading conditions. Chronic sucralose exposure was associated with cardiac dysfunction, myocardial lipid accumulation, mitochondrial structural injury, ATP depletion, oxidative stress-associated signals, reduced glutathione redox buffering capacity, and reduced oxidative phosphorylation (OXPHOS) protein abundance. Quantitative cardiac proteomics identified mitochondrial ribosome- and oxidative phosphorylation-related changes, with MRPL12 emerging as a candidate mechanistic node. In cardiomyocytes, sucralose reduced MRPL12 abundance, altered the distribution of 39S/55S-enriched mitoribosomal fractions, suppressed residual nascent protein synthesis under cytosolic translation-suppressed conditions, reduced mitochondrially encoded OXPHOS proteins, impaired mitochondrial respiration, and aggravated lipid accumulation. Restoration of MRPL12 in cardiomyocytes or mouse hearts partially attenuated sucralose-associated redox-bioenergetic impairment, lipid deposition, and cardiac remodeling. Conversely, siRNA-mediated MRPL12 knockdown phenocopied key sucralose-associated abnormalities, including reduced abundance of mtDNA-encoded OXPHOS subunits, impaired respiration, increased mitochondrial superoxide-associated signal, and lipid accumulation. These findings support MRPL12-associated mitoribosomal impairment as a contributing mechanism linking sucralose exposure to mitochondrial redox-bioenergetic dysfunction and metabolic remodeling in the heart.

Keywords:  MRPL12; cardiac lipid accumulation; mitoribosomal stress; oxidative stress; redox-bioenergetic imbalance; sucralose

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.052
bioRxiv. 2026 Jul 21. pii: 2026.07.17.739095. [Epub ahead of print]

Harmonized nucleoside mass spectrometry enables reproducible cross-platform RNA modification quantification.

Jan Felix Dalwigk, Kira Kerkhoff, Oskar Knittelfelder, Robert L Ross, Maria Cristina Petrella, Anna Kuśnierczyk, Tulsi Bhandari, Aurore Attina, Alicia Burkard, Carolina Brás-Costa, Michael S DeMott, Kitty Johnson, Xenia Kerkhoff-Bernaciak, Jennifer Kist, Ken Kögel, Martina Krämer, Ricardo Moreno-Ballesteros, Ganna Podoprygorina, Kaley Simcox, Özge Simsir, Anton Skriba, Sam Wein, Hana Cahova, Benjamin A Garcia, Mark Helm, Alexandre David, Katharina Höfer, Sebastian Leidel, Patrick A Limbach, Eva Novoa, Eduard Sabidó, Sabine Schneider, Philippe Wolff, Peter Dedon, Vivian Cheung, Stefanie Kaiser.

RNA modification analysis by LC-MS/MS is central to epitranscriptomics, yet quantitative comparison across laboratories and instrument platforms remains poorly standardized. Here, we performed a community-driven benchmarking study during the first Human RNome Project workshop to systematically evaluate cross-platform reproducibility of ribonucleoside mass spectrometry workflows. Using the same analytical column and gradient, standardized RNA samples, and shared reagents, we compared nucleoside quantification across quadrupole, time-of-flight, and orbitrap-based LC-MS platforms employing distinct acquisition strategies. While chromatographic separation was highly reproducible across systems, nucleoside-specific MS response behavior differed substantially between platforms and limited direct comparability of relative signal intensities. These response differences varied across analytes and concentration ranges, demonstrating that harmonized chromatography alone is insufficient for transferable quantitative analysis. Stable isotope-labeled internal standard (SILIS) normalization substantially reduced platform-and method-dependent response and improved agreement for most evaluated modifications. External calibration improved agreement between qTOF and Orbitrap workflows for a subset of modifications but did not fully resolve residual intersystem differences. Based on these findings, we establish benchmark-derived recommendations for harmonized relative and absolute RNA modification quantification, including guidance for calibration design, quality control, and data reporting. Together, this work provides a methodological framework for reproducible nucleoside LC-MS/MS workflows and establishes a foundation for large-scale comparative epitranscriptomic studies.
Graphical abstract:

DOI: https://doi.org/10.64898/2026.07.17.739095
Int J Mol Sci. 2026 Jul 22. pii: 6532. [Epub ahead of print]27(14):

Decoding Protein-Methylating METTLs in Humans: Structural, Functional, and Disease Insights over the Past Decade.

Byron Baron.

  Methylation of proteins is a critical post-translational modification that regulates diverse cellular processes, including signal transduction, protein stability, and enzymatic activity. The methyltransferase enzymes that catalyse the addition of such methyl groups onto target molecules fall into a wide variety of categories and as such are classified into numerous families. Among them, the methyltransferase-like (METTL) family represents a unique cluster of enzymes with structural similarity to arginine methyltransferases. This family comprises 27 members, many of which methylate lysine residues on proteins, while others target various forms of RNA. Although discovered just over a decade ago, the protein-methylating METTLs remain incompletely characterised. Notably, most identified protein substrates are non-histone proteins, underscoring the distinctive functional roles of these enzymes. This review focuses exclusively on the protein-methylating METTL family members, summarising current knowledge of their structural features, enzymatic targets, sub-cellular localisation, and expression patterns. Their emerging relevance to disease, particularly cancer, is also highlighted, alongside areas where mechanistic understanding remains limited. By consolidating recent advances, this review aims to provide a comprehensive overview of protein-methylating METTLs in humans and to identify the critical knowledge gaps that will guide future research into their biological roles and therapeutic potential.

Keywords:  colorectal cancer; glioblastoma; methyltransferase-like (METTL) enzymes; protein methyltransferases

DOI:  https://doi.org/10.3390/ijms27146532