bims-mirnam 2026-07-26 papers

Issue of 2026–07–26
six papers selected by
Hana Antonicka, McGill University

MedScience. 2026 Jul 24.

Mitochondrial RNA modifications in gene expression and cancer biology.

Haixia Wang, Lili Ren, Dongling Zou, Rui Su.

RNA modifications are essential in regulating gene expression at the post-transcriptional level. Recent studies, including our own, have highlighted that RNA modifications, such as N6-methyladenosine (m6A) and methyl-5-cytosine (m5C), play a crucial role in tumorigenesis, metabolism, and anti-tumor immunity. Targeting RNA modification machinery may represent a promising therapeutic strategy in cancer. Intriguingly, emerging evidence reveals numerous modifications in mitochondrial RNA (mt-RNA), expanding the concept of epitranscriptomics to mitochondria. The mammalian mitochondrion possesses its own genome, which encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins necessary for energy production via oxidative phosphorylation (OxPhos). The mitochondrial transcriptome is produced from large polycistronic transcripts, implying that mitochondrial gene expression is predominantly regulated post-transcriptionally. In this review, we summarize all currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism. Additionally, given that this field is still in its infancy, we discuss several critical knowledge gaps and propose future research directions to clarify the mechanistic and clinical significance in the study of mt-RNA modifications.

Keywords: RNA modifications; cancer; epitranscriptomics; metabolism; metastasis; mitochondria; tumor immunity

DOI: https://doi.org/10.1007/s11684-026-1233-z

Nat Commun. 2026 Jul 21. pii: 6128. [Epub ahead of print]17(1):

Mitochondrial translation termination, recycling, reinitiation, and rescue for in-frame and out-of-frame contexts.

Taisei Wakigawa, Mari Mito, Qi Fang, Yuzuru Itoh, Yoichi Shinkai, Shintaro Iwasaki.

Because mitochondria diverged from a bacterial ancestor during evolution, the mitochondrial protein synthesis system includes both mRNAs and translation factors with unique characteristics. However, the molecular mechanisms underlying translation termination, recycling, and quality control remain unclear. Here, via high-resolution mitochondrial Ribo-Seq and Disome-Seq, we reveal: the specificity of release factors for different kinds of stop codons; the role of mtRF1 in vertebrates, which do not have noncanonical stop codons in their main translons; the recycling-coupled translation of internal translons; and the rescue of mitoribosomes in the early elongation stage. mtRF1L recognizes all stop codons, whereas mtRF1 recognizes only AGA/AGG noncanonical stop codons. Additionally, mtRF1 terminates the translation of out-of-frame translons that end with AGA/AGG. We also found that mtRRF and mtIF3 are required for mitoribosome recycling on stop codons and for the reinitiation of internal translon translation. Mitoribosomes that stall at the start codons and/or at the early elongation phase are major substrates of the rescue factors ICT1, mtRF-R, and mtRES1. Moreover, HEMK1-mediated methylation of release factors enhances the termination reaction on stop codons. Our results provide insights into the mitoribosome dynamics that are associated with the completion of protein synthesis.

DOI: https://doi.org/10.1038/s41467-026-75248-6

JCI Insight. 2026 Jul 22. pii: e199182. [Epub ahead of print]11(14):

Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.

David Alsina, Diana Rubalcava-Gracia, Kristina Bubb, Rodolfo Garcia-Villegas, Akos Vegvari, Roberta Filograna, Florian A Rosenberger, Camilla Koolmeister, Nils-Göran Larsson.

Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.

Keywords: Cell biology; Metabolism; Mitochondria; Mouse models

DOI: https://doi.org/10.1172/jci.insight.199182

Nat Rev Mol Cell Biol. 2026 Jul 24.

Mitochondrial tRNA biogenesis, modifications and disease relevance.

Wen-Yu Zhu, Ilias Skeparnias, Athanasios-Nasir Shaukat, Jinwei Zhang, Ru-Juan Liu.

The biogenesis, modifications and function of mitochondrial transfer RNAs (mt-tRNAs) reflect the symbiotic relationship and coordinated evolution between the domesticated organelle and the outer cell. Through evolution, mt-tRNA structures have been severely degenerated, and mt-tRNA-associated proteomes have acquired additional domains and interfaces, leveraging post-transcriptional modifications to maintain functional affinity and specificity. Considerable progress has been made in the past decade in elucidating mt-tRNA structure, biogenesis, modifications and functions. In this Review, we outline how mt-tRNAs are excised from polycistronic transcripts and mature through coordinated actions of mitochondrial processing enzymes. We then examine how mitochondrial aminoacyl-tRNA synthetases and mitoribosomes have coevolved to recognize degenerated mt-tRNAs and support a streamlined genetic code. The roles of post-transcriptional modifications in mt-tRNA structure stabilization, mt-tRNA decoding and the coupling of metabolism to translation are also discussed. Moreover, we review mt-tRNA-associated pathologies and emerging therapeutic strategies, highlighting unifying principles that inform efforts to restore coherence of mitochondrial translation.

DOI: https://doi.org/10.1038/s41580-026-00999-5

Biochim Biophys Acta Mol Cell Res. 2026 Jul 20. pii: S0167-4889(26)00093-5. [Epub ahead of print]1873(7): 120194

Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.

Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.

Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.

Keywords: Evolution; Gene expression; Mitochondria; Mitoribosomes; Translation initiation; Translational activators; Translational regulation

DOI: https://doi.org/10.1016/j.bbamcr.2026.120194

Mol Genet Genomic Med. 2026 Jul;14(7): e70274

A Homozygous Founder ELAC2 Variant in Kuwaiti Infants With Fatal Cardiomyopathy and Refractory Severe Lactic Acidosis: A Retrospective Review of the Clinical, Cardiological and Molecular Findings.

Hind Alsharhan, Worood Alostad, Alshaymaa A Ali, Mohammad A Ebrahim, Hesham A F Mohammed, Ahmad Alahmad, Hashem Alhashemi, Walid M Hassan, Ahmad E M S Alhaj, Rasha M Alsafi, Buthaina Albash.

BACKGROUND: Infantile-onset cardiomyopathy due to mitochondrial dysfunction is a severe condition frequently associated with poor prognosis. Biallelic pathogenic variants in ELAC2, an essential mitochondrial tRNA processing gene, have been implicated in this phenotype. This study investigates the clinical and genetic spectrum of ELAC2-related disease in a national cohort from Kuwait.
METHODS: We conducted a retrospective cohort study using data from the Kuwait Medical Genetics Center registry, including individuals with genetically confirmed or clinically suspected ELAC2-related cardiomyopathy. Clinical, metabolic, and molecular data were reviewed. Exome sequencing or targeted mutation testing was performed in affected individuals and at-risk family members.
RESULTS: A total of 34 individuals from 23 consanguineous families were identified, of whom 30 were genetically confirmed to harbor the homozygous ELAC2 founder variant c.460T>C; p.(Phe154Leu). All individuals presented in infancy with severe cardiomyopathy and refractory lactic acidosis. Neurological involvement was observed in 39% of cases. The majority exhibited hypertrophic cardiomyopathy, with variable dilated features and pericardial effusion. The disease course was fatal in all, with most patients dying in infancy.
CONCLUSION: This is the largest single-country cohort reported to date with ELAC2-related mitochondrial cardiomyopathy, raising the global case total to over 70. The uniform presence of the Phe154Leu variant across unrelated Bedouin families highlights a strong founder effect. Given the rapid disease progression and high mortality, we recommend targeted ELAC2 screening in infants with idiopathic cardiomyopathy and persistent lactic acidosis, particularly in consanguineous populations. Premarital carrier testing and early family counseling should be prioritized to support preventive strategies.

Keywords: ELAC2 ; Kuwait; consanguinity; dilated cardiomyopathy; founder mutation; hypertrophic cardiomyopathy; lactic acidosis; mitochondrial disease; pericardial effusion

DOI: https://doi.org/10.1002/mgg3.70274