bims-mirnam 2026-08-16 papers

Issue of 2026–08–16
eight papers selected by
Hana Antonicka, McGill University

Nucleic Acids Res. 2026 Aug 10. pii: gkag805. [Epub ahead of print]54(15):

The pseudouridine synthase PUSL1 modifies U39 of mitochondrial tRNAs and is linked to human neurological phenotypes.

Pedro Rebelo-Guiomar, Nadav Kra-Oz, Christopher Powell, Guillaume Jouret, Morgane Plutino, Veronique Paquis-Flucklinger, Schraga Schwartz, Aldema Sas-Chen, Michal Minczuk.

Variants in the mitochondrial and nuclear genomes are linked to a wide range of human disorders marked by impaired mitochondrial function. Among these disorders, there is a growing number of patients with variants affecting mitochondrial RNA biology. Mitochondrial transcripts are pseudouridylated, and some enzymes responsible for this modification-pseudouridine synthases (PUS)-have been identified. Although known as the 'fifth nucleotide' owing to its high abundance in transcripts, the exact cellular role of pseudouridine is still unclear. Here, we expand the group of mitochondrial PUS enzymes by demonstrating that the protein encoded by PUSL1 is an active pseudouridine synthase with mitochondrial localization. Nucleotide-resolution pseudouridine mapping (mito-Ψ-Seq) followed by primer extension analysis showed that PUSL1 selectively modifies universal position 39 of all mitochondrial transfer RNAs (tRNAs) with a uridine residue in this position. Two newly described clinical PUSL1 variants, c.704G > A (p.Arg235Gln) and c.634del, p.Glu212Argfs*26, were functionally studied, presenting defects in pseudouridylation of mt-tRNA position 39 in patient-derived material, corroborating the association of this enzyme with human pathology. Our data show that PUSL1 regulates mitochondrial RNA post-transcriptional processing and its dysfunction and could be associated with neurological phenotypes.

DOI: https://doi.org/10.1093/nar/gkag805

Biochem J. 2026 Sep 02. 483(9): 1635-1651

Structural and single-molecule insights into the core human mitochondrial DNA replisome.

Ismael Plaza-G A, Samuel Miguez-Amil, Allison M Hayes, Grzegorz L Ciesielski, Rafael Fernandez-Leiro, Borja Ibarra.

Replication of human mitochondrial DNA (mtDNA) is essential for the maintenance of oxidative phosphorylation and cellular energy homeostasis. Impairment of this process leads to mtDNA deletions, depletion, and point mutations that underlie a broad spectrum of mitochondrial diseases, as well as contributing to neurodegeneration, aging, and cancer. The core human mitochondrial replisome, composed of DNA polymerase γ (Polγ), the replicative helicase Twinkle, and the mitochondrial single-stranded DNA-binding protein (mtSSB), is the main complex responsible for replicating the mitochondrial genome through a highly coordinated yet still incompletely understood mechanism. Mutations in the nuclear genes encoding these proteins represent the most common cause of inherited disorders affecting mtDNA maintenance, underscoring the importance of understanding their coordinated molecular function. Recent advances in cryo-electron microscopy and single-molecule approaches have provided unprecedented insight into the structural organization and dynamic operation of the core components of the mitochondrial replisome. These complementary methods are establishing a quantitative mechanistic framework for understanding how the mitochondrial replisome initiates, progresses, and regulates the replication of the light and heavy strands of mtDNA. In the present review, we integrate recent structural and single-molecule findings to describe the mechanisms governing the activity of Polγ, Twinkle, and mtSSB at the mitochondrial replication fork, and discuss remaining challenges toward reconstructing a complete mechanistic model of human mtDNA replication.

Keywords: DNA replication; mitochondria; protein structure; single-molecule

DOI: https://doi.org/10.1042/BCJ20260373

Biochim Biophys Acta Mol Cell Res. 2026 Aug 12. pii: S0167-4889(26)00106-0. [Epub ahead of print] 120207

Mitochondrial RNA polyadenylation: Defining RNA fate through 3' end regulation.

Linden Muellner-Wong, William Carter, Christoph Freyer, Anna Wredenberg.

Polyadenylation is a conserved post-transcriptional RNA modification with fundamentally different consequences for RNA fate across biological systems. In bacteria, chloroplasts, and plant mitochondria, adenylation is generally associated with RNA turnover and degradation, whereas its role in metazoan mitochondria remains incompletely understood. In metazoa, polyadenylation is best known for generating complete UAA stop codons in a subset of mitochondrial mRNAs. However, this explanation does not fully account for the evolutionary conservation of the modification, its diverse RNA substrates, or the broad phenotypic consequences of disrupted polyadenylation. In this review, we re-examine RNA adenylation and propose that, in metazoan mitochondria, polyadenylation primarily establishes a permissive 3' end state that governs RNA maturation, stability, translational competence, and decay. This perspective provides a unifying explanation for the diverse functions attributed to mitochondrial polyadenylation.

Keywords: Gene expression; Mitochondria; Polyadenylation; RNA homeostasis; mtPAP

DOI: https://doi.org/10.1016/j.bbamcr.2026.120207

Cell Biochem Funct. 2026 Aug;44(8): e70277

Activation of a TFAM-Dependent Mitochondrial Translational Axis Drives Oxidative Metabolism in Grade 2 Meningiomas.

Stella G Cavalcante, Benedito Jamilson Araújo Pereira, Antonio M Lerario, Paula R Sola, Sueli M Oba-Shinjo, Suely K N Marie.

Meningiomas exhibit marked biological heterogeneity that is not fully captured by current histopathological grading. Increasing evidence suggests that mitochondrial metabolism contributes to tumor aggressiveness; however, the molecular mechanisms regulating mitochondrial function in meningiomas remain poorly defined. Here, we investigated the role of mitochondrial transcription factor A (TFAM)-driven mitochondrial biogenesis and translation in meningioma progression. We performed integrative transcriptomic, immunohistochemical, and mitochondrial DNA analyses in a well-characterized cohort of 91 meningiomas, comprising World Health Organization grade 1 (G1) and grade 2 (G2) tumors with long-term clinical follow-up. RNA sequencing identified enrichment for mitochondrial metabolic pathways, including oxidative phosphorylation and ATP metabolism, that was preferentially activated in G2 meningiomas. TFAM and its upstream regulator PGC1α were significantly upregulated at both mRNA and protein levels in G2 tumors and exhibited a positive correlation, consistent with enhanced mitochondrial biogenesis. Although mitochondrial DNA copy number did not differ significantly between grades, G2 meningiomas showed a trend toward increased mitochondrial mass. Notably, G2 meningiomas demonstrated marked enrichment of mitoribosomal genes, including MRPL15, MRPL35, MRPL42 and MRPS22, whose expression correlated positively with TFAM and PGC1α expression levels. Network analysis identified TFAM as a central hub linking mitochondrial biogenesis, translation, and metabolic pathway activation. These findings were independently validated using a publicly available meningioma transcriptomic dataset. Together, our results reveal a TFAM-centered mitochondrial regulatory program that integrates mitochondrial biogenesis, translational capacity, and oxidative metabolism in higher-grade meningiomas. This mitochondrial translational axis represents a previously unrecognized mechanism underlying meningioma progression and highlights potential metabolic vulnerabilities for therapeutic intervention.

DOI: https://doi.org/10.1002/cbf.70277

Cells. 2026 Jul 25. pii: 1336. [Epub ahead of print]15(15):

m5C Methylation of mRNA: Still More Questions Than Answers.

Elena S Babaylova, Elizaveta A Zolotenkova, Alexey A Malygin.

mRNA plays a pivotal role in cellular processes of genetic information transfer, and post-transcriptional modifications of its nucleotides enable regulation of these processes with each particular mRNA. m5C methylation is a specific RNA modification that is rather common in tRNA, rRNA, lncRNA and other types of non-coding RNAs, whereas in mRNA it is found not very often. However, the functioning of m5C-methylated mRNAs differs from the non-methylated ones quite dramatically. Of the eight m5C RNA methyltransferases in humans, only two, NSUN2 and NSUN6, were found to be capable of modifying the main portion of cellular mRNAs. A deficiency of NSUN2 and NSUN6 causes global changes in the transcriptome and translatome, and a corruption of the NSUN2 gene in humans is associated with neurodegenerative diseases and intellectual disability. Despite intensive research of m5C mRNA methylation in recent years, many aspects of this phenomenon and its significance remain problematic and far from understood. In this review, we discuss the available information on mRNA methylome biogenesis, methods for its study and analysis, effects of m5C modification on mRNA life, and place it in the general context of cell biology, attempting to draw the biological relevance of m5C mRNA methylation. We highlight the main inconsistencies and difficulties that arise, analyze their possible causes, and propose potential directions for further research that could clarify the controversial issues and provide a link between the NSUN2 deficiency and neurodegenerative diseases.

Keywords: ALYREF; NSUN2; NSUN6; YBM1; gene expression; m5C RNA methylation; mRNA; neurodegenerative diseases

DOI: https://doi.org/10.3390/cells15151336

Cancer Res Commun. 2026 Aug 11.

Mitochondrial tRNA-derived fragments as candidate metastasis-modifying RNA.

Katy L Swancutt, R McKinnon Walsh, Sydney Quijano, Emily Schueddig, Devin C Koestler, Adam D Scheid, Tony Vanden Bush, Yi Jing, Isidore Rigoutsos, Danny R Welch.

How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using Mitochondrial-Nuclear eXchange (MNX) mice, we previously showed that mtDNA single nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences. The only mtDNA SNP correlating with these phenotypes resides in the gene encoding mitochondrial tRNA-Arginine (mt-tRNAArg (UCG), mt-TR), suggesting a role for non-protein-coding loci. Here we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TR. Northern blotting revealed distinct tRF that are differentially expressed among mtDNA SNP, between lung and liver, and between sexes. Surprisingly, small RNA sequencing untreated RNA did not detect the same tRF in high abundance. However, demethylating and restoring 5'-OH and 3'-PO4 termini allowed detection of sequences consistent with the northern blot bands. Enforcing exact matching to the mitochondrial genome and normalizing to their parental molecule revealed putative tRF sequences with shared cleavage sites. Based on connections among mtDNA SNP, the resulting SNP-dependent tRF, and SNP-metastasis correlation, we propose that these tRF may function as metastasis modifiers. These data also expand the functional output of the mitochondrial genome that can contribute to phenotype modification.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0360

Circulation. 2026 Aug 11.

ABHD11-Mediated mtDNA Transcription Restored Mitochondrial Function to Attenuate Cardiomyocyte Ferroptosis After Myocardial Infarction.

Yu Liu, Yijin Chen, Hao Zheng, Yingxuan Li, Chuling Li, Wenlong Xu, Wei Chen, Zhiwen Xiao, Guojun Chen, Senlin Huang, Xinzhong Li, Jia-Guo Zhou, Ying Wu, Wangjun Liao, Yulin Liao, Jianping Bin, Yanmei Chen.

BACKGROUND: Cardiomyocytes exhibit marked susceptibility to ferroptosis after myocardial infarction (MI), rendering ferroptosis inhibition a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is recognized as a core driver of ferroptosis, the potential role of mitochondrial DNA transcription in regulating cardiomyocyte ferroptosis remains unexplored.
METHODS: To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in cardiomyocyte ferroptosis, we integrated RNA sequencing and single-nucleus RNA sequencing data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 (αβ-hydrolase domain-containing protein 11) in cardiomyocyte ferroptosis and cardiac repair after MI, we used loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, nontargeted lipidomics, site-specific mutagenesis, molecular docking, coimmunoprecipitation, native gel electrophoresis, proximity ligation assay, methylation-specific polymerase chain reaction, and chromatin immunoprecipitation assay.
RESULTS: We found that cardiac ferroptosis peaked at day 7 after MI and was enriched in peri-infarct cardiomyocytes. Mitochondrial dysfunction was a key driver of cardiomyocyte ferroptosis after MI, and the lipid enzyme ABHD11 was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts, and its transcription was repressed by DNMT1 (DNA methyltransferase 1)-mediated promoter hypermethylation. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated cardiomyocyte ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Mechanistically, independent of its canonical enzymatic activities, ABHD11 acted as a mitochondrial DNA transcription coactivator by enhancing the TEFM (mitochondrial transcription elongation factor)-POLRMT (mitochondrial RNA polymerase) interaction. This promoted mitochondrial DNA transcription, restored mitochondrial function, and reduced reactive oxygen species/PUFA-PLs (polyunsaturated fatty acid-containing glycerophospholipids)-driven lipid peroxidation and 4-hydroxynonenal generation. The reduction in 4-hydroxynonenal stabilized YY1 (Yin Yang 1), which subsequently regulated key ferroptosis-driving genes governing iron deposition, reactive oxygen species production, and polyunsaturated fatty acid lipids accumulation, further inhibiting lipid peroxidation and ferroptosis, and ultimately promoting cardiac recovery after MI.
CONCLUSIONS: This study revealed that ABHD11-mediated mitochondrial DNA transcription attenuated cardiomyocyte ferroptosis after MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.

Keywords: ferroptosis; mitochondria; myocardial infarction; transcription

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.078593

Cancer Sci. 2026 Aug 13.

m6A-Mediated Stabilization of MRPS23 Drives NSCLC Progression Via HSPA8 and ERK Signaling Modulation.

Sihong Le, Yitao Le, Xianshen Sha, Feng Qiu, Ling Zhang.

Lung cancer remains the leading cause of cancer-related mortality worldwide, largely due to therapeutic resistance and tumor progression. Mitochondrial ribosomal proteins (MRPs), particularly MRPS23, have recently emerged as critical regulators of cancer progression in various malignancies, while N6-methyladenosine (m6A) modification has been established as a key epigenetic mechanism driving tumorigenesis. However, whether MRPS23 is regulated by m6A modification and contributes to lung cancer pathogenesis remains completely unexplored. Here, we identified MRPS23 as a critical oncogenic driver in non-small cell lung cancer (NSCLC). MRPS23 expression was significantly upregulated in NSCLC tissues and cell lines, and high MRPS23 levels correlated with poor patient prognosis. Mechanistically, we demonstrated that WTAP-mediated m6A methylation and subsequent IGF2BP3 recognition stabilized MRPS23 mRNA. Functionally, MRPS23 promoted lung cancer progression both in vitro and in vivo. Further mechanistic studies revealed that MRPS23 exerted its oncogenic effects through physical interaction with the molecular chaperone HSPA8, and this interaction was functionally associated with activation of the RAS-RAF-MEK-ERK signaling cascade. However, the precise molecular steps linking the MRPS23-HSPA8 complex to ERK phosphorylation remain to be fully defined. Collectively, our findings unveil a previously unrecognized m6A-dependent MRPS23/HSPA8/ERK regulatory axis in NSCLC progression, highlighting MRPS23 and its associated components as promising prognostic biomarkers and therapeutic targets.

Keywords: ERK signaling; HSPA8; MRPS23; lung cancer; m6A

DOI: https://doi.org/10.1111/cas.70496