bims-mirnam 2026-05-24 papers

Issue of 2026–05–24
five papers selected by
Hana Antonicka, McGill University

Biochem Pharmacol. 2026 May 19. pii: S0006-2952(26)00416-8. [Epub ahead of print] 118081

Mrps15/Mrps21 induced by Zhx1 protects mice from hypertensive heart disease by restoring mitochondrial translation.

Meixin Shi, Jia Xu, Ye Jin, Xiaoxue Li, Shiyun Dong, Ying Fan, Haoran Jing, Zhaojun Wang, Can Wei.

Mitochondria and mitochondrial proteins represent attractive pharmacological candidates in the search for novel molecular targets to counteract the onset of hypertensive heart disease (HHD). In this work, we aimed to dissect the role and mechanism of mitochondrial ribosomal protein S21 (Mrps21) and Mrps15 in modulating mitochondrial dysfunction during HHD. Mrps15/Mrps21 expression was reduced in myocardial tissues of HHD mice induced by a 5-week gavage of L-NAME (70 mg/kg). Knockdown of Mrps15/Mrps21 inhibited mitochondrial translation in cardiomyocytes, which resulted in depolarization of mitochondrial membrane potential, impaired mitochondrial respiration, reduced membrane translocation of nuclear-encoded mitochondrial proteins, and mitochondrial reactive oxygen species production associated with reduced mitochondrial glutaredoxin-2. Mrps15/Mrps21 ameliorated myocardial injury associated with mitochondrial translation, thereby restoring cardiac function in mice. Zinc fingers and homeoboxes protein 1 (Zhx1) promoted the transcription of Mrps15/Mrps21. Zhx1 activator mithramycin treatment or Zhx1 overexpression ameliorated mitochondrial damage in HHD mice and L-NAME/Ang Ⅱ-stimulated cardiomyocytes, whereas combined silencing of Mrps15/Mrps21 compromised the protective effect of Zhx1 on cardiomyocytes. Our results demonstrate that Zhx1-mediated activation of Mrps15/Mrps21 transcription inhibits HHD progression through the mitochondrial pathway, and a potential therapeutic strategy for the clinical management of HHD is represented by pharmacological activation of Zhx1.

Keywords: Hypertensive heart disease; Mitochondrial translation; Mrps15; Mrps21; Zhx1

DOI: https://doi.org/10.1016/j.bcp.2026.118081

Genet Med. 2026 May 20. pii: S1098-3600(26)00926-3. [Epub ahead of print] 102608

Mitochondrial aminoacyl-tRNA synthetase (ARS)-defects: a review of phenotypes and therapeutic strategies in 899 patients.

Eva M M Hoytema van Konijnenburg, Jingjing Ying, Gajja S Salomons, Saskia B Wortmann, Irena J J Muffels, Sabine A Fuchs.

PURPOSE: Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are crucial for protein translation. The number of identified patients with mitochondrial (mt)ARS-deficiencies is rapidly increasing, but treatment is limited to supportive care. Recently, cognate amino acid supplementation has been explored. Early diagnosis and insights into the natural history are necessary to evaluate potential treatment effects.
METHODS: We performed a scoping literature search for patients with mtARS-deficiencies focusing on phenotype (using Human Phenotype Ontology (HPO) terms), disease progression, death rate and targeted treatments.
RESULTS: We identified 899 patients with 19 different mtARS-deficiencies with a wide variation in age of disease presentation (0-63 years), clinical symptoms and death rate (0-57%). Although neurological problems were common across many mtARS-deficiencies, symptoms were surprisingly different and highly specific for one or a few ARS-deficiencies. Supplementation with cognate amino acids, has been explored in 11 patients, but studies were largely observational and the observed effects were variable.
CONCLUSION: MtARS-deficiencies are an important subgroup within primary mitochondrial disorders with already 899 patients reported. The genotype-phenotype correlation between specific symptoms and mtARS-deficiencies is not yet understood. Treatment with cognate amino acids is a theoretically appealing potential disease-modifying treatment modality that needs to be explored further with well-designed controlled studies.

Keywords: Aminoacyl-transfer RNA (tRNA) synthetase; mitochondrial disorder; mtARS-deficiency

DOI: https://doi.org/10.1016/j.gim.2026.102608

J Neurosci. 2026 May 21. pii: e1936252026. [Epub ahead of print]

Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation.

Hadassah Mendez-Vazquez, Avanti Gokhale, Maureen M Sampson, Felix G Rivera Moctezuma, Adriana Harbuzariu, Anson Sing, Stephanie A Zlatic, Anne M Roberts, Milankumar Prajapati, Blaine R Roberts, Thomas B Bartnikas, Levi B Wood, Steven A Sloan, Victor Faundez, Erica Werner.

Manganese is an essential trace element required for various biological functions, but in excess is neurotoxic and leads to significant health concerns. The mechanisms underlying manganese neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, and neuroinflammation. Here, we present a novel manganese-dependent mechanism linking mitochondrial dysfunction to neuroinflammation. We found that manganese disruption of the mitochondrial transcriptome processing results in the accumulation of double-stranded RNA (dsRNA). This dsRNA is released into the cytoplasm, where it activates the cytosolic sensor MDA5, triggering type I interferon responses and inflammatory cytokine production. This mechanism is evident in 100-day human cerebral organoids, where manganese-increased mitochondrial dsRNA and induced inflammatory responses in mature astrocytes. Similarly, we observed an increase in mitochondrial dsRNA content, the activation of an inflammatory transcriptome and the production of cytokines in female and male mouse brains carrying mutations in the Slc30a10 gene, a model for human hypermanganesemia with dystonia 1 disorder. These findings highlight a previously unrecognized role for mitochondrial dsRNA in manganese-induced neuroinflammation and provide insights into the molecular pathogenesis of manganism. We propose that this mitochondrial dsRNA-induced inflammatory pathway could be active in other neurological diseases caused by environmental or genetic factors.Significance Statement Environmental exposures and genetic defects that perturb manganese homeostasis are an underappreciated cause of neurodegeneration and neuroinflammation. We describe a new paradigm for inducible neuroinflammation, where manganese disruption of mitochondrial transcriptome processing leads to the accumulation of mitochondrial double-stranded RNA (dsRNA), which activate antiviral responses in the cytoplasm driving type I interferon-dependent inflammation. This manganese-dsRNA axis is induced in cell lines in vitro and a subpopulation of mature astrocytes in exposed human cerebral organoids. Brain cortex of mice deficient in the manganese efflux transporter Slc30a10, a genetic model of chronic manganese accumulation, show dsRNA accumulation, and up-regulation of type I interferon response and astrogliosis markers, supporting a role for this pathway in neurotoxicity and parkinsonism.

DOI: https://doi.org/10.1523/JNEUROSCI.1936-25.2026

Nat Commun. 2026 May 19.

An engineered viral RNA degrader on mitochondrial surface that mitigates RNA virus infection.

Chih-Wei Chen, Wei-Ting Liao, Tung Chao, Yi-Han Chen, Shih-Che Weng, Shin-Hong Shiao, Ching-Yang Kao, Yun-Jung Li, Kai-An Cheng, Zee-Fen Chang.

Infections by RNA viruses cause diseases. Host factor(s) that restrain viral propagation offer new anti-virus strategies. We use vesicular stomatitis virus (VSV) as a model and observe the synthesis of VSV RNAs at mitochondria/endoplasmic reticulum (Mito/ER) spheres, accompanied by the leakage of endonuclease G (ENDOG), a mitochondrial nuclease, to the cytosol. We provide evidence that ENDOG released from mitochondria is a host anti-viral factor by eliminating viral RNAs for replication. However, ENDOG outside mitochondria can translocate to nuclei and cause nuclear DNA damages. We engineer an ENDOG expressed on mitochondrial outer membrane (MOM), namely MOM-ENDOG, to increase the accessibility to viral RNA transcripts synthesized at mitochondrial sites without damaging nuclear DNA (nDNA). Delivery of modified mRNA of wild-type but not catalytic-dead MOM-ENDOG markedly suppresses not only the propagation of VSV, but also Dengue and Zika virus. Thus, this organelle-specific viral RNA degrader may be developed as a broad-spectrum anti-viral agent.

DOI: https://doi.org/10.1038/s41467-026-73487-1

Transl Androl Urol. 2026 Apr 27. 15(4): 134

Aberrant methylation of mitochondrial genes as a link between oxidative phosphorylation dysregulation and the pathogenesis of hypospadias: a multiomics and clinical sample study.

Hongchao Yang, Jian Wang, Youtian Zhang, Wei Wang, Liqiong Guo, Shuhao Shi, Zhenhua Zhang, Yong Guan, Hualei Cui.

Background: Hypospadias is among the most prevalent congenital malformations in male newborns. Despite its clinical significance, the molecular etiology of hypospadias has not extensively characterized. Although environmental exposures, epigenetic dysregulation, and mitochondrial dysfunction have been identified as potential contributing factors, the role of mitochondrial DNA (mtDNA) methylation in the pathogenesis of hypospadias has not been systematically examined. Therefore, this study aimed to investigate the potential involvement of mtDNA methylation in hypospadias and to explore its association with mitochondrial gene expression and oxidative phosphorylation-related pathways.
Methods: To investigate mtDNA-related epigenetic alterations in hypospadias, an integrated analysis of transcriptomic and methylomic data was conducted. Alongside control specimens, preputial tissue samples were obtained from patients diagnosed with distal, midshaft, and proximal hypospadias. RNA sequencing (RNA-seq) was performed to profile gene expression. Subsequent functional enrichment analyses were conducted to identify the key disturbed biological pathways. Additionally, mtDNA methylation patterns were examined via publicly available methylation datasets, and this was followed by targeted validation with bisulfite pyrosequencing in order to facilitate the quantification of site-specific methylation levels of the selected mitochondrial genes.
Results: RNA-seq identified 96 differentially expressed genes (DEGs), of which 87 were upregulated and 9 downregulated. Subsequent functional enrichment analysis indicated that oxidative phosphorylation (OXPHOS)- and reactive oxygen species (ROS)-related pathways were the most significantly affected biological processes. Further analysis of mitochondrial gene transcriptomes revealed broadly similar upregulation patterns across different hypospadias subtypes, with MT-CO1, MT-CO3, MT-RNR2, and MT-ND6 being identified as the commonly dysregulated genes. Methylation analysis of target genes revealed unique epigenetic features in hypospadias tissue: MT-CO1 and MT-RNR2 exhibited significant hypomethylation, MT-ND6 showed hypermethylation, and MT-CO3 demonstrated no significant methylation changes. Notably, this methylation pattern was not significantly different across clinical subtypes, suggesting that it may represent a potentially shared epigenetic feature independent of anatomical classification.
Conclusions: Our findings indicate that aberrant mtDNA methylation is associated with altered mitochondrial gene expression and disrupted OXPHOS in hypospadias. This type of epigenetic dysregulation may impair mitochondrial energy metabolism and redox balance, thereby contributing to abnormal urethral development. These results constitute novel evidence linking mitochondrial epigenetic modifications to the pathogenesis of hypospadias and highlights potential of molecular targets in future risk assessment, early diagnosis, and preventive interventions.

Keywords: Hypospadias; mitochondrial DNA methylation (mtDNA methylation); mitochondrial dysfunction; multiple transcriptomic profiling; oxidative phosphorylation (OXPHOS)

DOI: https://doi.org/10.21037/tau-2026-0251