bims-ripira 2025-12-14 papers

Issue of 2025–12–14
six papers selected by
Martín Lopo

Adv Sci (Weinh). 2025 Dec 08. e17721

Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.

Zhuoyuan Zhang, Tsering Yangzom, Ning Lu, Shenglong Deng, Xianglu Xiao, Guang Yang, Kristina Xiao Liang.

Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA) copy number and the expression of mitochondrial replisome proteins (POLG, POLG2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin-induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox-related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for POLG-related disorders.

Keywords: POLG‐related disorders; cortical organoids; iPSCs; mitochondrial dysfunction; neurogenesis impairment

DOI: https://doi.org/10.1002/advs.202417721

Int J Mol Sci. 2025 Nov 21. pii: 11257. [Epub ahead of print]26(23):

Urinary Multi-Omics Profiling Reveals Systemic Molecular Alterations in Progressive External Ophthalmoplegia.

Michela Cicchinelli, Guido Primiano, Francesca Canu, Jacopo Gervasoni, Aniello Primiano, Lavinia Santucci, Anna Percio, Viviana Greco, Chiara Leoni, Andrea Sabino, Michelangelo Ardito, Giuseppe Zampino, Serenella Servidei, Andrea Urbani, Federica Iavarone.

Advances in next-generation sequencing have significantly improved the molecular diagnosis of mitochondrial diseases (MDs), a group of heterogeneous neurogenetic disorders. However, progress in understanding their pathogenic mechanisms and translating this knowledge into effective therapies remains limited. Elucidating the molecular determinants of phenotypic variability in primary MDs is essential to uncover disease mechanisms and identify novel therapeutic targets. We investigated a cohort of eight adult patients with genetically confirmed Progressive External Ophthalmoplegia (PEO)-an extremely rare mitochondrial disorder-and compared them with eight age- and sex-matched healthy controls. A comprehensive multi-omics approach combining LC-MS/MS-based proteomics, UPLC-MS/MS-based metabolomics, ATR-FTIR spectroscopy, and chemometric multivariate analysis was employed to identify molecular alterations associated with mitochondrial dysfunction. Distinct proteomic and metabolic patterns related to energy metabolism were observed in PEO patients, correlating with their genetic background. Metabolomic analysis showed altered amino acid levels (seven statistically relevant) and disruptions in the metabolism of cysteine, methionine, and glutathione; proteomics finding (154 differentially expressed proteins) revealed dysregulation in extracellular matrix (ECM) organization and immune response pathways. This integrative analytical strategy offers new insights into the molecular complexity of PEO and mitochondrial disorders. The identification of disease-associated molecular signatures may enhance the understanding of pathogenic mechanisms and support the development of improved diagnostic and therapeutic approaches for MDs.

Keywords: ATR-FTIR; LC-MS/MS; Progressive External Ophthalmoplegia (PEO); extracellular matrix; immune response; metabolomics; mitochondrial diseases; mitochondrial dysfunction; molecular mechanisms; multi-omics; multi-omics integration; proteomics; urine biomarkers

DOI: https://doi.org/10.3390/ijms262311257

bioRxiv. 2025 Dec 01. pii: 2025.11.27.690007. [Epub ahead of print]

Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis.

Di Ran, Yongguo Zhang, Yueqing An, Ying Hu, Yinglin Xia, Jun Sun.

Background and aims: Transfer RNA (tRNA) modifications determine translation fidelity and efficiency. It occurs through the action of specific enzymes that modify the nucleotides within the tRNA molecule. Our previous study demonstrated tRNA modopathies and altered queuine-related metabolites in inflammatory bowel diseases. Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) and QTRT 2 co-localize in mitochondria and form a heterodimeric TGT participating in tRNA Queuosine (tRNA-Q) modification. Human body acquires Queuine/Vitamin Q from intestinal microbiota or from diet. However, the roles of tRNA-Q modifications in the maintenance of intestinal mitochondrial homeostasis and microbiome are still unclear.
Methods: We used publicly available human IBD datasets, QTRT1 knockout (KO) mice, QTRT1 intestinal epithelial conditional KO (QTRT1 ΔIEC ) mice, cultured cell lines with QTRT1-specific siRNA, and organoids from patients with IBD to investigate the mechanism of tRNA-Q modifications in intestinal mitochondrial homeostasis and therapeutic potential in anti-inflammation.
Results: In single cell RNA sequencing datasets of human IBD, we identified significant reduced intestinal epithelial QTRT1 expression in the patients with Crohn's Disease. Using publicly available datasets, we identified significantly changes of Vitamin Q-associated bacteria in human IBD, compared to the healthy control. Qtrt1 -/- mice had significant reduction of Q-associated bacteria, e.g., Bacteroides . Alcian Blue and Mucin-2 staining revealed mucosal barrier damage and disrupted homeostasis, with reduced colonic cell proliferation. Intestinal tight junction integrity was impaired in QTRT1-KO mice, as evidenced by reduced ZO-1 and increased Claudin-10 expression. QTRT1 ΔIEC mice also showed dysbiosis and disrupted TJs. ATP synthesis was significantly decreased in the colon of QTRT1-KO mice, accompanied by severe mitochondrial dysfunction: reduced mitochondrial quality, Cytochrome-C release, and mitochondrial DNA (mtDNA) leakage. Mitochondrial dysfunction contributed to colonic cell death, as shown by elevated expressions of Cleaved Caspase-3 and Cleaved Caspase-1, increased BAX/Bcl-2 ratio, and positive TUNEL signals. Elevated CDC42, CD14, and CD4 levels in QTRT1-KO colon suggested mucosal immune activation and tissue repair responses. QTRT1-deficient CaCO2-BBE cells showed mitochondrial dysfunction. Cytochrome-C and mito-DNA release leading to cell death characterized by elevated expressions of Cleaved Caspase-3 and Caspase-1, increased BAX/Bcl-2 ratio, and higher apoptosis rate. Organoids isolated from patients with IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1.
Conclusions: These findings underscore the critical role of QTRT1/Q-tRNA modification in maintaining intestinal and microbial homeostasis. Mechanistically, QTRT1 loss impacts mitochondrial integrity and mucosal homeostasis. Our study highlights the novel roles of tRNA-Q modification in maintaining mucosal barriers and innate immunity in intestinal health.
What is already known about this subject?: Eukaryotes acquire queuine (q), also known as Vitamin Q, as a micronutrient factor from intestinal microbiota or from diet.Vitamin Q is needed for queuosine (Q) modification of tRNAs for the protein translation rate and fidelity.Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) is reduced in human IBD.However, health consequences of disturbed availability of queuine and altered Q-tRNA modification in digestive diseases remain to be investigated.
What are the new findings?: QTRT1 deficiency leads to altered microbiome and reduced Vitamin Q-associated bacteria in human IBD and a QTRT1 KO animal model.QTRT1 protects the host against losing intestinal integrity during inflammation.QTRT1 localizes in mitochondria and plays novel functions by maintaining intestinal mitochondrial function. QTRT1 loss impacts tRNA modification in the intestine, linking to mitochondrial integrity and mucosal homeostasis.Human IBD showed reduced levels of QTRT1 and dysfunctional mitochondria. Restoring mitochondrial function leads to enhanced QTRT1.
How might it impact on clinical practice in the foreseeable future?: Targeting tRNA-Q modification in enhancing mitochondrial function will be a novel method to maintain intestinal health.

DOI: https://doi.org/10.1101/2025.11.27.690007

Neuropsychobiology. 2025 Dec 12. 1-30

Mitochondrial Insights into Lithium Response in Bipolar Disorder: A State-of-the-Art Review.

Sinem Balaç, Fulya Dal Yöntem, Bilge Karacicek, Izel Cemre Aksahin, Claudia Pisanu, Sevin Hun Senol, Mirko Manchia, Anna Meloni, Odeya Damri, Galila Agam, Ayşegül Özerdem, Sermin Genc, Alessio Squassina, Deniz Ceylan.

Bipolar disorder (BD) is a severe, recurrent mood disorder associated with mitochondrial and bioenergetic dysfunction, which may contribute to both symptom expression and variability in treatment response. Although lithium remains the gold standard treatment, a significant proportion of patients fail to achieve full benefit, and reliable predictive biomarkers are still lacking. Increasing evidence suggests that lithium exerts part of its therapeutic effects through modulation of mitochondrial function, including enhanced oxidative phosphorylation, regulation of mitochondrial dynamics, and reduction of oxidative stress. In this state-of-the-art review, we synthesize the current literature on the relationship between lithium and mitochondrial function, with the aim of evaluating how this relationship may inform our understanding of lithium response in BD. We reviewed findings on mitochondrial bioenergetics, oxidative stress, and mitochondrial DNA alterations, and discussed the roles of key regulatory proteins such as Drp1, Opa1, Mfn2, and Nrf2. In addition, we explore peripheral and epigenetic biomarkers, including mitochondrial DNA D-loop methylation, microRNAs and a potential therapeutic target ⎻ mitochondrial transfer mechanism. In addition to synthesizing the existing literature, we identify key gaps that hinder progress, such as clinical studies being predominantly cross-sectional, lacking standardized mitochondrial assessments, and rarely employing longitudinal or genetically informed designs like mitochondrial twin studies. We highlight the need for unified protocols, integration of omics technologies, extracellular vesicle-based sampling strategies, and improved in vitro and in vivo models. A better understanding of mitochondrial signatures related to lithium may enable biomarker discovery and advance personalized treatment in BD.

DOI: https://doi.org/10.1159/000549993

Mol Syndromol. 2025 Dec;16(6): 550-558

EpiSignature Utility for Variant of Uncertain Significance Reclassification in an Apparently Atypical Presentation of HNRNPU-Related Neurodevelopmental Disorder: A Case Report.

Andrella Zuelke, Rachel Li, Connie Taylor, Cartney Gilkerson, Dylan Platt.

Introduction: Current guidelines recommend broad sequencing as a first-tier test for epilepsy, identifying a genetic etiology in 40% of cases. Sequencing subsequently increases the number of patients identified with variants of uncertain significance (VUSs). Clinicians desire additional investigatory methods to better classify these VUSs.
Case Presentation: The HNRNPU gene (MIM #602869) is associated with a neurodevelopmental condition characterized by intellectual disability and developmental delay, epilepsy, and characteristic facial features. To date, only de novo variants with complete penetrance have been described. We present a 7-year-old female with HNRNPU variant c.669_691dup; p.Gly231Valfs*116, classified as both pathogenic (Laboratory A) and as a VUS (Laboratory B). This patient exhibits an isolated seizure phenotype, and familial studies revealed the proband's father (asymptomatic), paternal uncle (epilepsy), and paternal grandmother (asymptomatic) all carry this variant. Laboratory B theorized the potential for alternative splicing, reducing concerns about pathogenicity. Methylation studies were pursued for more accurate classification and are conclusively negative for the HNRNPU episignature. This, in the context of the variant not segregating with the familial epilepsy phenotype, indicates a benign classification for the c.669_691dup; p.Gly231Valfs*116 variant.
Conclusion: The number of epilepsy patients with nondiagnostic genetic results requires additional modes of investigation. Reclassification often takes years due to the novelty of variants identified. This case highlights the importance of laboratory scrutiny when multiple variants are detected, the need for greater data sharing between laboratories to reduce inconsistent classifications, and the utility of ancillary testing, such as methylation studies, to aid in VUS reclassification.

Keywords: Developmental and epileptic encephalopathy 54 syndrome; EpiSignature methylation analysis; EpiSignature utility; HNRNPU-related neurodevelopmental disorder; Variant of uncertain significance reclassification

DOI: https://doi.org/10.1159/000543302

BMJ Case Rep. 2025 Dec 11. pii: e269373. [Epub ahead of print]18(12):

Juvenile/adult-onset POLG-related disease unmasked by valproate-associated fulminant hepatic failure.

Akshay Mathavan, Kanika Rathi, Lalitkumar J Mundhra, Akash Mathavan.

DNA polymerase subunit gamma-1 (POLG)-related disease is a heterogeneous spectrum of mitochondrial disorders with neurologic and hepatic manifestations. We report a woman in her 20s who developed refractory seizures followed by fulminant hepatic failure after valproic acid exposure. Laboratory evaluation revealed low copper indices without evidence of Wilson disease, neuroimaging demonstrated evolving posterior-predominant abnormalities, and liver biopsy showed acute hepatitis with microvesicular change and 'two-toned' hepatocytes. Rapid whole-genome sequencing identified compound-heterozygous POLG variants c.1399G>A p.(Ala467Thr) and c.2243G>C p.(Trp748Ser), confirming a juvenile/adult-onset POLG-related disorder. This case highlights key diagnostic pitfalls, including potential misdirection of copper studies and risk of valproate hepatotoxicity in patients with unrecognised POLG variants. Supportive clues like occipital-predominant electroencephalogram/MRI changes, rapid neurologic-hepatic progression and hepatic microvesicular pathology can aid early suspicion but are not universally present. Prompt genetic testing and multidisciplinary follow-up are essential to guide management, avoid harmful therapies and anticipate the trajectory of this multisystem disease.

Keywords: Epilepsy and seizures; Genetics; Immunology; Liver disease

DOI: https://doi.org/10.1136/bcr-2025-269373