EMBO Molecular Medicine最新文献

{"title":"Apc-deficient pituitary stem cells drive adamantinomatous craniopharyngioma through senescence-associated inflammation.","authors":"James Blackburn, James G Nicholson, Laura Gomez-Corral, Jingyi Xue, Ashutosh Rai, Bryan Padraig Finn, Rachael J L Tan, Kalyana C Chakravarthi, Angelica Gualtieri, Charlotte L Hall, Gabor Czibik, Pinaki Dutta, Márta Korbonits, Federico Roncaroli, Shannon W Davis, Carles Gaston-Massuet","doi":"10.1038/s44321-026-00525-2","DOIUrl":"https://doi.org/10.1038/s44321-026-00525-2","url":null,"abstract":"<p><p>Adamantinomatous craniopharyngiomas (aCPs) are complex intracranial neoplasms that arise in the sellar and suprasellar region of the brain, affecting the endocrine and nervous systems, causing severe sequelae. Although most of aCPs are driven by somatic mutations in β-catenin (CTNNB1), some cases remain genetically unresolved. Here, we show that disruption of the Wnt-antagonist and tumour suppressor adenomatous polyposis coli (Apc) leads to pituitary tumours that present all classic molecular and histopathological hallmarks of aCPs. Mechanistically, we show that a hypomorphic allele of Apc leads to tumour development and that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells can initiate aCP formation. Apc-driven tumour-initiating cells show a distinct transcriptional signature of p21-mediated senescence-associated secretory phenotype (SASP) with methylomic analyses revealing shared epigenetic alteration of SASP-like inflammatory programme across aCP subtypes. Our data demonstrate a causal role of disruption of Apc in driving aCPs, reinforcing the importance of genetic testing for mutations in APC in patients with aCP. Furthermore, our work highlights the need to screen patients with familial adenomatous polyposis (FAP) or the spectrum of APC-pathogenic syndromes for aCP development early in life.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel Torque teno virus qPCR assay reveals longitudinal viral load variability among non-immunosuppressed subjects.","authors":"Lara Valder, Thomas G Grigore, Christian Schaaf, Quirin Bachmann, Lutz Renders, Samuel D Jeske, Marc Lütgehetmann, Sibylle Bierbaum, Hartmut Hengel, Christopher Dächert, Ulrike Protzer, Jochen M Wettengel","doi":"10.1038/s44321-026-00540-3","DOIUrl":"https://doi.org/10.1038/s44321-026-00540-3","url":null,"abstract":"<p><p>Torque teno virus (TTV) DNA is an emerging biomarker of the individual immune status with considerable potential for guiding immunosuppressive therapy. However, widespread clinical implementation has been hampered by the lack of standardized, high-throughput diagnostic assays and limited understanding of the physiological variability of TTV viral loads over time. Here, we developed and analytically validated a novel fully automated high-throughput quantitative PCR assay for standardized TTV-DNA measurement in routine diagnostics and large-scale clinical studies. The assay demonstrated high analytical sensitivity and specificity, with a limit of detection of 32.3 copies/ml. Using this platform, we performed longitudinal profiling of plasma and serum samples collected over up to 51 months from non-immunosuppressed individuals. We observed substantial inter- and intra-individual fluctuations in TTV-DNA levels in a subset of healthy subjects, revealing intrinsic biological variability independent of immunosuppressive therapy. These findings establish a robust platform for standardized TTV monitoring while demonstrating that longitudinal viral load dynamics must be interpreted in the context of natural biological variation. Our study provides an important framework for the clinical implementation of TTV-guided immune monitoring and the need for development of evidence-based thresholds for individualized immunosuppressive therapies.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human prostaglandin reductases dearomatize and inactivate benzothiazinone antitubercular drugs","authors":"Myriam Briki,Caroline A Wagner,Vincent Desfontaine,Anthony Vocat,Onya Opota,Sarah Abou-Zite,Océane Corpataux,Benedetta Cena,Sylvie Guinchard,François Versace,Amarande Murisier,Thomas Mercier,Emilyne Blattes,Carine Bardinet,Paul Thoueille,Vladimir Wsol,Lenka Lastovickova,Haithem Chtioui,Laura E Rothuizen,Aimable Nahimana,Axel Bellotti,Laurent R Chiarelli,Dany Spaggiari,Neeraj Dhar,Richa Mishra,Raphaël Sommer,Andréanne Lupien,Michel A Duchosal,Benoît Guery,François R Girardin,Giuseppina Milano,Olga Riabova,Vadim Makarov,Thierry Buclin,Stewart T Cole,Eva Choong,Laurent A Decosterd","doi":"10.1038/s44321-026-00526-1","DOIUrl":"https://doi.org/10.1038/s44321-026-00526-1","url":null,"abstract":"Abstract Macozinone (MCZ, PBTZ169) is a potent clinical-stage benzothiazinone antitubercular agent that covalently inhibits the essential mycobacterial flavoenzyme DprE1. In some mammals, MCZ undergoes reductive dearomatization to H 2 MCZ, a Hydride Meisenheimer Complex, identified as the major circulating metabolite in humans. We demonstrate for the first time that the NADPH-dependent human prostaglandin reductases PTGR1 and PTGR2 catalyze MCZ dearomatization into H 2 MCZ, resulting in loss of antimycobacterial activity. This reaction represents a heretofore undescribed host-mediated metabolic inactivation pathway for a therapeutic agent. Although H 2 MCZ may constitute a transient reactive intermediate, ex vivo and cellular data indicate that it does not contribute to antimycobacterial activity in vivo. Pharmacological inhibition of PTGR1 and PTGR2 using diclofenac, indomethacin, dicumarol, or the selective inhibitor PTGR2-IN-1 suppresses H 2 MCZ formation and partially restores MCZ antimycobacterial activity in vitro. Together, these findings uncover a previously unrecognized noncanonical enzymatic mechanism of drug metabolism involving dearomatization in humans. Targeting prostaglandin reductases may represent a strategy to enhance benzothiazinone exposure and efficacy.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"25 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO","authors":"Aftab Mohammed,Tavleen Kaur,Priyanka Panwar,Samanwita Ghosh,Hanif Ahmad,Sadananda Kumbhakar,Meltem Muftuoglu,Carlo Viscomi,Sagar Sengupta","doi":"10.1038/s44321-026-00532-3","DOIUrl":"https://doi.org/10.1038/s44321-026-00532-3","url":null,"abstract":"Abstract POLGA, the catalytic subunit of the mitochondrial DNA polymerase, is essential for mitochondrial DNA (mtDNA) replication and maintenance. Mutations in POLGA cause progressive external ophthalmoplegia (PEO), but the underlying pathogenic mechanisms remain unclear. Here, we show that the mitochondrial E3 ligase MITOL hyperubiquitylates PEO-associated POLGA mutants at lysine 1060, triggering conformational changes and formation of insoluble aggregates that impair their mitochondrial import and consequently compromise mtDNA replication and mitochondrial homeostasis. To identify compounds that disrupt POLGA aggregates and restore mutant POLGA function, we screened an FDA/EMA/PMDA-approved drug library using a split-GFP system. We identified two clinically approved compounds, diltiazem hydrochloride (C1) and sulbactam (C4), that disrupted POLGA aggregates, prevented aberrant MITOL recognition, restored mitochondrial import, and rescued mtDNA replication and mitochondrial function. Importantly, treatment with either compound significantly improved motor performance in a knock-in mouse model carrying the disease-relevant A467T-equivalent POLGA mutation. These findings establish pathogenic aggregation as a previously underrecognized disease mechanism and demonstrate that disrupting POLGA aggregates with repurposed drugs can restore mitochondrial function in vivo, providing a potential therapeutic strategy for POLGA-associated mitochondrial disease.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"24 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of CDK12/CDK13-CYCLIN K rewires P-TEFb signaling to reverse HIV-1 latency and modulate cellular gene expression","authors":"Praveenkumar Murugavelu,Jagrity Rani,Heli Glebko,Ina Ambiel,Nadine Tibroni,Nili Tickotsky,Ferdinand Heyn,Philipp Schommers,Liron Levin,Alona Kuzmina,Oliver Till Fackler,Ran Taube","doi":"10.1038/s44321-026-00536-z","DOIUrl":"https://doi.org/10.1038/s44321-026-00536-z","url":null,"abstract":"Abstract Persistent HIV-1 latency in long-lived CD4⁺ T-cell reservoirs remains a major obstacle towards viral eradication. Current antiretroviral therapy (cART) exhibits limited clinical efficacy, highlighting the need for new therapeutic interventions. Here, we identify the CDK12/CDK13-Cyclin K (CCNK) complex as a regulator of HIV-1 latency. Pharmacological inhibition of CDK12/CDK13-CCNK with the SR-4835 inhibitor robustly reversed HIV-1 latency in the absence of additional stimuli, both in T cell models and in primary CD4⁺ T cells from people living with HIV-1 receiving cART. Targeting of CDK12/CDK13-CCNK with SR-4835 further synergized HIV-1 latency reversal and enhanced viral reactivation when co-treated with established Latency Reversal Agents. Mechanistically, CDK12/CDK13-CCNK inhibition promoted the release of P-TEFb (CDK9/CYCLIN T) from its inhibitory 7SK snRNP complex, resulting in increased recruitment of RNA polymerase II, CDK9 activation, and remodeled chromatin that overall drove productive HIV-1 transcription. Beyond HIV-1 reactivation, our findings reveal a previously unrecognized compensatory interplay between transcriptional kinases that activate gene expression, thereby rewiring cellular transcriptional programs. Together, this study identifies CDK12/CDK13-CCNK complex as a therapeutic target for HIV-1 latency reversal and provides a mechanistic rationale for improving strategies aimed at achieving an HIV cure.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"86 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases","authors":"Claire Almyre,Anne-Louise Cayer,Nolwenn Bounaix,Anaïs Hoarau,Marie-Alix Derieppe,Julie Martineau,Pierre Costet,Camille Charles,Mélody Dufossée,Cécile Duplaa,Jim Dompierre,Bénédicte Salin,Marc-Alexandre D’Elia,Corinne Blancard,Aurélie Massoni-Laporte,Stéphane Claverol,Caroline Tokarski,Yaser Hashem,Alexandre Favereaux,Yeranuhi Hovhannisyan,Juliette Jouhet,Cyrille Guimaraes,Jean-François Dumas,Olivier R Baris,Laetitia Dard,Jérémy Richard,Vanessa Bergeron,Naïg Gueguen,Valérie Desquiret-Dumas,Jordan Rivron,Douglas Strathdee,Carole H Sellem,Nathalie Bonnefoy,Laurent Monassier,Estelle Ayme-Dietrich,Onnik Agbulut,Stéphane Azoulay,Jean-Paul di Rago,Vincent Procaccio,François Godard,Déborah Tribouillard-Tanvier","doi":"10.1038/s44321-026-00518-1","DOIUrl":"https://doi.org/10.1038/s44321-026-00518-1","url":null,"abstract":"Abstract Despite major advances in the genetic diagnosis of mitochondrial disorders, effective disease-modifying therapies remain scarce. Here, we identify ebselen (EBS) as a promising therapeutic candidate through a phenotypic drug screen in a yeast model of Barth syndrome, a cardiomyopathy caused by defective cardiolipin maturation. EBS improved oxidative phosphorylation-dependent growth across diverse fungal models of mitochondrial diseases, including defects in complex I, complex IV, mitochondrial DNA maintenance, mitochondrial translation, and ATP synthase. Therapeutic efficacy was further validated in patient-derived fibroblasts, iPSC-derived cardiomyocytes, and a cardiolipin-deficient mouse model. Mechanistically, EBS acts independently of its established antioxidant activity by engaging a conserved metabolic program that suppresses cytosolic translation while stimulating pyruvate dehydrogenase-dependent tricarboxylic acid cycle activity, thereby improving proteostasis and mitochondrial bioenergetic function. These effects are likely coordinated through lysosome-associated mTOR signaling, consistent with the localization of EBS to lysosomes and its colocalization with mTOR. Together, our findings identify a conserved mechanism for enhancing mitochondrial function and establish ebselen as a strong candidate for therapeutic repurposing in Barth syndrome and a broad spectrum of inherited mitochondrial disorders.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"4 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic potential of transposable element activity modulation","authors":"Gabriele Morelli,Marco D’Onghia,Arianna Mangiavacchi,Valerio Orlando","doi":"10.1038/s44321-026-00528-z","DOIUrl":"https://doi.org/10.1038/s44321-026-00528-z","url":null,"abstract":"Abstract The reactivation of transposable elements (TEs) is a recurrent molecular event across cancer, neurodegeneration, autoimmune disease, and aging, yet its therapeutic implications remain largely unexplored. Normally repressed under strict epigenetic surveillance, reactivated transposable elements can generate immunostimulatory nucleic acids that engage cytosolic pattern-recognition receptors, converging on type I interferon signaling and driving chronic sterile inflammation. Yet this inflammatory potential is inherently dual: the same reactivation that drives pathology in some contexts can be harnessed to prime immunity in others. Here, we review two complementary strategies that exploit this duality. Suppressive approaches, including nucleoside reverse transcriptase inhibitors, antisense oligonucleotides, and epigenetic silencing agents, aim to quench pathological TE-driven inflammation in diseases and restore other adaptive mechanisms governing homeostasis. Conversely, controlled TE reactivation through epigenetic priming can induce a viral mimicry state in tumor cells, sensitizing them to immune checkpoint blockade. In parallel, TE-derived peptides presented on MHC class I molecules are emerging as a largely unexploited reservoir of shared tumor antigens for next-generation vaccines and engineered T cell therapies. Together, these observations reframe transposable elements not as mere viral relics to be tolerated, but as a tunable immunological switch whose therapeutic modulation holds promise across some of the most challenging diseases of our time.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"10 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostaglandin E2-mediated aging microenvironment fuels pathogenic fibrosis in cesarean section scar defect","authors":"Yujia Yin,Huihui Chen,Weiwei Xie,Yizhi Wang,Yujing Qian,Rong Sheng,Danning Li,Jiarui Li,Xingchen Zhou,Zhiyuan Dai,Zhiyong Mao,Ziyi Li,Xipeng Wang","doi":"10.1038/s44321-026-00521-6","DOIUrl":"https://doi.org/10.1038/s44321-026-00521-6","url":null,"abstract":"Abstract With the increasing rates of cesarean section (CS), cesarean section scar defect (CSD) has become an escalating clinical concern due to uterine dysfunction and reduced fertility. However, the biological basis of CSD remains poorly understood, particularly the mechanisms of impaired uterine repair after CS and the causes of failure in conventional repair surgeries. This study integrates metabolomics, transcriptomics, a newly developed mouse model, and functional assays to elucidate the complex interplay between senescence and fibrosis in CSD. Our findings identify upregulation of the PGES/prostaglandin E2 (PGE2) axis as a key upstream event that disrupts uterine healing. Elevated PGE2 preferentially induces early senescence of macrophages, which transmit pro-senescent signals to uterine fibroblasts through IL-1β/IL-1R signaling. This sequential senescence cascade drives excessive fibroblast activation and progressive fibrosis, ultimately impairing uterine structure and function. In mouse CS models, inhibition of the PGES/PGE2 pathway and anti-aging strategies significantly attenuate fibrosis and restore coordinated myometrial and endometrial repair. Our findings uncover a macrophage–fibroblast senescence relay to fibrotic scar formation in CSD and provide a translational rationale for targeting PGE2 signaling and senescence to improve uterine repair after CS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"26 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: A circRNA signature predicts postoperative recurrence in stage II/III colon cancer.","authors":"Huai-Qiang Ju, Qi Zhao, Feng Wang, Ping Lan, Zixian Wang, Zhi-Xiang Zuo, Qi-Nian Wu, Xin-Juan Fan, Hai-Yu Mo, Li Chen, Ting Li, Chao Ren, Xiang-Bo Wan, Gong Chen, Yu-Hong Li, Wei-Hua Jia, Rui-Hua Xu","doi":"10.1038/s44321-026-00510-9","DOIUrl":"10.1038/s44321-026-00510-9","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"4173-4176"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease.","authors":"Johan L K Van Hove, Marisa W Friederich, Roxanne A Van Hove, Jessica C Lee, Kaz M Knight, Tonia E Donovan, Lori Silveira, Rebecca D Ganetzky, Michio Hirano, Jose Abdenur, Merlin G Butler, David Cassiman, Bruce H Cohen, Sarah H Elsea, Gregory M Enns, William A Gahl, Ralitza Gavrilova, Gabrielle C Geddes, Emma E Glamuzina, Amy Goldstein, Richard H Haas, Aneal Khan, Kimberly A Kripps, Austin A Larson, April N Lehman, Uta Lichter-Konecki, Johannes A Mayr, Eva Morava, James T Peterson, Jill A Rosenfeld, Russell P Saneto, Fernando Scaglia, Emily Shelkowitz, Mariella Simon, Joél E G Smet, Wendy E Smith, Claudia Soler-Alfonso, Mark Tarnopolsky, Rudy N A Van Coster, Arnaud V Vanlander, Pieter Vermeersch, Jerry Vockley, Kristen Wigby, Lynne A Wolfe, Saskia B Wortmann, Jennifer H Yang","doi":"10.1038/s44321-026-00497-3","DOIUrl":"10.1038/s44321-026-00497-3","url":null,"abstract":"<p><p>Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"4153-4172"},"PeriodicalIF":7.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}