bims-polgdi Biomed News
on POLG disease
Issue of 2026–07–12
47 papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
  2. Mitochondria setting the stage for ferroptosis.
  3. Mitochondrial DNA Inheritance and Germline Purifying Selection: Insights From Drosophila.
  4. Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
  5. Mitochondrial transplantation reverses the senescence phenotype of SH-SY5Y cells.
  6. Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.
  7. RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases.
  8. Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
  9. Immune regulation in mitochondrial transfer: knowledge structure and emerging trends from a bibliometric perspective.
  10. SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
  11. The role of mitochondrial proteases in inflammation and immunity.
  12. Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.
  13. Discordance in orphan drug approvals between the U.S. Food and Drug Administration and the European Medicines Agency: A retrospective observational analysis.
  14. The gut microbiome and mitochondrial function in metabolism, immunity, and disease.
  15. Integrative and systematic genomic approaches to improve diagnosis in rare and undiagnosed diseases: results from the RareBoost project.
  16. The Orphanet Nomenclature and Classification of Rare Diseases for Improved Patient Recognition and Data Interoperability: Qualitative and Quantitative Analysis.
  17. RankVar: machine learning-based variant ranking and reinterpretation for rare genetic diseases.
  18. Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
  19. Implementation of exome sequencing for rare undiagnosed diseases in LMICs: the G2MC rare diseases exome sequencing pilot project.
  20. Microbiota and immunotherapy: The birth of a new paradigm?
  21. Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
  22. Subcellular Localization of Telomerase Reverse Transcriptase Regulates Gene-Specific Modulation of Mitochondrial DNA Copy Number in Neuronal Cells.
  23. Securing Educational Support for Children With Rare Genetic Conditions: Mothers' Experiences and Impacts on the Family.
  24. Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
  25. Efficacy assessment in trials of complex and rare diseases: a comparison between the meta-analytic global statistical test and co-primary analysis.
  26. The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?
  27. Mitochondrial regulation of brain development: evidence from zebrafish models.
  28. Biomarkers and surrogate endpoints for drug development in propionic acidemia.
  29. From molecular damage to regulatory constraint: epigenetic and metabolic limits of cellular plasticity in aging.
  30. Medicinal Chemistry Perspectives on Drug Repurposing: Innovative Approaches and Therapeutic Breakthrough.
  31. The CARE Model: A Framework for Artificial Intelligence Integration in Chronic Disease Management.
  32. RESCUE: An end-to-end multi-agent LLM system for proactive rare-disease patient screening in the EHR.
  33. Health Data Quality Skill Gaps and Training Needs Among European Health Data Stakeholders: Cross-Sectional Survey.
  34. Development of Metabolic Stress in Vascular Organoids under Normal Conditions and with AD/PD-Associated Genetic Backgrounds.
  35. Deciphering the clinical and genetic spectrum of early-onset inborn errors of immunity in a Brazilian pediatric cohort.
  36. Qualitative Evaluation of Fatigue and Pruritus Among Patients with Primary Biliary Cholangitis.
  37. Stimulating proteasomal degradation in human proteinopathies.
  38. Clinical rationale for thymic restoration in adult immunosenescence.
  39. Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature.
  40. Developing a Specialized Dravet Syndrome Ontology for Rare Disease Informatics and AI Applications.
  41. Polygenic scores as modifiers in Mendelian diseases.
  42. ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
  43. Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
  44. FRRS1L gene replacement ameliorates disease phenotypes in the mouse model of developmental and epileptic encephalopathy 37.
  45. Artificial Intelligence That Changes Clinical Neurology Practice: Translating Algorithms Into Actionable Care.
  46. Best Practices in Physiologically Based Pharmacokinetic (PBPK) Modeling.
  47. When network biology meets human genetics.
  1. Protein Sci. 2026 Aug;35(8): e70703
    Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
    Lena J Reichert, F-Nora Vögtle, Carlotta Peselj.
      Mitochondria respond to proteotoxic stress through the mitochondrial unfolded protein response, traditionally viewed as a transcriptional program that restores proteostasis by inducing chaperones and proteases. Emerging evidence indicates that mitochondrial membrane remodeling constitutes an additional adaptive component of this response. Regulated changes in mitochondrial lipid composition, particularly involving the signature phospholipid cardiolipin, support mitochondrial function during stress by stabilizing protein import machineries, promoting mitochondrial protein biogenesis, and facilitating recovery from dysfunction. In addition, stress originating in other organelles, especially the endoplasmic reticulum, reshapes mitochondrial membranes through altered lipid biosynthesis, inter-organelle lipid trafficking, and stress signaling pathways. These findings suggest that mitochondrial membrane remodeling represents a regulatory layer of organelle quality control integrated within interconnected stress response networks and may provide new opportunities to enhance mitochondrial resilience in disease.
    Keywords:  ER–mitochondria crosstalk; cardiolipin; mitochondrial membrane remodeling; mitochondrial protein biogenesis; mitochondrial unfolded protein response (UPRmt); organelle stress signaling
    DOI:  https://doi.org/10.1002/pro.70703
  2. Trends Endocrinol Metab. 2026 Jul 07. pii: S1043-2760(26)00150-5. [Epub ahead of print]
    Mitochondria setting the stage for ferroptosis.
    Sofia Ahola.
      Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron-sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.
    Keywords:  coenzyme Q; ferroptosis; iron–sulfur cluster; lipid peroxidation; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.tem.2026.06.006
  3. Annu Rev Genet. 2026 Jul 09.
    Mitochondrial DNA Inheritance and Germline Purifying Selection: Insights From Drosophila.
    Zhe Chen, Hong Xu.
      The mitochondrial genome resides in a highly mutagenic environment and is typically maternally inherited with little recombination, features that should render mitochondrial DNA (mtDNA) prone to the accumulation of deleterious variants. Contrary to this expectation, mtDNA integrity is remarkably well-preserved over evolution. Purifying selection in the female germline that limits transmission of deleterious mtDNA mutations has been documented in various animal models and in humans. Here, we synthesize the literature, with an emphasis on insights from Drosophila, revealing that replication competition-the preferential propagation of healthy genomes over deleterious ones-is the main mechanism driving mtDNA purifying selection in the germline. We highlight developmentally orchestrated mitochondrial processes that couple genome function to replication, enabling selection based on the bioenergetic performance of individual genomes during oogenesis. Finally, we discuss how replication competition can generate genetic conflicts, particularly through the emergence of selfish mtDNA, and how such conflicts may have shaped mtDNA evolution and features of mitochondrial genetics, including maternal inheritance and the mitochondrial bottleneck.
    DOI:  https://doi.org/10.1146/annurev-genet-011626-033825
  4. Front Aging. 2026 ;7 1830839
    Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
    Nengneng Shi, Xiaojing Li.
      Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology. However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts. In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.
    Keywords:  age-related disease; aging; inflammation; mitochondria; mitochondrial transcription factor A; oxidative stress
    DOI:  https://doi.org/10.3389/fragi.2026.1830839
  5. Mol Ther Adv. 2026 Sep 10. 34(3): 201788
    Mitochondrial transplantation reverses the senescence phenotype of SH-SY5Y cells.
    Liqun Xu, Yilang Wu, Wanfei Wu, Xiao Li, Ronghao Deng, Haibao Zhu, Aihua Mao, Pingnan Sun, Xin Zhang, Wencan Xu, Chi-Ju Wei.
      Fusogenic plasma membrane vesicles (PMVs) were engineered as carriers for mitochondrial delivery into senescent SH-SY5Y cells, a human neuroblastoma cell line widely used as an in vitro model for neurodegenerative diseases. Mitochondrial transfer was achieved via cell fusion mediated by the fusogenic vesicular stomatitis virus glycoprotein G. After mitochondrial transplantation, senescent SH-SY5Y cells exhibited marked phenotypic reversal, accompanied by restoration of glucose metabolism, ATP production, lactate levels, and mitochondrial respiratory activity to near-normal levels. In addition, mitochondrial transplantation regulated the senescence-associated secretory phenotype and associated inflammatory signaling pathways, while significantly enhancing antiapoptotic activity. Single-nucleotide polymorphism tracing of mitochondrial DNA confirmed the stable persistence of transplanted mitochondria within recipient cells, which was associated with recovery of normal mitochondrial morphology, function, and biogenesis. Notably, autophagic activity decreased after mitochondrial transplantation. Finally, alpha-synuclein expression was reduced, whereas dopamine production and the activities of enzymes involved in dopamine synthesis were increased after mitochondrial transplantation. The results demonstrated that mitochondrial transplantation can effectively reverse the senescence phenotype of SH-SY5Y cells, suggesting that mitochondrial transplantation may represent a promising therapeutic strategy for neurodegenerative disorders such as Parkinson disease.
    Keywords:  PMVs; Parkinson disease; SH-SY5Y cells; SNP analysis; autophagy; cellular senescence; mitochondria transplantation; plasma membrane vesicles; single-nucleotide polymorphism analysis
    DOI:  https://doi.org/10.1016/j.omta.2026.201788
  6. Mol Genet Metab. 2026 Jun 26. pii: S1096-7192(26)00481-6. [Epub ahead of print]148(4): 110198
    Non-invasive urinary heteroplasmy screening outperforms blood testing for certain mitochondrial DNA variants in mitochondrial disease patients.
    Atsuko Okazaki, Yukiko Yatsuka, Takuya Fushimi, Takanori Onuki, Yuko Aida, Hisato Aihara, Toshiyuki Imasawa, Akira Ohtake, Kei Murayama, Yasushi Okazaki.
       BACKGROUND: Mitochondrial diseases present diagnostic challenges due to variations in heteroplasmy levels of mitochondrial DNA (mtDNA) in different tissues. Current diagnostic approaches primarily rely on blood testing, which may miss pathogenic variants present at higher levels in other accessible tissues.
    METHODS: We analyzed tissue samples from 164 individuals (125 probands and 39 family members) with genetically confirmed mitochondrial diseases using droplet digital PCR (ddPCR). We quantified heteroplasmy levels in five tissue types: blood, urine, cardiac muscle, skeletal muscle, and kidney tissue.
    RESULTS: Among the 108 blood samples and 87 urine samples from patients carrying the m.3243A>G variant, urine samples demonstrated significantly higher heteroplasmy levels than blood samples (median: 76.6% [interquartile range (IQR): 50.8-91.8%] vs. 20.9% [IQR: 11.3-41.4%], p < 0.001). In a paired analysis of 80 patients with the m.3243 A > G variant who provided both blood and urine samples, urine heteroplasmy exceeded blood levels in all cases (median difference: 44.6% [interquartile range (IQR): 26.9-56.7%], p < 0.001). Moderate positive correlations were observed between blood and urine heteroplasmy (all variants: r = 0.68, n = 94 pairs; m.3243 A > G: r = 0.66, n = 80 pairs; both p < 0.001). Using an exploratory 10% heteroplasmy threshold based on prior reports for m.3243A>G, blood classified 24 of the 94 paired cases (25%, or one in four patients) as <10% while urine was ≥10%. Cardiac tissue exhibited the highest heteroplasmy levels (mean: 86% ±8% in m.3243A>G patients), though this likely reflects selection bias, as cardiac biopsies were obtained only from patients with cardiac involvement.
    CONCLUSIONS: Urine specimens demonstrate higher heteroplasmy levels and more often place individuals above an exploratory 10% heteroplasmy threshold compared with blood specimens for certain mitochondrial DNA (mtDNA) variants, most notably m.3243A>G. Using this exploratory threshold, 24 of 94 paired blood-urine samples (25%) had blood heteroplasmy <10% while urine heteroplasmy was ≥10%, supporting the use of urine as an important noninvasive complementary specimen, and in many cases a preferred specimen, for suspected m.3243A>G. However, blood testing remains appropriate for variants that typically show high blood heteroplasmy and a relatively high threshold for clinical expressivity, such as m.8993 T > G. These findings support the implementation of urine-based screening protocols for suspected m.3243A>G cases, which may reduce underestimation of variant load and improve diagnostic evaluation.
    Keywords:  Droplet digital PCR; Heteroplasmy; Inherited metabolic disorder; Mitochondrial disease; Tissue-specific diagnosis; m.3243A>G
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110198
  7. bioRxiv. 2026 Jul 03. pii: 2026.06.29.735296. [Epub ahead of print]
    RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases.
    Huanfei Wang, Shixue Sun, Ewy A Mathé, Qian Zhu.
      Rare diseases (RD) impact over 30 million individuals in the United States, yet fewer than 5% of the identified conditions have FDA-approved treatments. Progress in RD research is hindered by small patient cohorts, biological heterogeneity, and the fragmented, inconsistently annotated publicly available omics data, which limits integrative analysis and translational discovery. Here, we present RD-OMICS, a data inventory with integrated and structured RD omics data from Gene Expression Omnibus (GEO), in the form of a knowledge graph. We developed a metadata harmonization pipeline that combines rule-based mapping and large language model (LLM)-assisted semantic categorization. The graph-based data model was defined to integrate different types of data including disease conditions, experiments, samples, platforms, projects, and publications into a centralized inventory graph. In this preliminary study, 11,049 GEO series for 126 rare diseases were processed and integrated into RD-OMICS, which includes 375,930 individual biospecimen samples, 1,578 sequencing and array platforms, 10,938 biological projects. Case studies demonstrate the use of RD-OMICS in supporting rare disease research, omics cohort construction, and transcriptome-based drug repurposing for amyotrophic lateral sclerosis (ALS). RD-OMICS provides a scalable foundation for transforming fragmented omics data into a structured, harmonized and interoperable resource, facilitating therapeutic development and other translational discoveries in rare diseases.
    DOI:  https://doi.org/10.64898/2026.06.29.735296
  8. J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):
    Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
    Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.
      Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.
    DOI:  https://doi.org/10.1083/jcb.202511211
  9. Front Immunol. 2026 ;17 1850600
    Immune regulation in mitochondrial transfer: knowledge structure and emerging trends from a bibliometric perspective.
    Qiyu He, Zhimin Tan, Juan Xu, Tianhong Wang, Qian Li, Xiaoqiang Li.
       Background: Mitochondrial transfer has emerged as an important form of intercellular communication with growing relevance to immune regulation, inflammation, tissue repair, and tumor immunity. However, the knowledge structure, developmental trajectory, and emerging hotspots of this field remain unclear.
    Methods: We conducted a bibliometric analysis of studies on mitochondrial transfer and immune regulation published between 2016 and 2025. Publications were retrieved from PubMed, Embase, the Cochrane Library, Scopus, and Web of Science, and analyzed using bibliometrix in R and CiteSpace. Annual publication trends, contributions of countries, institutions, authors, and journals, as well as keyword co-occurrence, clustering, burst detection, and co-citation patterns were evaluated.
    Results: A total of 967 publications were included. Annual publication output increased steadily, with faster growth after 2020. China and the United States were the leading contributors and occupied central positions in international collaboration networks. Keyword and co-citation analyses showed that early studies mainly focused on mitochondrial DNA-associated inflammatory sensing, innate immunity, and inflammatory injury, whereas recent studies increasingly emphasized intercellular mitochondrial transfer, mitochondrial transplantation, T-cell function, tumor-associated macrophages, cancer immunotherapy, metabolic rewiring, and autophagy-associated mitochondrial quality control. Mitochondrial transplantation and tunneling nanotube were among the most prominent burst terms. Co-citation analysis identified major knowledge domains related to mitochondrial danger signaling, intercellular transfer mechanisms, mesenchymal stem cell-mediated immune regulation, tumor immunity, and translational applications.
    Conclusion: Bibliometric mapping shows a clear shift from mitochondrial danger signaling toward intercellular transfer and immune-cell metabolic remodeling. Current evidence suggests that immune outcomes are shaped by mitochondrial source, transfer route, recipient-cell state, and disease context. More source-defined and context-specific studies are needed to clarify the therapeutic potential of mitochondrial transfer.
    Keywords:  bibliometric analysis; immune regulation; immunometabolism; mitochondrial transfer; mitochondrial transplantation
    DOI:  https://doi.org/10.3389/fimmu.2026.1850600
  10. Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):
    SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
    Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.
      Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation
    DOI:  https://doi.org/10.1007/s12035-026-06050-0
  11. Front Immunol. 2026 ;17 1761658
    The role of mitochondrial proteases in inflammation and immunity.
    Anna Rebeka Oliveira Ferreira, Emily A Day.
      The global rise in chronic inflammatory and autoimmune disorders has intensified research to understand cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses. By selectively degrading misfolded or damaged proteins, they maintain mitochondrial function and bioenergetic capacity. Beyond housekeeping roles, mitochondrial proteases also influence immune signaling by modulating mitochondrial stress pathways, reactive oxygen species production, and the release of mitochondrial-derived danger signals. Dysregulation of these proteases has been linked to chronic inflammation and contributes to the pathogenesis of inflammatory diseases. This review summarizes current knowledge on the role of mitochondrial proteases CLPXP, LONP1, i-AAA, m-AAA, as well as processing peptidase OMA1, in immune cells and inflammatory pathologies. We explore the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating the results from immune cells as well as other non-immune cell types, including those involved in cancer, neurodegeneration, renal injury, and other inflammatory pathologies. We explore mitochondrial proteases function as context-dependent regulators of immunometabolic signaling, with effects shaped by cell type, metabolic state, and stress conditions. Finally, we discuss emerging small molecules and drugs targeting mitochondrial proteases to highlight their potential therapeutic role in modulating inflammation. By situating mitochondrial proteases at the crossroads of immunometabolism and therapeutic intervention, this review underscores their untapped potential in the development of innovative anti-inflammatory strategies.
    Keywords:  MAVS; cGAS-STING; immune cells; inflammatory disease; innate immunity; macrophages; mitochondrial dysfunction; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2026.1761658
  12. Psychoneuroendocrinology. 2026 Jul 02. pii: S0306-4530(26)00212-X. [Epub ahead of print]192 107952
    Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.
    Lauren Petri, Sun Ah Lee, David Shire, Samantha Leonard, Alexander Behnke, Idan Shalev, Jody Greaney, Lacy Alexander, David M Almeida, Martin Picard, Caroline Trumpff.
      The present study analyzes the impact of naturalistic stress and emotions on saliva cell-free mitochondrial DNA (cf-mtDNA) in daily life across two independent cohorts with different temporal resolutions. Study 1 examined the interaction between daily stress and major depressive disorder (MDD) on cf-mtDNA in young adults (n = 18, 8 MDD, 10 controls). Across four days, participants provided 4 saliva samples and nightly stress inventories. Among individuals with MDD, cf-mtDNA concentrations were 68% lower on days with reported stress exposure compared with days without reported stress exposure. Among stress-exposure days, a greater number and higher severity of stressors were associated with 24-27% lower cf-mtDNA concentrations. Study 2 extended this framework by implementing a finer temporal resolution in healthy young adults (n = 25), measuring saliva and momentary affective states with hourly ecological momentary assessments, up to 20 times per day for 2 days. Higher positive affect was associated with higher cf-mtDNA; however, this relationship weakened as negative affect increased. Exploratory analyses of individual emotions showed that cf-mtDNA tended to be higher during positive emotional states and lower during negative emotional states; however, person-specific models indicated that these associations, particularly for happiness and stress, varied substantially across participants. Overall, cf-mtDNA did not exhibit a uniform stress response in daily life; rather, the dynamics were dependent on diagnostic status and stress exposure timing in Study 1, and on momentary emotional context in Study 2. Accordingly, cf-mtDNA should be conceptualized as a dynamic biobehavioral signal rather than a static indicator of between-person differences.
    Keywords:  Affect dynamics; Cell-free mitochondrial DNA (cf-mtDNA); Daily stress; Ecological momentary assessment (EMA); Major depressive disorder (MDD); Saliva biomarkers
    DOI:  https://doi.org/10.1016/j.psyneuen.2026.107952
  13. PLoS Med. 2026 Jul 06. 23(7): e1004861
    Discordance in orphan drug approvals between the U.S. Food and Drug Administration and the European Medicines Agency: A retrospective observational analysis.
    Jin Ding, Michael M Hopkins, Paul A Martin.
       BACKGROUND: The United States (US) and European Union (EU) have long-established orphan drug regulations to incentivise the development of medicines for rare diseases. While the numbers of orphan approvals have risen rapidly, there is increasing discordance in regulatory outcomes between the US and EU. This discordance primarily stems from two sets of cases: US Food and Drug Administration (FDA) orphan approvals not authorised by the European Medicines Agency (EMA), and FDA orphan approvals with EMA authorisation but without orphan designation. We examined factors associated with these two sets of cases to understand the growing gap in orphan approvals between the US and EU.
    METHODS AND FINDINGS: We collected data on FDA orphan drug approvals between 2011 and 2023 from the FDA Orphan Drug Designations and Approvals Database and their corresponding EMA regulatory status from EMA medicines database. We used descriptive statistical analysis to examine trends and identify discordance in outcomes between agencies. Univariable logistic regression assessed pre-specified factors associated with discordance, including therapeutic area (cancer/non-cancer), company size (large/medium/small), company headquarters location (US/EU/others) and approval period (2011-2016/2017-2023). The main methodological limitations are that the study identified associations but does not establish causality, with unmeasured factors potentially contributing to the observed discordance. Of 814 FDA orphan approvals, only 29% received corresponding EMA marketing authorisation with orphan designation. A further 38% were authorised by the EMA but without orphan status, while the remaining 33% were not authorised by the EMA. Compared with the 2011-2016 period, cases in the 2017-2023 period were associated with lower odds (OR 0.66 (95% CI [0.48,0.92]; p = 0.013)) of EMA marketing authorisation. Compared with cancer approvals, non-cancer approvals were associated with lower odds (OR 0.53 (95% CI [0.38, 0.75]; p < 0.001)) of having EMA marketing authorisation, but when authorised, were associated with higher odds (OR 2.36 (95% CI [1.50, 3.70]; p < 0.001)) of receiving orphan designation. Compared with large companies, orphan approvals from small and medium-sized companies were associated with lower odds (OR 0.45 (95% CI [0.28, 0.74]; p = 0.001) and (OR 0.29 (95% CI [0.20, 0.43]; p < 0.001)) of EMA marketing authorisation, but among authorised products they were associated with higher odds (OR 2.95 (95% CI [1.75, 4.99]; p < 0.001) and (OR 2.14 (95% CI [1.17, 3.90]; p = 0.014)) of orphan-designated marketing authorisation, respectively. EU companies were associated with higher odds (OR 1.69 (95% CI [1.17-2.43]; p = 0.005)) of receiving EMA orphan approvals compared with US companies.
    CONCLUSIONS: Between 2011 and 2023, regulatory outcomes for orphan drug approvals increasingly diverged between the FDA and the EMA, particularly for cancer indications and approvals sponsored by small US sponsors. Among FDA orphan drugs authorised by the EMA, many were not designated as orphan products because of regulatory differences, particularly regarding requirements around significant benefit and biomarker-defined sub-populations in oncology. FDA-approved orphan drugs that lack EU marketing authorisation may be withheld by companies not because of regulatory barriers but due to insufficient commercial incentives to launch in Europe, resulting in fewer treatment options for European rare disease patients. Our findings suggest that orphan incentives are not the primary driver of commercial EU-launch decisions and that recent EU regulatory reform of these incentives may not achieve their goal of improving access to therapy for rare diseases.
    DOI:  https://doi.org/10.1371/journal.pmed.1004861
  14. Gut Microbes. 2026 Dec 31. 18(1): 2699451
    The gut microbiome and mitochondrial function in metabolism, immunity, and disease.
    Eui Jeong Han, Da-Hye Kim, Jeong Jae Lee, Hea-Jong Chung.
      The gut microbiome is a key regulator of host physiology, yet its effects remain difficult to predict across individuals and contexts. Similar microbial compositions frequently give rise to divergent and delayed phenotypic outcomes, indicating that models based solely on signal strength or steady-state responses are insufficient to explain microbiome-driven host function. In this review, we propose a conceptual perspective in which microbiome-associated variability is shaped by the capacity of host cells to maintain mitochondrial function under persistent metabolic and immune stress. Microbiome-derived metabolites and immune activity define the metabolic and redox environments that constrain mitochondrial performance, thereby influencing how effectively cells recover from repeated stress. When mitochondrial membrane potential, redox balance, and energy production are not fully restored, mitochondria may show increased engagement of quality-control pathways. Over repeated stress-recovery cycles, this pattern may be associated with reduced functional reserve despite preserved baseline activity. This testable perspective may help explain why microbiome-associated phenotypes are delayed, variable, and context-dependent, and it highlights mitochondrial recovery capacity as a potential determinant of disease vulnerability and host-microbiome interactions.
    Keywords:  Gut microbiome; cellular stress response; host–microbe interactions; immunometabolism; mitochondrial function
    DOI:  https://doi.org/10.1080/19490976.2026.2699451
  15. Eur J Hum Genet. 2026 Jul 09.
    Integrative and systematic genomic approaches to improve diagnosis in rare and undiagnosed diseases: results from the RareBoost project.
    Rare and Undiagnosed Diseases Advisory Board Consortium
      Rare and undiagnosed diseases pose diagnostic challenges due to phenotypic and genetic heterogeneity and the limitations of conventional molecular testing. As part of the RareBoost project, we implemented an integrated, stepwise genomic strategy in a cohort of 134 patients from 120 families with previously inconclusive genetic testing. Our strategy combined systematic exome sequencing with subsequent genome sequencing when indicated, followed by targeted RNA-sequencing, and complemented with comprehensive phenotyping and follow-up segregation analysis. Definitive molecular diagnoses (pathogenic/likely pathogenic variants) were achieved in 25.0% of families, and an additional 25.8% harbored clinically relevant variants of uncertain significance with phenotypic correlation. This approach identified non-coding and structural variants while resolving cases through systematic reanalysis of previously negative data. Collectively, our findings demonstrate that integrated genomic and transcriptomic analyses with reanalysis of existing data enhance diagnostic yield in complex rare disease cohorts and provide a scalable framework for implementing genomic medicine in clinical practice.
    DOI:  https://doi.org/10.1038/s41431-026-02177-9
  16. JMIR Med Inform. 2026 Jul 08. 14 e84553
    The Orphanet Nomenclature and Classification of Rare Diseases for Improved Patient Recognition and Data Interoperability: Qualitative and Quantitative Analysis.
    Caterina Lucano, David Lagorce, Annie Olry, Houda Ali, Valérie Lanneau, Mickael De Carvalho, Aysegul Dilsizoglu Senol, Marta Fructuoso, Emilie Gaillard, Marie-Cécile Gaillard, Seed Mihic, Mariana Tannoury, Florence Sauvage, Charlotte Rodwell, Sylvie Maiella, Marc Hanauer, Ana Rath.
       BACKGROUND: Although individually uncommon, rare diseases (RDs) collectively affect an estimated 329-624 million people worldwide. There are over 6500 known RDs, 85% of which affect fewer than 1 person per million. Consequently, the critical amount of data necessary to improve knowledge, care, and treatment can only be achieved through cumulative data collection across countries. However, RDs remain underrepresented in medical terminologies and classification systems, hindering data sharing, interoperability, and public health monitoring.
    OBJECTIVE: This paper presents the Orphanet Nomenclature and Classification of RDs detailing its content, production and update methodology, and mappings to other semantic resources. It also provides an up-to-date count of RDs based on the consensus operational definition describing their distribution by medical domain.
    METHODS: The Orphanet Nomenclature of RDs is a multilingual standardized system composed of clinical entities, each defined by a unique and time-stable ORPHAcode, a preferred term, synonyms, a classification level, and a textual definition. This nomenclature is structured into 3 classification levels organized within a multihierarchical and multiparental classification system by medical domain. Its production, updates, and mappings to major biomedical resources rely on standardized and published procedures, continuous literature review, manual curation, and expert validation, reflecting advancements in RDs knowledge and clinical practice. Presented data metrics were computed using the Orphanet July 2025 release to quantitatively characterize the content, structure, classification, and semantic alignments of the Orphanet Nomenclature and Classification system.
    RESULTS: As of July 2025, the Orphanet Nomenclature of RDs includes a total of 9784 active clinical entities, including 6527 disorders (corresponding to the RDs definition), 1084 subtypes of disorders, and 2173 groups of disorders. Disorders are multiclassified into 29 classification hierarchies, each corresponding to a distinct medical domain, accurately representing the complex multisystemic nature of RDs. Extensive qualified mappings ensure semantic interoperability: 97.4% (6355/6527) of disorders are mapped to at least 1 ICD-10 (International Statistical Classification of Diseases, Tenth Revision) code (415/6527, 6.4% with an exact proximity relationship), 71.8% (4683/6527) are mapped to at least 1 ICD-11 (International Classification of Diseases, Eleventh Revision) Mortality and Morbidity Statistics code (958/6527, 14.7% with an exact relationship) and 94.8% (6191/6527) are mapped to Systematized Nomenclature of Medicine Clinical Terms (all with an exact relationship). Genetic disorders represent 72.2% (4715/6527) of all RDs, and 63.4% (4141/6527) are mapped to at least 1 phenotypic Online Mendelian Inheritance in Man number.
    CONCLUSIONS: The Orphanet Nomenclature and Classification of RDs is the only RDs-specific interoperable medical terminology meeting the needs of health care, research, and public health systems. By addressing the underrepresentation of RDs in medical terminologies, it enables accurate RDs identification, coding, and monitoring, supporting cross-border data interoperability, and contributing to improved knowledge, policymaking, and ultimately better care for people living with an RD.
    Keywords:  Interoperability; ORPHAcodes; classification; codification; medical terminology; nomenclature; rare diseases
    DOI:  https://doi.org/10.2196/84553
  17. Genome Med. 2026 Jul 04.
    RankVar: machine learning-based variant ranking and reinterpretation for rare genetic diseases.
    Yuan Zhang, Mian Umair Ahsan, Peng Wang, Xiaoqi Lin, Ian M Campbell, Cong Liu, Wendy K Chung, Chunhua Weng, Kai Wang.
       BACKGROUND: Prior biological knowledge and phenotype information can help identify disease genes from whole genome/exome sequencing studies, but how best to incorporate external knowledge with variant data remains challenging. We developed a machine learning algorithm called RankVar to prioritize causative variants for rare diseases, based on clinical notes and genome/exome sequencing profiles.
    METHODS: RankVar uses a random forest classifier trained on ~ 1 million variants from the 1000 Genomes Project with spiked-in pathogenic variants. For testing, we compiled sequencing data and phenotype information from several independent datasets: 260 subjects from the Children's Hospital of Philadelphia (CHOP) with positive genetic diagnosis of various Mendelian diseases, 135 subjects from Birth Defects Biorepository (BDB), as well as 356 and 97 subjects with candidate causal variants for autism spectrum disorders from the Simons Simplex Collection (SSC) and the Simons Foundation Powering Autism Research for Knowledge (SPARK), respectively.
    RESULTS: RankVar achieves a top 10 variant accuracy of 90.0%, 81.5%, 46.1%, and 76.3% for CHOP, BDB, SSC, and SPARK, respectively, with improved performance over existing approaches. Notably, RankVar successfully identified X-linked and Y-linked disease-causal variants, such as KDM6A (p.N915Kfs5*) and SRY (p.W98X), as the top candidate variants. Moreover, we evaluated RankVar for genomic reinterpretation of 130 unsolved CHOP cases with hearing loss and successfully identified 61 candidate causal variants after manual review.
    CONCLUSIONS: In summary, RankVar performed favorably relative to existing methods in our evaluation, accommodated different genetic models and X/Y chromosome variants, and may provide a useful framework for prioritizing variants in monogenic or oligogenic diseases. We anticipate that RankVar may aid in primary genetic diagnosis, genome reinterpretation of previously unsolved cases, and the discovery of novel disease genes.
    Keywords:  Machine learning; Rare genetic disease; Variant prioritization
    DOI:  https://doi.org/10.1186/s13073-026-01701-2
  18. Front Aging Neurosci. 2026 ;18 1865383
    Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
    Lingzhe Wang, Bin Xu.
      Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of nigral dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited. Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network. This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.
    Keywords:  PINK1; Parkin; Parkinson’s disease; functional uncoupling; lysosomal dysfunction; mitochondrial quality control; mitophagy; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2026.1865383
  19. Hum Genet. 2026 Jul 08. pii: 61. [Epub ahead of print]145(1):
    Implementation of exome sequencing for rare undiagnosed diseases in LMICs: the G2MC rare diseases exome sequencing pilot project.
    Yasas D Kolambage, Claudia Gonzaga-Jauregui, Guillermo Lay-Son, Rupesh Mishra, Njabulo Christian Mabaso, Sok-Kun Tae, Kristin A Maloney, Carolina I Galaz-Montoya, Dineshani Hettiarachchi, Bronwyn Dillon, Nilam Thakur, Ludivine de Menten, Cecilia Mellado, Carol L Greene, Toni I Pollin, Amanda Krause, Meow-Keong Thong, Alan R Shuldiner, Vajira H W Dissanayake.
      Rare undiagnosed diseases impose a substantial burden on patients, families, and health systems. Collectively they affect an estimated 300-350 million people worldwide. Of these, approximately 250 million live in low- and middle-income countries (LMICs). Many rare diseases have a genetic basis and can be diagnosed using molecular testing. However, patients in LMICs often lack access to advanced diagnostics and specialist care, leading to prolonged diagnostic odysseys and significant distress. To address this gap, the Global Genomic Medicine Collaborative (G2MC) implemented a Rare Disease Pilot Project to enable clinical genomic testing at six LMIC sites (Chile, Malaysia, Mexico, Nepal, South Africa, Sri Lanka). Using trio exome sequencing for 18 selected families, supplemented by chromosomal microarray as indicated, definitive molecular diagnoses were established in 5 families (pathogenic/likely pathogenic variants explaining the phenotype). An additional 8 families had suspected molecular diagnoses with strong phenotype correlation that require functional validation, while 5 families remained undiagnosed at the end of the pilot. The integration of genomic data into clinical decision-making enabled definitive diagnoses, precise management, and genetic counseling for these patients. The pilot also strengthened local capacity building by conducting cross-site case conferences and enabling local reanalysis of sequence data at sites with bioinformatics capabilities. This study demonstrates the feasibility, effectiveness, and adaptability of implementing exome sequencing in resource-limited settings and highlights its potential to transform rare disease diagnosis and care in LMICs.
    DOI:  https://doi.org/10.1007/s00439-026-02849-y
  20. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00233-0. [Epub ahead of print]38(7): 1269-1272
    Microbiota and immunotherapy: The birth of a new paradigm?
    Rachel C Newsome, Christian Jobin.
      Emerging data suggest fecal microbiota transplantation (FMT) may improve cancer patients' responses to immune checkpoint blockade not only by enriching beneficial bacteria but also by depleting harmful taxa. Here, we discuss the "supplementation" and new "depletion" FMT paradigms in cancer management and highlight key knowledge gaps to be addressed to move this field forward.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.007
  21. CNS Neurosci Ther. 2026 Jul;32(7): e71013
    Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
    Zou Pan, Li Yang, Haiyan Tang, Chen Chen, Qian Yang, Tenghui Wu, Fang He, Zhanwei Zhang, Fangyun Liu, Jing Peng.
       AIM: To delineate the clinical features of AFG3L2-related developmental and epileptic encephalopathy (DEE) and explore its pathogenic mechanisms.
    METHODS: Whole-genome and blood transcriptome sequencing were performed in undiagnosed DEE patients. Patient-derived skin fibroblasts were established for the analysis of RNA and protein expression as well as for mitochondrial functional assays, including OPA1 processing, mtDNA copy number, membrane potential, ATP production, mitochondrial morphology analysis, and mitochondrial stress testing. Additionally, published AFG3L2-related epilepsy cases were systematically reviewed.
    RESULTS: We identified four novel AFG3L2 variants in four DEE patients from two unrelated families, including splice-site/intronic variants in one family and exon-deletion/intronic variants in the other, fitting a recessive model of disease. In these patients, plus six additional previously reported DEE patients, symptoms included severe developmental delay, intractable seizures, microcephaly, generalized spasticity, and progressive cerebral atrophy. Transcriptome and fibroblast functional analyses revealed aberrant splicing, reduced AFG3L2 expression, defective OPA1 processing, decreased mtDNA content, impaired membrane potential and ATP production, fragmented mitochondrial networks, and diminished respiratory capacity, supporting a loss-of-function mechanism. Compared with spastic ataxia 5-usually involving null-missense or missense-missense genotypes-DEE predominantly features null-null combinations.
    SIGNIFICANCE: We implicate AFG3L2 as a novel causative gene for DEE, likely through mitochondrial proteostasis failure and bioenergetic compromise, expanding the phenotypic and genotypic spectrum of AFG3L2-related disorders.
    Keywords:   AFG3L2 ; developmental and epileptic encephalopathy; genomic and transcriptomic sequencing; mitochondrial dysfunction; m‐AAA protease
    DOI:  https://doi.org/10.1002/cns.71013
  22. Mol Neurobiol. 2026 Jul 08. pii: 750. [Epub ahead of print]63(1):
    Subcellular Localization of Telomerase Reverse Transcriptase Regulates Gene-Specific Modulation of Mitochondrial DNA Copy Number in Neuronal Cells.
    Jiao Li, Wenji Fang, Zhi Fang, Jing Shi, Yi Feng, Haiting Liu, Hongju Chen.
      Telomerase reverse transcriptase (TERT) exhibits non-canonical neuroprotective functions; its overexpression protects against hypoxic-ischemic brain injury and preserves mitochondrial function. Here, we identified a novel phenomenon in an in vitro model in which oxygen-glucose deprivation/reoxygenation induced a phase-dependent redistribution of endogenous TERT in HT22 neuronal cells, characterized by early mitochondrial accumulation followed by predominant nuclear localization. We aimed to determine whether subcellular localization of TERT dictates its functional specificity in regulating the copy number of mitochondrial DNA-encoded genes in neurons. HT22 cells expressing TERT, targeted to either the mitochondria (mito-TERT) or nucleus (nuc-TERT), were generated using adenoviral transfection. Subcellular localization was confirmed using western blotting. Mitochondrial DNA copy number was assessed using quantitative polymerase chain reaction (qPCR), and direct mito-TERT binding was assessed using chromatin immunoprecipitation (ChIP)-qPCR; ND1 and ND2 mRNA levels were measured using qRT-PCR. Both nuc-TERT and mito-TERT models were successfully established. qPCR analysis showed that mito-TERT specifically upregulated the copy number of mitochondrial complex I genes (nicotinamide adenine dinucleotide-hydrogen dehydrogenase subunit [ND]1/2), whereas nuc-TERT broadly upregulated genes across complexes I, III, IV, and V. A regulation specificity index showed that mito-TERT selectively enhanced ND1 copy number. ChIP-qPCR confirmed mito-TERT enrichment at the ND1 and ND2 promoters. Together, these findings demonstrate that TERT regulates mitochondrial DNA copy number through distinct, compartment-dependent mechanisms. Mito-TERT exhibited gene-specific regulation via direct promoter binding, whereas nuc-TERT displayed broader effects. The stress-induced redistribution of TERT and these mechanistic insights reveal a novel paradigm for multiphasic TERT-mediated neuroprotection in brain injury.
    Keywords:  Brain injury; Mitochondria; Mitochondrial DNA; Neuron; Nucleus; Telomerase reverse transcriptase
    DOI:  https://doi.org/10.1007/s12035-026-06044-y
  23. J Intellect Disabil Res. 2026 Jul 08.
    Securing Educational Support for Children With Rare Genetic Conditions: Mothers' Experiences and Impacts on the Family.
    Lowri O'Donovan, Anne-Marie Burn, Tamsin Ford, Marianne van den Bree.
       BACKGROUND: Children with rare genetic conditions are more likely to experience neurodevelopmental challenges requiring additional educational support. Although the governments in the United Kingdom and Ireland are committed to providing such support, securing it can be challenging for parents, with potential adverse implications for their mental health. Children who do not receive the educational support they need are at greater risk of poorer educational outcomes. This study aimed to remedy the lack of empirical data about the experiences of parents of children with rare genetic conditions in obtaining educational support and how these experiences affect them and their families.
    METHOD: Sixteen mothers were interviewed about their experiences of securing educational support for their child(ren) with a rare genetic condition. Qualitative data were collected during the Covid-19 pandemic. Participants reflected on experiences both prior to and during this period. Data were analysed using Framework Analysis.
    RESULTS: Five main themes were identified: (1) fighting for access into 'the system', (2) a lengthy process to secure support, (3) factors enabling access, (4) challenges after securing support and (5) impact of experience on mothers.
    CONCLUSIONS: Accessing educational support was challenging, lengthy and stressful, with negative effects on mothers' mental health and relationships with wider family members. Parents of children with rare genetic conditions may face additional challenges securing support.
    Keywords:  SEN; educational support; qualitative; rare conditions
    DOI:  https://doi.org/10.1111/jir.70141
  24. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2529208123
    Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
    Stefano Bettinazzi, Avishikta Chakraborty, Finley Grover-Thomas, Damian K Dowling, M Florencia Camus.
      Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.
    Keywords:  Drosophila; ageing; mitochondrial metabolism; mitohormesis; mitonuclear discordance
    DOI:  https://doi.org/10.1073/pnas.2529208123
  25. Front Med Technol. 2026 ;8 1819463
    Efficacy assessment in trials of complex and rare diseases: a comparison between the meta-analytic global statistical test and co-primary analysis.
    Samuel P Dickson, Abe Durrant, Caleb W Dayley, Joshua R Christensen, Craig H Mallinckrodt, Suzanne B Hendrix.
       Introduction: Choice of the primary outcome can be problematic in 1) diseases with heterogeneous signs and symptoms, 2) trials of disease-modifying treatments (DMTs) that are expected to affect all aspects of the disease, 3) in complex and rare diseases with minimal data on clinical trial outcomes. In such situations, a single outcome measuring a single domain of disease will rarely suffice as a primary outcome. To address this issue, regulatory bodies often suggest co-primary endpoints or require efficacy on both primary and key secondary endpoints for confirmatory trials, to ensure that at least two different domains of disease are affected by treatment. However, obtaining statistical significance on two outcomes is a much stricter requirement than on a single primary outcome. Global statistical tests (GST) combine multiple outcomes into a single score and could provide a viable alternative to the co-primary approach. Importantly for rare diseases, combining multiple assessments reduces the risk of selecting a poorly performing outcome simply because it has not been studied extensively.
    Methods: We conducted simulations to compare GST to single primary and co-primary endpoint approaches with two moderately or highly correlated outcomes with various effect sizes.
    Results: For scenarios with the same true effect size on both outcomes, the GST had greater power than single primary and co-primary approaches, regardless of the correlation level between outcomes. This was also true with different effect size combinations at the same correlation level. With an effect observed on one outcome only, GST was more likely to yield statistical significance than the co-primary approach. Unlike the co-primary approach, The GST yielded lower p-values in scenarios with lower correlation between the outcomes due to the independence of the information from each endpoint.
    Conclusions: Using GST as a prespecified endpoint is appropriate in trials where a clear primary endpoint has not been identified, sample sizes are insufficient to support multiple primary endpoints, and/or more comprehensive assessments across multiple endpoints are needed to fully evaluate outcomes.
    Keywords:  Global Statistical Test (GST); clinical trials; co-primary endpoints; complex disease; rare disease
    DOI:  https://doi.org/10.3389/fmedt.2026.1819463
  26. Ageing Res Rev. 2026 Jul 08. pii: S1568-1637(26)00240-0. [Epub ahead of print]121 103248
    The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?
    Surendar Ellappan, Punit Prasanna Kujur, Amal Chandra Mondal.
      Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.
    Keywords:  Autophagy; Glial senescence; Inflammasome; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.arr.2026.103248
  27. Fish Physiol Biochem. 2026 Jul 06. pii: 114. [Epub ahead of print]52(4):
    Mitochondrial regulation of brain development: evidence from zebrafish models.
    Ahmet Topal.
      Mitochondria play a vital role in maintaining cellular energy balance, regulating apoptosis and controlling redox signaling during neurodevelopment. Disruption of these biological processes has emerged as a key mechanism underlying neurodevelopmental disorders and developmental neurotoxicity. Mitochondria influence neurodevelopmental phases, including neuronal proliferation and differentiation. The zebrafish serves as an exemplary model for examining the impact of mitochondria and energy metabolism on neurodevelopment, owing to its optical transparency, rapid embryonic development, and suitability for genetic manipulation. In this review, we summarize current knowledge on how mitochondrial processes direct brain development in zebrafish, providing a comprehensive overview of findings related to energy metabolism, calcium signaling, oxidative stress, and apoptosis. The findings show that mitochondrial health is a decisive factor for neurodevelopment and suggest that zebrafish-based models may play a critical role in developing new treatment strategies for neurodevelopmental disorders in the future.
    Keywords:  Brain; Energy metabolism; Mitochondria; Zebrafish
    DOI:  https://doi.org/10.1007/s10695-026-01739-4
  28. Mol Genet Metab. 2026 Jul 04. pii: S1096-7192(26)00485-3. [Epub ahead of print]149(1-2): 110202
    Biomarkers and surrogate endpoints for drug development in propionic acidemia.
    Agnieszka Jurecka, Sabine Scholl-Bürgi, Barbara Burton, Roberto Zori, Nicola Longo, Jerry Vockley, Carlo Dionisi-Vici.
      Drug development in rare metabolic diseases is frequently limited by the lack of validated clinical trial endpoints, particularly for chronic disease modification. Propionic acidemia (PA) is an intoxication-type inherited metabolic disorder with significant morbidity and mortality that begins in early life, for which there are no approved disease-modifying therapies. While regulatory pathways such as accelerated approval permit the use of surrogate endpoints that are reasonably likely to predict clinical benefit, their acceptance requires strong biological rationale and evidence linking biomarker change to meaningful clinical outcomes. This review builds on prior work describing candidate biomarkers in PA by critically evaluating their suitability for use as surrogate- or response endpoints. We assess biomarkers derived from disrupted propionate metabolism, including methylcitric acid, propionylcarnitine, ammonia, and 13C-propionate oxidation, as well as biomarkers reflecting secondary mitochondrial dysfunction such as fibroblast growth factor 21. For each biomarker, we examine biological plausibility, empirical and clinical evidence, durability of response, and limitations relevant to regulatory decision making. Although several biomarkers are routinely used in clinical practice, most lack sufficient specificity, stability, or demonstrated linkage to clinically meaningful outcomes to support use as surrogate endpoints for chronic disease modification. Among those reviewed, fibroblast growth factor 21 and 13C-propionate oxidation show the strongest potential as response biomarkers within defined contexts of use, particularly for therapies that restore or augment enzymatic activity. However, substantial gaps remain, including prospective validation, standardized measurement, and direct correlation with clinical outcomes. This review outlines a framework for evaluating biomarker readiness in PA and defines the evidence required to advance selected biomarkers toward surrogate endpoint qualification for future clinical trials.
    Keywords:  Biomarkers; Clinical trial; Propionic acidemia; Regulatory science; Surrogate endpoints
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110202
  29. Front Aging. 2026 ;7 1872180
    From molecular damage to regulatory constraint: epigenetic and metabolic limits of cellular plasticity in aging.
    Antoni R Godlewski, Tomasz Dziaman.
      Aging is most often portrayed as the progressive buildup of molecular damage, yet this conventional view leaves much unexplained. Over time, cells and tissues appear to lose the regulatory flexibility that allows them to adapt, repair, and reconfigure their functional states. Genomic instability, metabolic imbalance, mitochondrial dysfunction, and proteostatic decline converge on aging, but their effects focus on chromatin organization, transcriptional coordination, and signaling networks that maintain cellular identity. In this review, we propose that aging can be usefully viewed as a progressive restriction of epigenetic and regulatory plasticity, rather than as the simple accumulation of lesions. Pathways such as Wnt signaling, TET-dependent DNA demethylation, and metabolic sensors including AMPK, mTOR, and sirtuins create an interconnected landscape that links environmental and metabolic conditions with long-term cellular behavior. As this landscape becomes increasingly rigid and constrained, cells retain viability but lose their capacity for dynamic responses, stabilizing in low-plasticity states that include cellular senescence. Framing aging as a shift from adaptive plasticity toward regulatory rigidity offers a possible integrative lens on classical hallmarks and epigenetic aging signatures, without replacing existing models. Rather than targeting individual hallmarks in isolation, future approaches may need to complement hallmark-focused strategies by restoring dynamic balance within epigenetic and signaling networks that preserve tissue-level homeostasis and regenerative potential, thereby suggesting specific, testable predictions for interventions acting on metabolic-epigenetic axes.
    Keywords:  TET dioxygenases; Wnt signaling; aging; cellular senescence; epigenetic aging; epigenetic plasticity; metabolism; regulatory networks
    DOI:  https://doi.org/10.3389/fragi.2026.1872180
  30. Ther Innov Regul Sci. 2026 Jul 06.
    Medicinal Chemistry Perspectives on Drug Repurposing: Innovative Approaches and Therapeutic Breakthrough.
    Sapna Ahuja, Divya Kanwar, Pragati Silakari, Sanjeev Kumar Sahu, Paranjeet Kaur.
      Drug repurposing involves the discovery of new therapeutic uses of existing drugs that have already been approved by the regulatory authorities. It provides an alternative with more efficient approaches to traditional drug discovery, leveraging already known safety profiles, shortened development and financial costs. Current advances in computational biology, artificial intelligence and big-data analytics have expanded the range of opportunities for systematic repurposing, but the successful translation of these opportunities is increasingly dependent on the holistic input of medicinal chemistry. The therapeutic relevance of medicinal chemistry-guided repurposing is being investigated over a range of unmet medical conditions, such as complicated diseases, rare diseases and new health crises, such as the COVID-19 pandemic. In this review, we underscore the critical importance of medicinal chemistry, including structure-activity relationship analysis, molecular optimization, target engagement assay, and ADMET refinement, in supporting the efficacy and safety of repurposed candidates. We further discuss the co-existence of these strategies with in silico predictions of the target, virtual screening, and phenotypic assays to narrow down lead compounds and improve translational success. Additionally, the role of medicinal chemistry in personalized medicine is also taken into account, where special attention is paid to the possibility of modifying pharmacological characteristics to patient-specific molecular and biological phenotypes. The study aims to encourage researchers and clinicians to adopt the revolutionary potential of drug repurposing to enhance treatment decisions and overall health outcomes among a large number of patients. Moreover, in a medical landscape that is becoming more complex, drug repurposing can transform the pharmaceutical industry, accelerate the process of making viable therapy available, and facilitate the delivery of quality healthcare.
    Keywords:  Drug development; Drug discovery; Drug repurposing; Medicinal chemistry; Therapeutic
    DOI:  https://doi.org/10.1007/s43441-026-01013-y
  31. J Healthc Manag. 2026 Jul-Aug 01;71(4):71(4): 235-243
    The CARE Model: A Framework for Artificial Intelligence Integration in Chronic Disease Management.
    Michael Tran.
       SUMMARY: Chronic diseases are long-lasting health conditions that require continual management and coordination across multiple levels of care. The persistent nature of these diseases strains healthcare systems due to fragmented delivery, inefficiency, and provider burnout. This research introduces the CARE Model (Chronic care AI for Redesign and Empowerment) as a comprehensive framework to integrate artificial intelligence (AI) across clinical, operational, and patient domains for chronic care management. The model consists of four pillars: coordination, analysis, redesign, and empowerment. Together, these components demonstrate how AI can enhance decision-making, foster communication among healthcare professionals, and improve outcomes for patients with long-term and complex conditions. The treatment of chronic obstructive pulmonary disease (COPD) serves as a case example, demonstrating how AI coordination can drive predictive analytics to prevent exacerbations, reduce readmissions, and empower self-management for patients. The CARE Model ultimately provides healthcare leaders with a blueprint for AI technology-enabled transformation in care delivery.
    DOI:  https://doi.org/10.1097/JHM-D-26-00132
  32. medRxiv. 2026 Jul 01. pii: 2026.06.24.26356357. [Epub ahead of print]
    RESCUE: An end-to-end multi-agent LLM system for proactive rare-disease patient screening in the EHR.
    Cong Liu, Alexa Geltzeiler, Adam Afyouni, Mengshu Nie, Kamalakkannan Ravi, Courtney French, Wendy Chung.
       Background: Rare diseases affect a significant portion of the global population, yet patients often endure a lengthy diagnostic odyssey, frequently missing the opportunity for timely whole-exome or whole-genome sequencing (WES/WGS). Existing informatics tools often rely on pre-identified patients or rigid, institution-specific rule sets, failing to address the broader operational question of clinical necessity and feasibility.
    Method: We introduce RESCUE, an end-to-end, multi-agent LLM-powered workflow designed for proactive rare-disease screening across the entire electronic health record (EHR). RESCUE utilizes a team of specialized agents including Ontology, Modeling, Screening, and Review, to automate the screening process. The Ontology Agent classifies clinical data into a four-tier genetic-evidence taxonomy; the Modeling Agent builds a positive-unlabeled (PU) XGBoost classifier to identify potential cases; the Screening Agent applies these models across the EHR population; and the Review Agent evaluates candidates by sampling clinical notes to ensure medical necessity and operational feasibility for sequencing.
    Results: Our retrospective evaluation on a holdout set (n=12,591) demonstrated strong discrimination (AUC 0.808). Among 175,842 eligible patients from an institutional base of ~494,577, RESCUE-flagged candidates were 7.4-fold more likely to receive subsequent genetic workups compared to controls. Blinded manual chart reviews confirmed that RESCUE identifies previously missed, medically necessary patients with 80% precision, while simultaneously accounting for prior testing history.
    Conclusion: By decoupling expert roles into modular agents, RESCUE offers a flexible, scalable, and adaptable framework for rare-disease screening. This approach overcomes the limitations of traditional rule-based methods and provides a reproducible, agentic pathway to reduce diagnostic delays and improve patient care at an institutional scale.
    DOI:  https://doi.org/10.64898/2026.06.24.26356357
  33. J Med Internet Res. 2026 Jul 06. 28 e86878
    Health Data Quality Skill Gaps and Training Needs Among European Health Data Stakeholders: Cross-Sectional Survey.
    Jens Declerck, Niina Eklund, Carlos Sáez, Peter Rijnbeek, Enrique Bernal-Delgado, Erik van Mulligen, Dipak Kalra.
       BACKGROUND: The secondary use of health data is accelerating across Europe driven by growing demand for data-enabled research, innovation, and policymaking. The European Health Data Space (EHDS) establishes a regulatory framework to support this ecosystem, including Article 78, which mandates a data quality and utility labeling mechanism for datasets intended for reuse. Implementing this framework requires that data holders, data users, and health data access bodies possess sufficient skills, training, and organizational capacity to assess, document, and communicate data quality. However, little empirical evidence exists on whether European health data stakeholders currently possess these capabilities or how their needs differ across the 3 EHDS-defined roles.
    OBJECTIVE: This study aimed to identify current skill gaps, training needs, and organizational readiness related to health data quality among European health data stakeholders within the context of the EHDS.
    METHODS: A cross-sectional online survey was conducted between March 2024 and April 2024 using convenience sampling through the QUANTUM (Quality, Utility, and Maturity Measured; Developing a Data Quality and Utility Label for the European Health Data Space) consortium network, professional mailing lists, and health data communities. The survey targeted individuals involved in the secondary use of health data who identified as data holders, data users, or health data access bodies. The survey assessed 5 domains: stakeholder roles and data interaction, individual skills and experience, perceived challenges and skill gaps, organizational support and tools, and learning needs and preferences. Overall, 64 responses were collected from participants representing 44 institutions across 18 European countries.
    RESULTS: Overall, 82.8% (53/64; 95% CI 71.8%-90.1%) of respondents interacted with health data at least weekly, and 84.4% (54/64; 95% CI 73.6%-91.3%) rated data quality as moderately to absolutely critical for their work. Despite this, 87.5% (56/64; 95% CI 77.2%-93.8%) reported that poor data quality limited their effectiveness, with missing or inconsistent data identified as the most prevalent challenge. While 79.7% (51/64; 95% CI 67.4%-88.3%) reported prior experience with data quality tasks, key skill gaps were identified in applying data quality metrics, auditing and reporting, and metadata management. At the organizational level, only 15.6% (10/64; 95% CI 8.7%-26.6%) reported clearly defined data quality roles, and 68.8% (44/64; 95% CI 56.6%-78.8%) lacked a dedicated data quality manager or team.
    CONCLUSIONS: This study provides an empirical assessment of data quality skills and organizational readiness across the 3 EHDS-defined stakeholder groups. The findings highlight that practical experience alone does not ensure data quality competence and that structural deficits, particularly unclear roles and limited governance, constrain effective data quality management. The results offer a role-specific, evidence-based road map for capacity-building efforts essential to the successful implementation of the EHDS Article 78 data quality and utility labeling framework. This evidence underscores the urgent need for coordinated capacity building to ensure successful EHDS data quality implementation.
    Keywords:  European Health Data Space; QUANTUM project; capacity building; data holders; data quality; data quality labeling; data secondary use; data users; health data; health data access bodies
    DOI:  https://doi.org/10.2196/86878
  34. Biochemistry (Mosc). 2026 Jun;91(6): 992-1005
    Development of Metabolic Stress in Vascular Organoids under Normal Conditions and with AD/PD-Associated Genetic Backgrounds.
    Anna V Blagova, Elizaveta S Perepelitsa, Anakha Satish, Dmitry A Lifanov, Victoria I Zhdankina, Anna A Kopylova, Polina V Guk, Alla B Salmina, Sergey N Illarioshkin.
      Vascular organoids derived from human induced pluripotent stem cells (iPSCs) are promising models for studying vascular pathology, including neurodegenerative diseases. In this study, we investigated signs of mitochondrial dysfunction in the vascular organoids derived from the iPSCs of a healthy donor, as well as patients with Alzheimer's disease (AD) and Parkinson's disease (PD). In the conditioned medium of vascular organoids from the PD patient-derived cells, but not from the AD patient-derived cells, a trend toward a disrupted NAD+/NADH balance was observed, accompanied by the reduced expression of the connexin 43 (Cx43) protein. A sign of metabolic vulnerability of endothelial cells in the vascular organoids from the PD patient-derived cells, but not from normal or AD patient-derived organoids, manifested as reduced expression of c-Myc was observed. Changes in the membrane potential were detected in the vascular organoids from the AD and PD patient-derived, as well as increase in the mitochondrial superoxide anion production were observed, which may indicate development of oxidative stress in the microvessel cells during neurodegeneration.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; iPSC; metabolic stress; mitochondrial dysfunction; vascular organoids
    DOI:  https://doi.org/10.1134/S0006297926600286
  35. Front Immunol. 2026 ;17 1839133
    Deciphering the clinical and genetic spectrum of early-onset inborn errors of immunity in a Brazilian pediatric cohort.
    Luiza de Mattos, Mayara Mayer Alves, Nickolas Piller Wegbecher, Ana Paula Diniz Iwamura, Irma Cecilia Douglas Paes Barreto, Marina Hideko Kinoshita Assahide, Flavia A T M Guimarães, Patricia Faddul, Gisele Kuntze, Herberto Jose Chong-Neto, Rafaela Wagner, Victor Horacio de Souza Costa Júnior, Saloe Bispo, Laire Schidlowski, Carolina Prando.
      Inborn errors of immunity are a heterogeneous group of rare genetic disorders associated with susceptibility to infections, autoimmunity, allergy, and malignancy. Owing to marked clinical variability, phenotypic overlap, and limited access to specialized diagnostic resources, their diagnosis remains challenging. To investigate the diagnostic contribution of whole-exome sequencing in this setting, we studied 100 Brazilian children up to 4 years of age with early-onset manifestations suggestive of inborn errors of immunity. Exome findings were classified as conclusive diagnoses, suggestive diagnoses, or alternative genetic diagnoses, according to variant pathogenicity and phenotype correlation. The cohort included children from 48 municipalities across Brazil, with a mean age of 16.7 ± 12.9 months at recruitment. A conclusive molecular diagnosis was established in 17% of cases. In this group, 21 disease-causing variants were identified, one-third of which were novel. Thirteen individuals had suggestive genetic findings, whereas five were diagnosed with conditions outside the inborn errors of immunity classification; in this latter group, two-thirds of the variants were novel. The most frequent category among conclusive diagnoses was combined immunodeficiencies with associated features or syndromes. Investigation of probands also led to the identification of 21 additional affected family members. Importantly, the molecular findings had a direct effect on clinical care, including the indication for hematopoietic stem cell transplantation in >50% of index cases with conclusive diagnoses, as well as implications for targeted treatment, genetic counseling, and reproductive planning. These findings demonstrate that whole-exome sequencing is a valuable diagnostic approach in children with early and complex presentations suggestive of inborn errors of immunity, while also contributing to genomic knowledge in an underrepresented population.
    Keywords:  South America; genetic diagnosis; inborn errors of immunity; next generation sequencing; rare disease
    DOI:  https://doi.org/10.3389/fimmu.2026.1839133
  36. Adv Ther. 2026 Jul 09.
    Qualitative Evaluation of Fatigue and Pruritus Among Patients with Primary Biliary Cholangitis.
    Cynthia Levy, Betsy Williams, France Ginchereau Sowell, Julie Dietrich, Elaine A Böing, Gail Wright, Jörn M Schattenberg.
       INTRODUCTION: Primary biliary cholangitis (PBC) is a rare cholestatic autoimmune liver disease. We aimed to generate evidence of the signs, symptoms, and impacts of PBC considered important by patients through interviews with clinicians and patients.
    METHODS: This noninterventional, qualitative study involved a targeted literature review (TLR), clinician interviews, and patient interviews. The TLR identified relevant signs, symptoms, and impacts of PBC, as well as their reported prevalence data. This information was developed into a preliminary conceptual model (PCM) of PBC and refined via interviews with gastroenterology/hepatology clinicians, focusing on patients' experiences. Next, PBC-related concepts were captured through patient interviews, and the PCM was finalized. A thematic approach was used to analyze data, and descriptive statistics were used to assess symptom and impact salience, ensuring a representative sample and achieving concept saturation.
    RESULTS: Fatigue and pruritus were confirmed as the most prevalent symptoms. Clinician interviews (n = 4) provided insights into biochemical abnormalities used for diagnosis and common symptoms. Patient interviews (n = 20) revealed 41 unique PBC signs and symptoms. Patients reported mental and/or physical fatigue, with both impacting daily activities and overall health-related quality of life. They also reported that pruritus interfered with sleep and social engagements. The final conceptual model could distinguish between salient and non-salient signs, symptoms, and impacts, reflecting patients' attributions to PBC and its treatment.
    CONCLUSIONS: PBC imposes a significant burden on patients' lives. This study highlights unmet patient needs, contributing valuable qualitative evidence to support clinical and observational studies in PBC.
    Keywords:  Concept elicitation; Fatigue; Interviews; Patient experience; Primary biliary cholangitis; Pruritus; Qualitative evidence
    DOI:  https://doi.org/10.1007/s12325-026-03691-4
  37. FEBS J. 2026 Jul 07.
    Stimulating proteasomal degradation in human proteinopathies.
    Maria E Gierisch, Enrica Barchi, Nico P Dantuma.
      The ubiquitin-proteasome system (UPS) comprises hundreds of proteins that orchestrate ubiquitin-dependent proteasomal degradation and represents a powerful therapeutic target for modulating intracellular protein turnover. Due to its central role in preventing the accumulation of misfolded and dysfunctional proteins, enhancing or suppressing UPS activity offers clinical potential across a wide spectrum of diseases. While oncology has successfully capitalized on this vulnerability through the development of proteasome inhibitors for the treatment of hematological malignancies, efforts to generate clinically relevant UPS activators have progressed more slowly. Bridging this therapeutic gap could be particularly beneficial for neurodegenerative diseases and other proteinopathies, where accelerating the removal of misfolded and aggregation-prone proteins may help counteract their progressive accumulation and delay, or prevent the onset of symptoms. In this review, we summarize the progress made so far toward finding strategies to boost UPS function through genetic or small-molecule interventions.
    Keywords:  aggregation; neurodegeneration; proteasome; protein degradation; ubiquitin
    DOI:  https://doi.org/10.1111/febs.70638
  38. Immun Ageing. 2026 Jul 08.
    Clinical rationale for thymic restoration in adult immunosenescence.
    Patrick E Sewell, Christopher Jensen.
      Age-related thymic involution is a central feature of immunosenescence and intersects with multiple "hallmarks of aging", including genomic instability, telomere attrition, mitochondrial dysfunction, and chronic inflammation. The decline in thymic epithelial integrity and FOXN1-driven thymopoiesis reduces naïve T-cell output, contracts TCR repertoire diversity, and perturbs central tolerance, contributing to increased susceptibility to infection, cancer, and autoimmunity. These changes occur alongside broader immune-aging phenomena such as inflammaging and frailty and are reflected in poorer vaccine responses and altered outcomes to novel pathogens such as SARS-CoV‑2. This review integrates mechanistic, preclinical, and human data to reassess the adult thymus as a therapeutic target. Higher-confidence domains for thymic restoration include cancer immunosurveillance, infectious disease vulnerability, vaccine responsiveness, and post-treatment immune reconstitution, supported by modeling of age-related disease incidence, transplant and HIV cohorts, and new observational links between radiographic thymic health, mortality, and immunotherapy outcomes. High-plausibility but less directly validated domains include autoimmunity, chronic herpesvirus control, HIV immunological non-responders, and post-acute infection syndromes such as long COVID, which share convergent patterns of T-cell dysfunction and persistent immune activation. The translational landscape spans hormonal and somatotropic modulation (sex steroid ablation, growth hormone/ghrelin), cytokine and growth-factor strategies (IL‑7, IL‑22, KGF/BMP4, FGF21), cell- and tissue-engineering approaches leveraging thymic epithelial stem cells and FOXN1-reprogrammed stromal cells, and gene-therapy concepts such as intrathymic AAV delivery of FOXN1, AIRE, chemokines, and stromal-support pathways. Collectively, these data support the biological plausibility of adult thymus restoration but highlight that robust, domain-specific clinical benefits have not yet been demonstrated in controlled trials. Future work should prioritize harmonized structural and functional biomarkers, domain-focused interventional studies in high-risk populations, and combined strategies that situate thymus-directed interventions within broader efforts to modify immune and organismal aging.
    Keywords:  Aging biology; Cancer immunosurveillance; FOXN1; Immune reconstitution; Immunosenescence; Inflammaging; Thymic epithelial stem cells; Thymic involution; Thymic regeneration; Vaccine responsiveness
    DOI:  https://doi.org/10.1186/s12979-026-00584-6
  39. Cureus. 2026 Jun;18(6): e110551
    Late-Onset Leber Hereditary Optic Neuropathy: A Report of a Case and Review of the Literature.
    Víctor J Altares, María Castro Rebollo, Julio González Martín-Moro.
      Leber hereditary optic neuropathy (LHON) constitutes a mitochondrial disorder characterized by subacute, bilateral central vision impairment, secondary to mitochondrial DNA (mtDNA) mutations. These mutations compromise Complex I, subsequently precipitating the degeneration of retinal ganglion cells (RGCs). While traditionally manifesting in young males, contemporary literature has documented a small number of cases of late-onset presentation. Numerous studies have suggested the existence of a distinct clinical phenotype, particularly concerning the funduscopic features of the optic disc. Elucidating this atypical manifestation is paramount to preclude diagnostic inaccuracies and to refine therapeutic intervention. In this context, we describe the case of a 70-year-old male presenting with progressive bilateral vision loss and diffuse thinning of the ganglion cell complex on optical coherence tomography (OCT), notably lacking the hyperaemic phase typical of younger patients. Genetic analysis confirmed the homoplasmic m.14484T>C mutation; however, despite the traditionally favourable prognosis associated with this variant, the patient progressed to permanent optic atrophy with no functional recovery. By reporting this case of late-onset LHON and providing a comprehensive review of clinical cases documented in recent literature, our objective is to ascertain whether late-onset presentation endows this clinical entity with additional distinguishing characteristics.
    Keywords:  age-related; case report; late-onset; leber hereditary optic neuropathy; lhon; mitochondrial disease; optic disc findings; senile
    DOI:  https://doi.org/10.7759/cureus.110551
  40. medRxiv. 2026 Jul 04. pii: 2026.07.01.26357055. [Epub ahead of print]
    Developing a Specialized Dravet Syndrome Ontology for Rare Disease Informatics and AI Applications.
    Pedram Golnari, Katrina Prantzalos, Dipak P Upadhyaya, Jeffrey Buchhalter, Satya S Sahoo.
      Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy whose clinical and research representation requires integration of heterogeneous knowledge spanning seizures, development, behavior, SUDEP/autonomic risk, genetics, comorbidities, electrophysiology, pharmacology, and drug responsiveness. We report the development of a DS-focused ontology created by expert-guided specialization of a previously published epilepsy ontology. Scope expansion was defined through a scientific advisory board, structured review meetings, and iterative ontology curation in OWL. The resulting resource reorganized DS content across nine major domains and expanded the publicly released ontology from the pre-extension baseline to the current BioPortal version. Beyond structural growth, the ontology was assessed through expert-guided curation and downstream task-based reuse, including two published ontology-enabled LLM studies and an ongoing ontology-derived DS knowledge graph and AI assistant platform. These results suggest that disease-focused ontology specialization can provide durable infrastructure for DS data harmonization, knowledge representation, and AI-enabled translational informatics.
    DOI:  https://doi.org/10.64898/2026.07.01.26357055
  41. Med Genet. 2026 Jul;38(3): 231-239
    Polygenic scores as modifiers in Mendelian diseases.
    Axel Schmidt, Kerstin U Ludwig, Henrike O Heyne.
      Mendelian diseases are caused by rare pathogenic variants with large effects. However, phenotypes are often different between individuals carrying the same variant ("variable expressivity"), or even absent in some carriers ("incomplete penetrance"), suggesting that the genetic architecture of Mendelian diseases is more complex than previously thought. Common genetic variants are a potential modifier of observed phenotypes. Individual common variants usually have small effects, but in aggregate their effects can be substantial and be quantified as a polygenic score (PGS). The present review summarises available data on how PGS modify phenotypes in Mendelian diseases. We show that modifying effects of PGS on penetrance and expressivity have been observed in carriers of rare pathogenic variants across a broad range of conditions. This suggests that in Mendelian diseases, a modifying effect of the common variant background on penetrance and expressivity might be the rule rather than the exception. We anticipate that increasing data availability and methodological advances will improve our understanding of the genetic architecture of Mendelian diseases, including the joint consideration of both common and rare variants.
    Keywords:  Mendelian diseases; common variants; incomplete penetrance; polygenic scores; variable expressivity
    DOI:  https://doi.org/10.1515/medgen-2026-3014
  42. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00693-5. [Epub ahead of print]45(7): 117615
    ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
    Anastasia Chugunova, Isabelle Schütz, Hannah Keresztes, Roksolana Kobylinska, Maria Novatchkova, Thomas Lendl, Marcus Strobl, Jörg Fallmann, David Márquez Oller, Michael Schutzbier, Gerhard Dürnberger, Richard Imre, Elisabeth Roitinger, Phylicia Kidd, Pawel Pasierbek, Alberto Moreno Cencerrado, Marlene Brandstetter, Thomas Köcher, Benedikt Agerer, Jakob-Wendelin Genger, Andreas Bergthaler, Andrea Pauli.
      Increased mitochondrial activity is essential for embryo development. Although conserved across organisms, the molecular basis of this increase is unknown, as detailed biochemical analysis in vertebrates is hampered by the limited availability of material. Using zebrafish as a model for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome, and phospho-proteome, as well as respiratory chain activity. Our data show that the mitochondrial proteome undergoes major changes during embryogenesis. While respiratory chain complex levels remain largely constant, we identify a marked increase in mitochondrial-ER association during early embryogenesis. Moreover, time-lapse imaging of mitochondrial dynamics reveals a transition from fragmented to elongated mitochondria starting during somitogenesis. Overall, our systematic profiling of the molecular and morphological changes of mitochondria during embryogenesis provides a valuable resource for further investigation of mitochondrial function. Our study reveals that increased mitochondrial-ER interaction and changes in mitochondrial morphology may contribute to its regulation during vertebrate development.
    Keywords:  CP: cell biology; CP: developmental biology; ER-mitochondrial interaction; metabolism; mitochondria; mitochondrial activation; proteomics; vertebrate embryogenesis; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117615
  43. Aging (Albany NY). 2026 Jul 06. 18(1): 787-812
    Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
    Yash Flora, Dhriti Shastri, Kathryn R DeLeo, K Adam Bohnert.
      Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
    Keywords:  cellular aging; inter-organelle crosstalk; lifespan; mitochondrial tubulation; pexophagy
    DOI:  https://doi.org/10.18632/aging.206395
  44. Neurotherapeutics. 2026 Jul 10. pii: S1878-7479(26)00131-5. [Epub ahead of print]23(4): e00961
    FRRS1L gene replacement ameliorates disease phenotypes in the mouse model of developmental and epileptic encephalopathy 37.
    Mehrnaz Sheibani, Esther O Alao, Ummay Mariam, Jun Wu, Sahba Kasiri, Afsaneh Talai, Jochen Schwenk, Bernd Fakler, Steven J Gray, Berge A Minassian.
      Gene therapy offers unique therapeutic potential for treating rare genetic disorders such as DEE37, a severe Developmental and Epileptic Encephalopathy caused by biallelic loss-of-function mutations in the Ferric Chelate Reductase 1 Like (FRRS1L) gene, presenting with seizures, developmental delay, dyskinesia, ataxia and progressive, eventually debilitating cognitive and motor impairments. There is currently no treatment for DEE37. FRRS1L encodes an auxiliary subunit essential for the tetrameric assembly of α-amino-3 hydroxy-5-methyl-4 isoxazolepropionic acid receptors (AMPARs) and their recruitment to synaptic membranes. FRRS1L is expressed brain-wide, with high levels in the cerebellum. Here, we developed an adeno-associated virus 9 (AAV9) gene replacement vector expressing human FRRS1L driven by the JeT promoter. Administering the virus intrathecally in two doses (5 × 1010 and 3 × 1011 vg) to Frrs1l-knockout mice, we evaluated safety and efficacy in multiple phenotypic traits shared with affected patients. We obtained robust, near-normal, FRRS1L expression in the cerebellum and low levels of expression elsewhere in the brain, which were associated with corresponding levels of increased synaptic AMPAR abundance. Importantly, our phenotypic assessments revealed dose-dependent improvement trends, or rescue, across multiple brain structural, electrocorticographic, and behavioral domains. Our results indicate that cerebrospinal fluid-directed virally mediated FRRS1L gene replacement partially restores synaptic AMPAR and ameliorates disease-relevant phenotypes, supporting gene therapy as a promising therapeutic strategy for children suffering from this catastrophic, FRRS1L-related, 37th form of DEE.
    Keywords:  AAV9; AMPA receptors; Epileptic encephalopathy; FRRS1L; Gene therapy; Neurodevelopmental disorders
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00961
  45. J Clin Neurol. 2026 Jul;22(4): 392-407
    Artificial Intelligence That Changes Clinical Neurology Practice: Translating Algorithms Into Actionable Care.
    Yongcheon Kim, Seung-Ah Choe, Seogsong Jeong, Ding Jie, Xinshi Wang, Hwamin Lee, Byung-Jo Kim.
      Artificial intelligence (AI) has stimulated extensive research in clinical neurology, but relatively few AI systems have meaningfully changed bedside decision-making. This translational gap is not explained solely by inadequate algorithms. More often, AI models in neurology remain outside routine practice because they are trained on unstable labels, validated in narrow or single-center datasets, evaluated primarily by discrimination metrics, disconnected from clinical workflow, and deployed without prospective monitoring, reimbursement frameworks, or accountability. In this review, we propose the NEURAL framework for practice-changing neurological AI: Novel clinical insight, External and prospective validation, Utility over accuracy, Real-time workflow integration, Algorithmic transparency, and Long-term outcome linkage. Using this framework, we examine evidence across acute stroke, epilepsy and electroencephalography (EEG), sleep medicine, neurodegenerative disease, movement disorders, headache, vestibular disorders, neuroimmunology, rehabilitation, and neurocritical care. The most clinically advanced examples come from acute stroke, where imaging-based selection, large-vessel occlusion detection, and automated notification are linked to urgent, pathway-defined interventions. Automated EEG triage, focal cortical dysplasia detection, selected sleep-analysis tools, quantitative biomarker pipelines, and AI-assisted longitudinal monitoring may also become clinically meaningful if tested prospectively in real-world workflows. Many high-performing models for dementia progression, prodromal Parkinson disease, outpatient treatment response, and long-horizon risk prediction remain pre-implementation tools because they do not yet define a validated clinical action. Future neurological AI should therefore be judged less by whether it recognizes complex patterns and more by whether it improves the right decision for the right patient at the right time. A clinically useful AI system must demonstrate not only accuracy, but also actionability, workflow fit, equity, safety, sustainability, and measurable benefit for patients and health systems.
    Keywords:  artificial intelligence; clinical decision support systems; epilepsy; machine learning; neurodegenerative diseases; stroke
    DOI:  https://doi.org/10.3988/jcn.2026.0312
  46. CPT Pharmacometrics Syst Pharmacol. 2026 Jul;15(7): e70295
    Best Practices in Physiologically Based Pharmacokinetic (PBPK) Modeling.
    Marylore Chenel, Andre Dallmann, Ibrahim Ince, Michaela Meyer, Jan-Frederik Schlender, Donato Teutonico, Erik Sjögren.
      Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic cornerstone of model-informed drug development (MIDD), providing evidence for regulatory decisions. PBPK models integrate physiological and pharmacological data and have been applied across a plethora of contexts of use, including assessing drug-drug interactions (DDIs), optimizing dosing for special populations (e.g., pediatrics and those with organ impairment), and supporting clinical study waivers. However, despite the established history of PBPK modeling, a significant gap persists between the quality of submitted PBPK analyses and regulatory expectations. Recent reviews by the European Medicines Agency (EMA) and other regulatory bodies indicate that many PBPK models are not deemed adequately qualified for their intended application. This discrepancy highlights the need for consolidated guidance on model development, evaluation, and application, particularly to harmonize terminology and expectations with the ICH M15 guideline. To address this challenge, this paper provides comprehensive best-practice guidance for the development, verification, validation, and applicability assessment of PBPK models. We delineate strategies for defining explicit technical criteria to ensure models are appropriately qualified and demonstrably fit-for-purpose for a specific context of use. This guidance aims to enhance the quality, consistency, and regulatory acceptance of PBPK analyses, thereby strengthening the reliability of MIDD evidence supporting drug development and approval.
    DOI:  https://doi.org/10.1002/psp4.70295
  47. Cell Genom. 2026 Jul 08. pii: S2666-979X(26)00161-8. [Epub ahead of print]6(7): 101299
    When network biology meets human genetics.
    Sai Zhang.
      Rare variant association analyses are typically performed at the single-gene level, overlooking the molecular interactions that organize cellular systems. In this issue, Nazeen et al. introduce NERINE, a probabilistic rare variant burden test that integrates gene and protein networks to improve statistical power and biological interpretability.
    DOI:  https://doi.org/10.1016/j.xgen.2026.101299
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