bims-polgdi Biomed News
on POLG disease
Issue of 2026–02–22
forty-two papers selected by
Luca Bolliger, lxBio
  1. Extracellular Vesicle-Derived Mitochondrial Genes as Potential Biomarkers for Brain Aging in Human.
  2. Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
  3. DoBSeqWF: a framework for sensitive detection of individual genetic variation in pooled sequencing data.
  4. The autophagy-senescence axis as a threshold model of aging and therapeutic targeting.
  5. Climate associated natural selection in the human mito-chondrial genome.
  6. Hydrogel-based mitochondrial therapies: A new frontier in disease treatment.
  7. AI succeeds in diagnosing rare diseases.
  8. Colostrum extracellular vesicles are neuroprotective in models of Parkinson's disease.
  9. Patent Analysis Perspectives on China's Orphan Drug R&D: Status and Technology Characteristics.
  10. Unraveling riboflavin-mediated mitochondrial modulation as a therapeutic pathway in neurological disorders: an integrative systematic review.
  11. Redox therapy for neuropsychiatric disorders: Molecular mechanisms and biomarker development.
  12. Convergence and divergence of molecular phenotypes in iPSC-derived models of 16p11.2 and 22q11.2 reciprocal copy number variants.
  13. Intermittent ketogenic fasting with medium-chain triglycerides improves ataxia in COQ8A-related coenzyme Q10 deficiency: A case report.
  14. The role of miRNAs in the development of Super-Tregs as a potential therapy for neurodegenerative diseases.
  15. Multidimensional integrative analysis unveils genetic architecture, risk factors, and health consequences of brain aging.
  16. Neuroinflammation and Cellular Senescence in Brain Aging and Neurodegeneration.
  17. Informing Dose for Pediatric Rare Diseases-A Survey of Recent Orphan Drugs Approvals.
  18. Epilepsy disease classification: a community effort to enhance the Mondo Disease Ontology.
  19. "Metabolic memory" of aging: anchoring, transmission, and frontiers of transgenerational intervention.
  20. An agentic system for rare disease diagnosis with traceable reasoning.
  21. From modality-specific to compositional foundation models for cell biology.
  22. CX3CL1/CX3CR1 axis in liver disease: context-dependent roles and balance.
  23. From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease.
  24. Advancements in Stem Cell Therapy for Managing Drug-Resistant Epilepsy.
  25. TBC1D15 functions as an Arl4D GAP and promotes the mitochondrial translocation of Arl4D for organelle homeostasis.
  26. The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.
  27. Glial cells in dementia: From cellular dysfunction to therapeutic frontiers.
  28. Interleukins in Major Depressive Disorder: Lessons From Autoimmune Diseases and Pathways to Clinical Translation.
  29. Neurodegenerative diseases need more mechanism-informed trials.
  30. Human lncRNA RMRP interacts with DEAD-box helicases and modulates mitochondrial function.
  31. Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.
  32. Clinical and genetic spectrum of inborn errors of immunity: a retrospective study on outcomes at a single center.
  33. Mitochondria: the central hub linking exercise to enhanced cardiac function.
  34. Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
  35. Organoid-engineered neurovascular units for drug discovery and neurodegeneration research.
  36. N-Acetylglucosamine Selectively Attenuates Neuroinflammation in a Mouse Model of Mitochondrial Dysfunction.
  37. Tiered modelling of a CACNA1A D1634N mutation linked to ataxia, epilepsy and cognitive deficits.
  38. Breaking the Bonds of Aging: The Underappreciated Roles of Aberrant Cysteine Crosslinks and Protective Thiol Interventions.
  39. Integrating the Genomic Revolution into Newborn Screening: Current Challenges and Future Perspectives.
  40. Genetic insights into biological aging and myasthenia gravis: a Mendelian randomization study of telomere length, epigenetic clocks, and mitochondrial DNA copy number.
  41. The clinical utility of genome sequencing is multi-dimensional: experience from the Hong Kong Genome Project.
  42. Phenotypic description and functional characterization of the mitochondrial disease associated with the SFXN4 gene.
  1. J Gerontol A Biol Sci Med Sci. 2026 Feb 17. pii: glag044. [Epub ahead of print]
    Extracellular Vesicle-Derived Mitochondrial Genes as Potential Biomarkers for Brain Aging in Human.
    Qian Yu, Shuyi Yu, Hang Chen, Zhikang Cui, Qian Cheng, Yan Jin, Shuai Zong, Yunshan Wang, Ming Li, Zhiming Lu.
      Aging significantly impacts brain function, and identifying reliable biomarkers for early detection of age-related neurodegeneration is crucial for improving diagnosis and treatment outcomes. This proof-of-principle study aims to evaluate the abundance of mitochondrial DNA (mtDNA) targets within plasma-derived extracellular vesicles (EVs) and to investigate whether they correlate with established biomarkers of brain aging, independent of chronological age and renal function. mtDNA copy number was quantified using absolute quantitative PCR (qPCR). Brain aging biomarkers were measured by ELISA. Multivariable regression analysis was performed to examine the associations between EVs mitochondrial genes and aging biomarkers. A multi-biomarker model was developed to assess the performance of combined biomarkers in distinguishing between age groups. We observed that EV mitochondrial gene levels were significantly increased with age (P < 0.001). Levels of neurofilament light chain (NfL), amyloid-beta (Aβ42 and Aβ40), also showed significant age-related increases (P < 0.001). A multi-biomarker model combining EVs mitochondrial genes and brain aging biomarkers showed the optimal performance in distinguishing older adults from younger individuals, with an area under the ROC curve (AUC) significantly higher than that of any single biomarker (P < 0.01). These findings collectively indicate that EV-derived mitochondrial genes, in combination with other biomarkers like NfL, hold great potential as a non-invasive tool for early detection and monitoring of brain aging and neurodegenerative diseases.
    Keywords:  Aging; Biomarker; Extracellular vesicles; Mitochondrial Genes
    DOI:  https://doi.org/10.1093/gerona/glag044
  2. PLoS One. 2026 ;21(2): e0343604
    Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
    Yufu Unten, Kazuaki Takafuji, Yumiko Masukagami, Isshin Shiiba, Keigo Horiuchi, Filip Husnik, Shigeru Yanagi, Norifumi Tateishi, Toshihide Suzuki.
      Age-associated declines in skeletal muscle function are linked to cellular senescence and mitochondrial alterations, yet mitochondrial phenotypes in aged human myoblasts remain insufficiently characterized. Here, we examined primary skeletal muscle myoblasts from young and elderly donors to assess mitochondrial function, morphology, and mitochondria-endoplasmic reticulum (ER) contact sites (MERCS). Myoblasts from older donors exhibited senescence features, including elevated SA-β-gal activity and reduced Lamin B1 expression, accompanied by increased mitochondrial oxidative stress. Despite marked mitochondrial hyperfusion and increased mitochondrial DNA content, mitochondrial oxygen consumption rate and membrane potential per mitochondrial area were comparable between young and old cells. MERCS were significantly elevated in aged myoblasts and were reduced by scavenging mitochondrial reactive oxygen species (mtROS), indicating an association between oxidative stress and MERCS formation. These findings suggest that mitochondrial hyperfusion and enhanced MERCS accompany cellular aging in human myoblasts and may contribute to maintaining mitochondrial function under elevated oxidative stress.
    DOI:  https://doi.org/10.1371/journal.pone.0343604
  3. NAR Genom Bioinform. 2026 Mar;8(1): lqag021
    DoBSeqWF: a framework for sensitive detection of individual genetic variation in pooled sequencing data.
    Mads Cort Nielsen, Christian Munch Hagen, Ulrik Kristoffer Stoltze, Thomas van Overeem Hansen, Mette Nyegaard, Henrik Hjalgrim, Marie Bækvad-Hansen, Anna Byrjalsen, Kjeld Schmiegelow, Karin Wadt, Jonas Bybjerg-Grauholm, Simon Rasmussen.
      Population screening for rare genetic diseases has the potential to increase early diagnosis and treatment, but the high cost of next-generation sequencing limits widespread implementation. Double-batched sequencing (DoBSeq) is a cost-effective method that uses two-dimensional overlapping pool sequencing to enable individual-level rare variant detection. However, the resulting high-depth, complex data require a specialized workflow for efficient, sensitive, and reproducible analysis. We developed DoBSeqWF (DoBSeq Workflow), a Nextflow-based pipeline that processes pooled sequencing data from alignment through variant calling, filtering, and final variant assignment. Using a childhood cancer cohort of 200 individuals with whole genome sequencing as a reference, we created training and validation datasets, benchmarked multiple variant callers, and implemented machine learning filters to improve rare variant detection while maintaining high sensitivity. DoBSeqWF demonstrates accurate and scalable rare variant detection within the evaluated experimental setting and provides a promising avenue for future cost-effective genetic screening programmes.
    DOI:  https://doi.org/10.1093/nargab/lqag021
  4. Redox Biol. 2026 Feb 10. pii: S2213-2317(26)00077-7. [Epub ahead of print]91 104079
    The autophagy-senescence axis as a threshold model of aging and therapeutic targeting.
    Md Entaz Bahar, Jin Seok Hwang, Trang Huyen Lai, Kazi-Marjahan Akter, Rizi Firman Maulidi, Deok Ryong Kim.
      Autophagy and cellular senescence are fundamental stress-response programs that critically shape aging and disease progression, yet their functional relationship has remained paradoxical. Autophagy is traditionally viewed as a cytoprotective process that preserves cellular homeostasis and delays senescence. In contrast, emerging evidence demonstrates that autophagy is also indispensable for the survival and pathological activity of established senescent cells. In this review, we propose a "threshold model" to reconcile these opposing roles and to provide a unified framework linking signal transduction, organelle quality control, and therapeutic intervention. According to this model, autophagy exerts stage-dependent functions governed by stress intensity and disease progression. Below a critical damage threshold, robust autophagic flux suppresses senescence initiation by maintaining mitochondrial integrity, limiting oxidative stress, and preserving proteostasis. Once this threshold is exceeded, autophagy is functionally reprogrammed to sustain the metabolic and biosynthetic demands of senescent cells, including production of the senescence-associated secretory phenotype (SASP). We highlight key signaling nodes that regulate this transition, including mTORC1, AMPK, p53, and p62, as well as spatial and organelle-specific mechanisms such as the TOR-autophagy spatial coupling compartment (TASCC), mitophagy failure, lipophagy blockade, and aberrant nucleophagy. These processes converge on innate immune pathways, notably cGAS-STING and NF-κB signaling, to drive chronic inflammation and tissue dysfunction. Importantly, we extend this mechanistic framework to clinical translation, synthesizing evidence from ongoing trials in cancer, neurodegeneration, metabolic liver disease, and fibrosis. We argue that effective targeting of the autophagy-senescence axis requires precision gerontology, integrating dynamic biomarkers to guide stage-specific interventions-autophagy activation for prevention and autophagy inhibition or senolysis for established disease. This threshold-based perspective provides a rational foundation for next-generation therapeutic strategies targeting aging and age-related disorders.
    Keywords:  Autophagy; Cellular stress; Senescence; Targeted senotherapy; Threshold-model
    DOI:  https://doi.org/10.1016/j.redox.2026.104079
  5. Mol Biol Evol. 2026 Feb 17. pii: msag044. [Epub ahead of print]
    Climate associated natural selection in the human mito-chondrial genome.
    Finley Grover-Thomas, Lucy van Dorp, Francois Balloux, Aida M Andrés, M Florencia Camus.
      Mitochondria are essential for cellular energy production and biosynthesis, thermogenesis, and cell signalling, and thus help coordinate physiological responses to changing environments. Humans (Homo sapiens) have adapted to cope with a wide range of climatic conditions, however the role of the mitochondrial genome (mtDNA) in mediating this process remains poorly understood. Here we curated a dataset of 19,570 publicly available full human mitochondrial genomes, an approximate 40-fold increase on earlier studies, paired with modern climate and reconstructed paleoclimate variables. Using a Generalised Linear Model approach, we identify independent candidate variants significantly associated with climatic conditions, suggesting local adaptation in human mitochondrial genomes. Candidate variants are distributed across multiple loci in regulatory, tRNA, rRNA and protein-coding regions - including prominently in ND2 and ND4 complex I subunits. Specific variants are predicted to impact mtDNA transcription, ribosome or protein structure, and multiple have been associated with disease pathologies. We further show that candidate variant genotype distributions are each best modelled by different paleo-bioclimatic variables, consistent with environmental stressors linked to our measured variables exerting subtly distinct selective effects. These stressors may reflect dietary changes or different thermogenic demands at lower temperatures. Our results provide genetic evidence to support the accumulating body of work from functional studies that mitochondria can modulate adaptation to diverse environments. This work underscores the importance of mtDNA in evolutionary biology and its relevance for understanding both disease and physiological variation in global populations.
    Keywords:   Homo sapiens ; Mitochondria; adaptation; climate; humans; mitochondrial genome; mtDNA; natural selection; rRNA; tRNA
    DOI:  https://doi.org/10.1093/molbev/msag044
  6. Biomaterials. 2026 Feb 11. pii: S0142-9612(26)00095-5. [Epub ahead of print]330 124071
    Hydrogel-based mitochondrial therapies: A new frontier in disease treatment.
    Zihua Tang, Yu Jiang, Huiling Ling, Yifei Shen, Xingbo Wu, Chun Hung Chu, Irene Shuping Zhao, Xueqi Gan.
      Mitochondria are essential for cell energy metabolism, redox homeostasis, and apoptosis. Meanwhile, numerous pathological conditions are linked with mitochondrial dysfunction, such as cardiovascular diseases, connective tissue disorders, chronic wounds, neurological disorders, and cancer. Mitochondria-targeted hydrogels (MTHs) have emerged for their ability to selectively deliver active agents to mitochondria, modulate mitochondrial function precisely, which plays a key role in improving treatment efficacy. Hydrogels offer unique advantages, including biocompatibility, structural tunability, and controlled drug release. With specific targeting ligands and stimuli-responsive mechanisms, hydrogels can achieve mitochondrial localization and therapeutic modulation. Recent advancements have demonstrated significant benefits of MTHs in reducing oxidative stress, promoting oxidative phosphorylation and restoring mitochondrial quality control across a variety of disease models. However, challenges remain, including optimizing targeting efficiency, as well as accuracy. Further exploration of therapeutic mechanisms and the integration of multi-dimensional targeting strategies are also essential for the clinical application of MTHs. The current review highlights the development of mitochondrial targeting strategies and specifically focuses on a series of applications of MTHs in mitochondrial-related diseases. Lastly, the discussion delves into the shortcomings of existing therapies and possible future research ideas.
    Keywords:  Hydrogel engineering; Mitochondria-related diseases; Mitochondria-targeted hydrogels; Mitochondrial quality control; Tissue regeneration
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124071
  7. Nature. 2026 Feb 18.
    AI succeeds in diagnosing rare diseases.
    Timo Lassmann.
      
    Keywords:  Genomics; Machine learning; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-00290-9
  8. Theranostics. 2026 ;16(8): 4190-4223
    Colostrum extracellular vesicles are neuroprotective in models of Parkinson's disease.
    Dawson Hollingsworth, Shefali Srivastava, Samia Akter, Mohit Kumar, Soumya Sagar Dey, Sudipta Panja, Xiaoqing Du, Arnab Saha, Pravin Yeapuri, Shaurav Bhattarai, Emma G Foster, Rana Kadry, Nada Fayez, Davina Oludipe, Emma Ehrenkranz, R Lee Mosley, John Oehlerking, Keith Swarts, Guoku Hu, Howard E Gendelman, Susmita Sil.
      Rationale: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement, muscle control, and balance. Effective therapeutic options for this condition are limited. Natural therapies, including lifestyle changes, probiotics, and muscle relaxants, have received attention for symptomatic relief. Colostrum, particularly its extracellular vesicles (C-EVs), has emerged as a promising nutraceutical with the potential to improve therapeutic outcomes in divergent diseases. Methods: We purified and characterized (C-EVs) as a putative cell-based therapy. Theranostic (biodistribution, diagnostic, and therapeutic) efficacy studies were performed in C-EV-treated mice intoxicated with methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The C-EV tissue distribution, anti-inflammatory and neurorestorative activities were examined. These include transcriptomic, immune, and neuroprotective profiles linked to disease outcomes. Results: C-EV-treated MPTP mice showed reduced microglial activation and restored neuronal responses. RNA sequencing and transcriptomic analyses have demonstrated reduced immune cell recruitment and activation in the disease-affected brain subregions. The activation of canonical inflammasomes, pro-inflammatory cytokines, and chemokine expression was controlled. C-EV treatment reduced the levels of disease-associated immune-regulatory transcription factors. Simultaneously, Treg-associated adaptive immune responses increased. Multiple C-EV-miR-isolated immune regulatory cargos are linked to neuroinflammation and nigral preservation. C-EVs loaded with miR-20a-5p, miR-23b-3p, let-7a-5p, miR-22-3p, and miR-30a-3p mimics attenuated pro-inflammatory cytokines in activated microglia. Conclusions: C-EVs elicit neuroprotective responses in MPTP-intoxicated mice. These responses control microglial activation and facilitate neuroprotective responses.
    Keywords:  Parkinson's disease; anti-inflammatory activities; neuroprotection; regulatory T cells; tyrosine hydroxylase neurons
    DOI:  https://doi.org/10.7150/thno.128257
  9. Ther Innov Regul Sci. 2026 Feb 16.
    Patent Analysis Perspectives on China's Orphan Drug R&D: Status and Technology Characteristics.
    Yang Jiao, Fangzhe Yuan, Tianyu Liu, Jiajia Han, Jingchun Sun, Shuzhen Chu, Shuxiang Li.
       BACKGROUND: Rare diseases present urgent public health challenges requiring coordinated global efforts. This study analyzes China's orphan drug innovation landscape through patent applications (1995-2023) to identify R&D patterns and policy implications.
    METHODS: We analyzed 323 Patent Cooperation Treaty applications from Chinese entities using IPC classification and bipartite network modeling. Data from World Intellectual Property Organization were retrieved via PatSnap, with diseases mapped to China's Rare Disease Catalogues (207 conditions). Network metrics quantified disease-technology linkages.
    RESULTS: Three key findings emerged: (1) Patent filings surged 58.2% (188 patents) during 2018-2023, coinciding with China's regulatory reforms; (2) Innovation concentrated in oncology/neurology (34.3% patents cover 2 diseases), with 66.2% of catalogued diseases lacking patents; (3) Dominant technologies are small molecules and genetic therapies. Network analysis revealed an R&D ecosystem without a single dominant entity, alongside robust collaborative ties between Chinese and U.S. organizations.
    CONCLUSIONS: China's orphan drug innovation is expanding rapidly but remains uneven, concentrated in specific diseases and technological platforms. Policy interventions are needed to address therapeutic neglect through tiered incentives, dedicated funding for neglected diseases, and global partnerships to accelerate equitable treatment access.
    Keywords:  Health policy; Innovation networks; Orphan drug development; Patent analysis; Rare diseases
    DOI:  https://doi.org/10.1007/s43441-026-00927-x
  10. J Nutr. 2026 Feb 18. pii: S0022-3166(26)00076-3. [Epub ahead of print] 101427
    Unraveling riboflavin-mediated mitochondrial modulation as a therapeutic pathway in neurological disorders: an integrative systematic review.
    Eulália Rebeca Silva-Araújo, Ana Elisa Toscano, Henrique José Cavalcanti Bezerra Gouveia, Paula Brielle Pontes, Joaci Pereira Dos Santos Júnior, Osmar Henrique Dos Santos-Júnior, Maria Daniele Teixeira Beltrão de Lemos, Nathalia Caroline de Oliveira Melo, Janaina Viana de Melo, Eduardo Padrón-Hernández, Raul Manhães-de-Castro.
       BACKGROUND: Mitochondrial dysfunction is recognized as a key pathophysiological mechanism in neurodegenerative diseases. Alterations in mitochondrial dynamics-including imbalances in fission and fusion, impaired biogenesis, and disrupted mitophagy-contribute to the onset and progression of neurological disorders. In this context, mitochondrial modulation has emerged as a promising therapeutic strategy.
    OBJECTIVE: This systematic review examined the role of riboflavin, a water-soluble vitamin and essential mitochondrial cofactor, in neurological interventions through mitochondrial modulation, with emphasis on elucidating the underlying molecular mechanisms.
    METHODS: A search of the PubMed, Embase, Scopus, and Web of Science databases identified 23 eligible studies, comprising 6 in vitro experiments, 10 rodent models, and 7 clinical trials.
    RESULTS: These studies evaluated the effects of riboflavin in monogenic, neurodegenerative, and demyelinating mitochondrial diseases, cerebrovascular/hypoxic injury, and pain/migraine. Clinical evidence indicated that riboflavin may regulate oxidative stress in stroke and perinatal asphyxia, with associated functional improvements. Preclinical findings revealed mechanisms of action involving energy homeostasis, cell cycle regulation, and mitochondrial dynamics across monogenic mitochondrial disorders, neurodegenerative diseases, hypoxic injury, and models of pain and migraine. Possibly through mitochondrial modulation, riboflavin appeared to reduce α-synuclein aggregation in Parkinson's disease, increase the number of tyrosine-hydroxylase-positive neurons in Alzheimer's disease models, enhance neuronal survival in Brown-Vialetto-Van Laere and Huntington's disease models, and normalize neuronal excitability in ataxia and migraine. In contrast, no therapeutic effects were observed in demyelinating diseases.
    CONCLUSIONS: Overall, the findings suggest that riboflavin may promote neuroprotection through redox modulation and gene regulation, stabilization of membrane potential, and enhanced mitochondrial complex activity via flavin cofactors, ultimately supporting neuronal metabolism and functional outcomes. Despite advances in mechanistic understanding, clinical applications in humans remain insufficiently defined for most conditions, with clearer dosage regimens currently established only for stroke and migraine.
    Keywords:  brain; degenerative diseases; mitochondria; mitochondrial biogenesis; vitamin B2
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101427
  11. Sci Adv. 2026 Feb 20. 12(8): eaea9014
    Redox therapy for neuropsychiatric disorders: Molecular mechanisms and biomarker development.
    Kyle W Cuklanz, Abigail Stein, Virginie-Anne Chouinard, Dost Ongur, Fei Du.
      Redox dysregulation, characterized by an imbalance in the NAD+ [nicotinamide adenine dinucleotide (oxidized form)]/NADH (reduced form of NAD+) ratio, is implicated in neurodegenerative and psychiatric disorders such as Alzheimer's disease and schizophrenia. This imbalance contributes to mitochondrial dysregulation, oxidative stress, and inflammation. Despite promising preclinical studies supporting therapeutic strategies aimed at restoring redox balance and thereby rescuing brain bioenergetic deficits, clinical outcomes and efficacy remain limited. Progress has been hindered by the incomplete understanding of NAD+ subcellular cycling, as well as a lack of in vivo biomarkers measuring target engagement of redox status and mitochondrial function. Thus, this review examines molecular mechanisms of NAD (nicotinamide adenine dinucleotide)-related bioenergetic deficits, current and emerging NAD-targeted therapies, and recent advances in the development of neuroimaging biomarkers, emphasizing personalized and mechanism-driven approaches.
    DOI:  https://doi.org/10.1126/sciadv.aea9014
  12. Curr Opin Genet Dev. 2026 Feb 12. pii: S0959-437X(26)00008-0. [Epub ahead of print]97 102441
    Convergence and divergence of molecular phenotypes in iPSC-derived models of 16p11.2 and 22q11.2 reciprocal copy number variants.
    Sandeep Rajkumar, Carrie E Bearden, Jonathan Sebat, Lilia M Iakoucheva.
      Deletions and duplications of 16p11.2 and 22q11.2, along with other copy number variants (CNVs), are strongly implicated in neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. While clinical data provide valuable insights, such data are limited in uncovering precise cellular and molecular mechanisms, and animal models often lack direct human relevance. Human induced pluripotent stem cell-derived 2D neuronal cultures, 3D brain organoids, and assembloids with 16p11.2 or 22q11.2 CNVs offer complementary systems to investigate altered pathways for future clinical translation. Studies using patient-derived or clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9-engineered induced pluripotent stem cells carrying these CNVs have identified a range of phenotypes that yield mechanistic insights. This review consolidates these findings, highlighting convergent and divergent phenotypes across reciprocal CNVs, and proposes promising molecular and cellular readouts for advancing translational research.
    DOI:  https://doi.org/10.1016/j.gde.2026.102441
  13. Mol Genet Metab Rep. 2026 Mar;46 101296
    Intermittent ketogenic fasting with medium-chain triglycerides improves ataxia in COQ8A-related coenzyme Q10 deficiency: A case report.
    Wiebke Hahn, Karla Erffmeier, Maximilian Schulze, Felix Zahnert, Susanne Knake, Panagiota-Eleni Tsalouchidou.
       Background: Mutations in COQ8A cause primary coenzyme Q10 deficiency, which can present clinically heterogeneously: Symptoms range from cerebellar ataxia, epilepsy, encephalomyopathy, macular degeneration to nephropathy. High-dose coenzyme Q10 supplementation is widely used, yet there is little evidence on complementary strategies, particularly for non-epileptic features such as cerebellar ataxia.
    Case presentation: We report a 46-year-old female with genetically confirmed COQ8A-related coenzyme Q10 (CoQ10) deficiency, presenting with ataxia and epilepsy characterized by myoclonic and bilateral tonic-clonic seizures, who participated in a clinical protocol of ketogenic intermittent fasting, a method of intermittent fasting combined with medium-chain triglycerides (MCT) primarily designed for seizure management. The patient followed a 16:8 intermittent fasting regime combined with MCT intake for three months, followed by three months of all-alone intermittent fasting. Routine blood markers and brain MRI, including diffusion imaging were obtained before and after ketogenic fasting.
    Results: During the study protocol, while no seizure reduction in myoclonic seizures could be observed, ataxia - quantified by the Scale for the Assessment and Rating of Ataxia (SARA) - improved significantly from 8.5 to 6.0 during the interventions. MRI showed a trend suggesting improved cerebellar microstructural integrity.
    Conclusions: This case highlights the potential of ketogenic intermittent fasting as an adjunct therapy for mitochondrial ataxia. Ketogenic intermittent fasting was associated with clinically meaningful improvement of ataxia in a patient with COQ8A-related CoQ10 deficiency, suggesting that ketogenic dietary strategies may represent a promising adjunct therapeutic approach for mitochondrial ataxia. Future research should assess this intervention in larger patient cohorts to confirm its potential benefits.
    Keywords:  Ataxia; Coenzyme Q10 deficiency; IF-MCT study; Intermittent fasting; Ketogenic diet; Mitochondrial diseasse
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101296
  14. Front Immunol. 2026 ;17 1708031
    The role of miRNAs in the development of Super-Tregs as a potential therapy for neurodegenerative diseases.
    Kamalika Mukherjee, Suvendra N Bhattacharyya.
      Regulatory T cells, or Tregs, are designed to limit unnecessary inflammation and serve as a safeguard mechanism to prevent tissue damage caused by heightened inflammatory responses from activated macrophages or effector T cells. Impaired Treg function has implications in autoimmunity and neuroinflammation. Neuroinflammation triggered by amyloid proteins and protein aggregates accelerates neurodegeneration due to increased cytokines and chemokines in the brains of individuals with Alzheimer's Disease and Parkinson's Disease. A simple approach involves preventing inflammation by suppressing T-effector cell activity in affected brains through boosting Tregs' function. Super-Tregs, with enhanced anti-inflammatory properties, can be engineered in vitro to combat inflammation in various tissues and, after homotropic transfer to the target tissue, prevent damage caused by inflammation. The development of Super-Tregs can be achieved through specific genetic and epigenetic modifications. Efforts to generate Super-Tregs utilizing miRNAs and miRNA-containing extracellular vesicles hold promise in treating neuroinflammation with miRNA-engineered Super-Tregs. In this review, we discuss the potential, progress, challenges, and limitations of Super-Treg development and their application in the treatment of neurodegeneration.
    Keywords:  Parkinson's disease; T regulatory cells; alzheimer’s disease; amyloid proteins; miRNA; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1708031
  15. J Adv Res. 2026 Feb 17. pii: S2090-1232(26)00161-X. [Epub ahead of print]
    Multidimensional integrative analysis unveils genetic architecture, risk factors, and health consequences of brain aging.
    Yushu Huang, Zihan Li, Yuxin Yuan, Mengying Wang, Manrui Zhang, Xiaoyu Li, Zilin Li, Xihao Li, Wenyuan Li.
       INTRODUCTION: Accelerated brain aging, reflected by greater brain-age-gap (BAG), has been linked to increased susceptibility to neurodegenerative and psychiatric disorders, yet its genetic underpinnings, modifiable factors, and broader health consequences remain undetermined.
    OBJECTIVES: To precisely estimate brain age and systematically investigate the genetic architecture, lifestyle and environmental determinants, and systemic disease risks associated with accelerated brain aging.
    METHODS: Using routinely collected magnetic resonance imaging data, we applied a DenseNet model to estimate brain age and calculated BAG as a biomarker of aging pace. We analyzed 500 K whole genome sequencing data from UK Biobank to elucidate the genomic architecture of BAG, capturing both common and rare variants, and used AlphaFold3 to assess protein structural alterations induced by missense mutations. We implemented multiple linear regression to examine associations of BAG with demographics, lifestyle, environment, and telomere length. We conducted a Phenome-wide association study (PheWAS) to investigate multisystem disease risk linked to BAG.
    RESULTS: Among a total of 42,385 participants (mean [SD] age, 65 [7.7] years; 52.8% female), the brain age model estimated BAG with a mean absolute error of 2.49 years. Whole genome sequencing identified two novel BAG-related noncoding variants, rare missense variants in KIAA0513 with a suggestive association, and significant enhancer DNase Hypersensitivity sites (DHS) of PAX6. Structural modeling revealed protein alterations from missense mutations, suggesting potential mechanisms of accelerated brain aging. In addition, unhealthy lifestyles, adverse environmental exposures, and shorter telomere length were linked to BAG. PheWAS analysis showed that 69 disease were significantly associated with BAG (HRs: 1.03-1.39 per BAG year), with mental and neurological disorders ranking highest, followe by cardiovascular and metabolic diseases.
    CONCLUSION: This study integrates neuroimaging, genomics, questionnaire, and medical records to provide a comprehensive framework for understanding the multifactorial mechanisms of brain aging and guiding precision prevention strategies.
    Keywords:  AlphaFold3; Brain age; Genetics; PheWAS; Rare variants; Whole Genome Sequencing analysis
    DOI:  https://doi.org/10.1016/j.jare.2026.02.029
  16. Aging Dis. 2026 Feb 10.
    Neuroinflammation and Cellular Senescence in Brain Aging and Neurodegeneration.
    Linlin Zhang, Longtu Li, Xin Wang, Liang Ma, Li Yan, Qian Xiang, Yimin Cui, Zhiyan Liu.
      Against the backdrop of a rapidly aging global population, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's continues to rise, imposing a severe socioeconomic burden. Neuroinflammation is recognized as the core mechanism linking physiological brain aging to pathological cognitive decline. This paper aims to systematically elucidate the multi-level activation mechanisms of neuroinflammation during aging and comprehensively evaluate drug intervention strategies targeting this process. Research reveals that the chronicity of neuroinflammation is driven by multiple cellular and molecular events. At the cellular level, aging and dysfunction in microglia and astrocytes lead to their respective transitions toward pro-inflammatory M1 and neurotoxic A1 phenotypes. These changes interact synergistically with blood-brain barrier dysfunction, peripheral immune cell infiltration, and abnormal aggregation of pathological proteins like Aβ and α-synuclein, forming a vicious cycle. At the molecular level, signaling pathways including NLRP3 inflammasome, NF-κB, and JAK/STAT are persistently activated, while epigenetic modifications play crucial regulatory roles. Addressing these mechanisms, this review systematically examines six major intervention strategies: modulating neuroimmune cell function, inhibiting core inflammatory pathways, targeting inflammatory mediators like cytokines, employing senolytics to clear senescent cells, enhancing endogenous anti-inflammatory defenses, and exploring multi-target natural products and drug repurposing. Research indicates that targeting neuroinflammation offers a highly promising new avenue for delaying brain aging and related diseases. However, this field still faces numerous challenges, including target specificity, blood-brain barrier delivery, individual heterogeneity, and difficulties in clinical translation. Future breakthroughs will depend on more precise drug design, innovative delivery technologies, biomarker development, and interdisciplinary collaborative research.
    DOI:  https://doi.org/10.14336/AD.2025.1538
  17. Clin Transl Sci. 2026 Feb;19(2): e70503
    Informing Dose for Pediatric Rare Diseases-A Survey of Recent Orphan Drugs Approvals.
    Elimika Pfuma Fletcher, Chloe Kim, Hannah Mei, Bilal AbuAsal, Sherbet Samuels, Rajanikanth Madabushi, Anuradha Ramamoorthy.
      Collectively, pediatric rare diseases affect millions of children worldwide. Yet, treatment options are limited. Dose selection presents unique challenges in pediatric rare disease drug development. Traditional dose-finding approaches are impractical for these populations, and conventional pediatric dosing methods like exposure matching face limitations when insufficient adult data exists. Herein, we analyzed dosing strategies and study design characteristics used for new molecular entities (NMEs) for orphan indications approved between 2013 and 2022 that included a pediatric indication at initial approval. Among 63 evaluable products included in this analysis, initial pediatric dose selection was supported by adult data in the same indication (37%), adult healthy volunteer data (33%), nonclinical data only (14%), adult data from different indications (10%), and pediatric data from different indications (5%). The use of modeling and simulation to support initial dose selection was explicitly mentioned for 21% of products. Nearly half (48%) utilized multiple data sources for dose selection. Study design characteristics included multiple dose level evaluation (49%), intra-patient dose escalation (33%), interim pharmacokinetic evaluation (10%), pharmacokinetic/biomarker-driven dosing (5%), and age group staggering (5%). Multiple design features were incorporated in 17% of drugs. This analysis reveals diverse approaches to pediatric dose selection in rare diseases and the use of adaptive study design elements suggests recognition of the need for flexible approaches in these challenging populations. Utility of modeling and simulation, ability to leverage all available data sources, and increased implementation of adaptive trial designs could improve dose selection and optimization in pediatric rare disease drug development.
    Keywords:  dosing; pediatric; rare disease; study design
    DOI:  https://doi.org/10.1111/cts.70503
  18. Database (Oxford). 2026 Jan 15. pii: baag004. [Epub ahead of print]2026
    Epilepsy disease classification: a community effort to enhance the Mondo Disease Ontology.
    Nicole Vasilevsky, Sarah Gehrke, Kathleen Mullen, Subit Barua, Ian Braun, Tobias Brünger, Curtis Coughlin, Alina Ivaniuk, Daniel Korn, Dennis Lal, Stephanie Marsh, Elaine O'Loughlin, Daniel Olson, Yousif Shwetar, Christalena Sofocleous, Vanessa Vogel-Farley, Heidi Grabenstatter, Melissa Haendel, Christopher Mungall, Sabrina Toro.
       MOTIVATION: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies-often severe and genetically complex-pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research.
    RESULTS: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical ontology, and patient community advocates systematically reviewed and revised the epilepsy hierarchy in Mondo, aligning it with the International League Against Epilepsy (ILAE) classification system. These updates include reclassification of epilepsy subtypes, including syndromes, age-related epilepsies, and developmental epileptic encephalopathies, resulting in a more granular, standardized, and clinically relevant structure. Mondo now offers an enhanced framework for integrating epilepsy data across resources, enabling improved interoperability and facilitating rare disease research and data curation, with continued efforts underway to further refine and expand this integration.
    DOI:  https://doi.org/10.1093/database/baag004
  19. Biogerontology. 2026 Feb 21. pii: 60. [Epub ahead of print]27(2):
    "Metabolic memory" of aging: anchoring, transmission, and frontiers of transgenerational intervention.
    Yue Zhao.
      Cellular senescence is the core cytological basis for organismal aging and the development of age-related diseases. Accumulating evidence indicates that senescent phenotypes can be maintained long-term even after the removal of senescence-inducing stressors, and may even affect daughter cells and offspring. This review systematically proposes an integrated theoretical framework of "aging metabolic memory", explaining the persistence, transmissibility, and potential heritability of aging from a systems biology perspective. First, it elaborates on how mitochondrial metabolic reprogramming reshapes the cellular epigenetic landscape (DNA methylation, histone modification) by altering the homeodynamics of key metabolites (NAD⁺, α-ketoglutarate, succinate, etc.), thereby forming stable senescence imprints; second, it in-depth analyzes the mechanisms by which the senescence-associated secretory phenotype (SASP) and extracellular vesicles (EVs) act as "memory carriers" to achieve intercellular transmission and systemic spread of senescent phenotypes; on this basis, combined with the latest progress in epigenetics, it proposes and demonstrates a hypothetical model for the transgenerational transmission of aging metabolic memory through germ cells, exploring its biological significance and evolutionary implications; finally, it systematically sorts out and prospects novel aging intervention strategies based on "memory intervention" (rather than mere elimination), including metabolic resetting, epigenetic remodeling, transmission blocking, and germ cell-targeted intervention. This review summarizes the spatiotemporal dynamic characteristics of aging and may provide multi-dimensional intervention pathways for the precise prevention and treatment of age-related diseases and the promotion of healthy aging.
    Keywords:  Aging intervention; Cellular senescence; Epigenetics; Extracellular vesicles; Metabolic memory; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1007/s10522-026-10410-7
  20. Nature. 2026 Feb 18.
    An agentic system for rare disease diagnosis with traceable reasoning.
    Weike Zhao, Chaoyi Wu, Yanjie Fan, Pengcheng Qiu, Xiaoman Zhang, Yuze Sun, Xiao Zhou, Shuju Zhang, Yu Peng, Yanfeng Wang, Xin Sun, Ya Zhang, Yongguo Yu, Kun Sun, Weidi Xie.
      Rare diseases affect more than 300 million people worldwide1-3, yet timely and accurate diagnosis remains an urgent challenge1,3-5. Patients often endure a prolonged 'diagnostic odyssey' exceeding 5 years, marked by repeated referrals, misdiagnoses and unnecessary interventions, leading to delayed treatment and substantial emotional and economic burden4,5. Here we present DeepRare-a multi-agent system for rare disease differential diagnosis decision support6-8 powered by large language models, integrating more than 40 specialized tools and up-to-date knowledge sources. DeepRare processes heterogeneous clinical inputs, including free-text descriptions, structured human phenotype ontology terms and genetic testing results to generate ranked diagnostic hypotheses with transparent reasoning linked to verifiable medical evidence. Evaluated across nine datasets from literature, case reports and clinical centres across Asia, North America and Europe spanning 14 medical specialties, DeepRare demonstrates exceptional performance on 2,919 diseases. In human-phenotype-ontology-based tasks, it achieves an average Recall@1 of 57.18%, outperforming the next best method by 23.79%; in multi-modal tests, it reaches 69.1% compared with Exomiser's 55.9% on 168 cases. Expert review achieved 95.4% agreement on its reasoning chains, confirming their validity and traceability. Our work not only advances rare disease diagnosis but also demonstrates how the latest powerful large-language-model-driven agentic systems can reshape current clinical workflows.
    DOI:  https://doi.org/10.1038/s41586-025-10097-9
  21. Cell Syst. 2026 Feb 18. pii: S2405-4712(26)00016-5. [Epub ahead of print]17(2): 101534
    From modality-specific to compositional foundation models for cell biology.
    Mojtaba Bahrami, Till Richter, Niklas A Schmacke, Aitana Egea Lavandera, Fabian J Theis.
      Deriving principles governing cell biology from single-cell measurements across modalities, called multimodal modeling, can advance our understanding of cellular states in health and disease. Realizing the full potential of multimodal models requires learning generalizable representations across data types, diseases, and biological contexts. This perspective examines the potential of compositional AI as a modular design approach for constructing multimodal foundation models that unify biological modalities-such as chromatin accessibility, protein abundance, spatial transcriptomics, microscopy imaging, and textual annotations-into cohesive representations of cellular behavior. We present key deep learning modeling approaches, along with transformer-based attention strategies to implement them, while addressing challenges posed by limited data availability and structural differences between modality representations. We also discuss how to connect and align partially overlapping multimodal measurements to build a comprehensive representation space. By synthesizing these technical advancements, we chart a path toward agentic virtual cell models, offering insights into opportunities, limitations, and future directions for leveraging multimodal AI to decode the complexity of cellular systems.
    Keywords:  compositional AI; single-cell foundation models; single-cell multi-omics
    DOI:  https://doi.org/10.1016/j.cels.2026.101534
  22. Front Immunol. 2026 ;17 1763348
    CX3CL1/CX3CR1 axis in liver disease: context-dependent roles and balance.
    Jing Liu, Zhen Guo, Xin Zheng.
      This review provides a systematic and critical examination of the multifaceted roles of the CX3CL1/CX3CR1 axis in liver diseases. We emphasize its context-dependent duality-exhibiting both pro- and anti-inflammatory, pro- and anti-fibrotic, and pro- and anti-tumor functions across different etiologies. Moving beyond a binary good or bad" paradigm, we propose a contextual signaling model that integrates cellular source, microenvironmental cues, and intersecting pathways to explain its divergent roles. We synthesize recent advances in its involvement in NAFLD/NASH, viral hepatitis, autoimmune hepatitis, schistosomiasis, liver fibrosis and hepatocellular carcinoma. The review critically evaluates the axis's potential as a biomarker, discusses methodological advances and limitations in human studies, and analyzes therapeutic strategies with a focus on translational challenges. We conclude with a forward-looking perspective on precision medicine approaches targeting this axis.
    Keywords:  CX3CR1; fractalkine (CX3CL1); immune regulation; liver diseases; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1763348
  23. Mol Genet Metab. 2026 Feb 12. pii: S1096-7192(26)00035-1. [Epub ahead of print]147(4): 109752
    From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease.
    Oliver Heath, Francisco Del Caño-Ochoa, Safa Baris, Rosalba Carrozzo, David Coman, Felix Distelmaier, Carolyn Ellaway, Rene G Feichtinger, Andrea Finocchi, Sergio Guerrero-Castillo, Rebecca Halligan, Iris Hannibal, Amy Kritzer, Uta Lichter-Konecki, Kajus Merkevicius, Bianca Panis, Robert D S Pitceathly, Chiara Pizzamiglio, Katarzyna Iwanicka-Pronicka, Shamima Rahman, Laurie Seltzer, Meinolf Siepermann, Galit Tal, Ron A Wevers, Szymon Ziętkiewicz, Santiago Ramón-Maiques, Johannes A Mayr, Saskia B Wortmann.
       BACKGROUND: CLPB-related mitochondrial disease causes congenital neutropenia, developmental delay/intellectual disability, progressive brain atrophy, movement disorders, cataracts, and 3-methylglutaconic aciduria. Both monoallelic and biallelic forms exist. This retrospective cohort study compared clinical outcomes and genotype-structure-phenotype correlations across zygosity groups.
    METHODS: Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey. In silico modeling assessed structural impact. A modified CLPB Disease Burden Index (DBI) quantified severity.
    RESULTS: Median age at last follow-up was 4.0 years (IQR: 0.25-12.6) in biallelic and 12.0 years (IQR: 5.3-21.0) in monoallelic cases. Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%). Stop/stop genotypes were associated with greater disease burden than missense combinations. Structural predictions-particularly variants causing nonsense-mediated decay or ankyrin domain disruption-were stronger survival predictors than zygosity or age of onset. Early-onset disease (<12 months) correlated with more severe progression. Later onset often resulted in milder phenotypes. Hematologic and neurologic features overlapped across zygosity; cataracts and dystonia were more common in biallelic cases. Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time. Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes. Granulocyte colony-stimulating factor was associated with improved survival.
    CONCLUSIONS: This is the largest cohort study to date comparing biallelic and monoallelic CLPB deficiency. Structural variant impact-particularly ankyrin domain disruption-emerged as a key prognostic factor.
    Keywords:  3-methylglutaconic aciduria; Ankyrin repeat region; CLPB; Cataracts; Congenital neutropenia; Genotype-phenotype correlation; Mitochondrial chaperonopathy; Protein modeling; Zygosity
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109752
  24. Mol Neurobiol. 2026 Feb 21. pii: 464. [Epub ahead of print]63(1):
    Advancements in Stem Cell Therapy for Managing Drug-Resistant Epilepsy.
    Munerah Hamed.
      Epilepsy is a common chronic disorder of the nervous system and it is typically characterized by repeated seizures that arise from dysregulated electrical activity in the brain. Even with widely used antiseizure drugs and the option of surgery in selected cases, roughly 20 to 30% of patients go on to develop drug-resistant epilepsy, with persistent seizures that are often accompanied by neuronal damage, oxidative stress, and signs of mitochondrial dysfunction. In this context, stem cell therapy has drawn strong interest as a possible therapeutic direction, largely because multiple stem cell populations carry regenerative and neuroprotective potential, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and adipose-derived regenerative cells (ADRCs). Evidence from animal studies and early clinical work suggests that transplantation approaches might support restoration of inhibitory neuronal networks, tone down neuroinflammatory signaling, and promote broader repair processes within injured circuits, which together could contribute to more durable seizure control. This review highlights recent advances in stem cell-based strategies for epilepsy, with attention to proposed mechanisms, reported therapeutic effects, and the animal models most often used to test these ideas. We also consider related regenerative medicine approaches, such as neuroprotection and electrical stimulation, as adjunct options that may strengthen outcomes in drug-resistant epilepsy by targeting at least part of the underlying biology rather than only suppressing symptoms.
    Keywords:  Drug-resistant epilepsy; Epilepsy; Neuroprotection; Regenerative medicine; Stem cell therapy
    DOI:  https://doi.org/10.1007/s12035-026-05753-8
  25. J Cell Sci. 2026 Feb 19. pii: jcs.264304. [Epub ahead of print]
    TBC1D15 functions as an Arl4D GAP and promotes the mitochondrial translocation of Arl4D for organelle homeostasis.
    Chia-Tang Chen, Tsai-Jung Liu, Shin-Jin Lin, Ting-Wei Chang, Fang-Jen S Lee.
      ADP-ribosylation factor-like 4D (Arl4D), a Ras small GTPases superfamily member, plays critical roles in membrane trafficking, cytoskeletal remodeling, and cell migration. GDP-bound Arl4D was discovered previously to locate at the mitochondria and alter mitochondrial morphology and activity; however, how the nucleotide binding state and mitochondrial targeting of Arl4D is regulated had remained unclear. We now discover that TBC1D15, a well-known Rab7 GTPase-activating protein (GAP), functions also as an Arl4D GAP to promote Arl4D mitochondrial targeting. We initially find that GDP-bound Arl4D translocates to the mitochondria under serum starvation and affects mitochondrial homeostasis. We then find that TBC1D15 interacts with Arl4D through the TBC domain and promotes GTP hydrolysis of Arl4D. Knockdown of TBC1D15 leads to an increase in Arl4D activity and decreased Arl4D mitochondrial translocation under serum starvation. These findings support that TBC1D15 acts as an Arl4D GAP and reveal a new role for this GAP in modulating mitochondrial homeostasis.
    Keywords:  ADP-ribosylation factor; Arl4; GTPase; GTPase activating protein; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.264304
  26. FASEB J. 2026 Feb 28. 40(4): e71603
    The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.
    Yalan Wan, Zhen Yu, Juan Yang, Wei Zhang, Meng Yu, Lingchao Meng, Zhaoxia Wang, Yun Yuan, Linhao Ruan, Jianwen Deng, Peng Wang.
      Aggregation of TDP-43 in neuronal cells is a defining neuropathological hallmark of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that TDP-43 pathology also occurs in skeletal muscle fibers, but its functional significance in myocytes remains poorly understood. In this study, we utilized the C2C12 myoblast cell to investigate the subcellular localization of TDP-43 during myogenic differentiation. Our findings demonstrate that TDP-43 progressively translocates to mitochondria in parallel with myotube maturation. Notably, increased mitochondrial localization of TDP-43 was also observed in skeletal muscle tissues from patients with ALS, corroborating the clinical relevance of this phenomenon. Functional assays revealed that inhibition of TDP-43 mitochondrial translocation significantly enhances myotube maturation. Collectively, these results support a pathophysiological role for aberrant mitochondrial mislocalization of TDP-43 in regulating myogenic differentiation and contributing to muscle degeneration in TDP-43 proteinopathies.
    Keywords:  TDP‐43; amyotrophic lateral sclerosis; mitochondria; myotube maturation
    DOI:  https://doi.org/10.1096/fj.202504624R
  27. Cell Transplant. 2026 Jan-Dec;35:35 9636897251414216
    Glial cells in dementia: From cellular dysfunction to therapeutic frontiers.
    Hassan Jubair.
      Neurodegenerative dementias, including Alzheimer's disease and vascular dementia, have long been viewed through a neuron-centric lens. However, growing evidence highlights the indispensable and multifaceted roles of glial cells, astrocytes, microglia, and oligodendrocytes in both the onset and progression of these disorders. While prior reviews have cataloged glial dysfunction in isolation, this review offers a novel, integrative framework that maps the interconnected roles of glial subtypes across molecular, cellular, and circuit-level pathology in dementia. We critically synthesize recent advances in single-cell RNA sequencing, spatial transcriptomics, and glial imaging to redefine glial heterogeneity and function in disease states. Special emphasis is placed on the dynamic cross talk between glial populations and the feedback loops that govern their dual roles in neuroprotection and neurodegeneration. Furthermore, we examine emerging therapeutic strategies targeting glial-specific pathways, including NF-κB, JAK/STAT, CSF1R, and TREM2 signaling, as well as remyelinating agents and stem cell-based interventions. By integrating glial biology with therapeutic innovation, this review positions glial cells not as supporting actors but as central regulators and potential gatekeepers of dementia pathogenesis and treatment.
    Keywords:  Alzheimer’s disease; glial cells; microglia modulation; neuroinflammation; remyelination therapy; single-cell RNA sequencing; vascular dementia
    DOI:  https://doi.org/10.1177/09636897251414216
  28. CNS Neurosci Ther. 2026 Feb;32(2): e70791
    Interleukins in Major Depressive Disorder: Lessons From Autoimmune Diseases and Pathways to Clinical Translation.
    Adnan Akif, Mohammad Fahim Kadir, Md Rabiul Islam.
       BACKGROUND: Major Depressive Disorder (MDD) is a leading cause of disability, and limitations of the monoamine hypothesis have driven the exploration of complementary models, including the inflammatory hypothesis. This hypothesis suggests that in a subset of patients, immune dysregulation, especially involving interleukins (ILs), contributes to depression. This review compares IL dysregulation in MDD and autoimmune diseases to identify common and unique inflammatory mechanisms for treatment.
    RESULTS AND CONCLUSION: Some MDD patients exhibit chronic, low-grade inflammation both systemically (in blood) and centrally (in CSF and brain). They show elevated pro-inflammatory IL-6, IL-1β, and IL-18, with insufficient anti-inflammatory IL-10. This immune dysregulation affects key neurobiological processes (monoamine metabolism, HPA axis, neurogenesis), linking inflammation to depressive symptoms. MDD and autoimmune diseases share inflammatory mediators and signaling pathways, supporting these as therapeutic targets; however, MDD's inflammation is low-grade and innate driven, whereas autoimmune diseases have high-grade, adaptive immune responses to specific antigens. Successful anti-IL therapies in autoimmune conditions provide a roadmap for treating inflammation-driven depression. Translating these findings to practice requires a precision immune-psychiatry approach. Biomarkers like C-reactive protein and IL-6 can identify an inflammatory depression subtype, and patients may benefit from targeted immunomodulatory strategies, repurposed biologics, novel small molecules, or lifestyle interventions particularly if standard antidepressants fail.
    Keywords:  autoimmune diseases; depression; inflammation; interleukin; major depressive disorder; rheumatoid arthritis
    DOI:  https://doi.org/10.1002/cns.70791
  29. Nat Med. 2026 Feb;32(2): 381
    Neurodegenerative diseases need more mechanism-informed trials.
      
    DOI:  https://doi.org/10.1038/s41591-026-04258-0
  30. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2522583123
    Human lncRNA RMRP interacts with DEAD-box helicases and modulates mitochondrial function.
    Higor Sette Pereira, Jason Luddu, Govardhan Reddy Veerareddygari, Shridhar Kiran Sanghvi, Priyanshi B Patel, Zachary E Robinson, M Quadir Siddiqui, Harpreet Singh, Trushar R Patel.
      The human long noncoding RNA (lncRNA) RMRP, initially identified as part of the RNase MRP complex, is linked to various human diseases. However, its structural flexibility and broader cellular roles are not well understood. Here, we offer a comprehensive analysis of RMRP's structure in solution, its interactions with human proteins, and its mitochondrial functions. Using small-angle X-ray scattering (SAXS), we show that RMRP adopts different Mg2+-dependent shapes, shifting from an extended Y-shaped form to a more compact one as Mg2+ levels increase. We identified and characterized interactions between RMRP and the DEAD-box RNA helicases DDX5 and DDX3X, with DDX5 binding strongly and exhibiting ATP-dependent helicase activity on RMRP, while DDX3X mainly acts as an expression regulator. Both helicases are crucial for the proper mitochondrial localization of RMRP, working within a complex regulatory network. Functionally, reducing RMRP levels disrupts mitochondrial stability, leading to membrane depolarization and an increase in reactive oxygen species, without affecting cell growth. Mechanistically, RMRP specifically controls nuclear-encoded mitochondrial proteins involved in cristae structure (DNAJC11) and respiratory chain function (NDUFS8). Our results position RMRP as a structurally adaptable lncRNA that collaborates with RNA helicases to preserve mitochondrial health through specific gene regulation. These insights provide perspectives on RMRP's biology and the molecular mechanisms underlying RMRP-related disorders, which could inform future therapies for conditions resulting from RMRP dysfunction.
    Keywords:  DEAD-box helicases; RMRP; long noncoding RNA; mitochondrial function
    DOI:  https://doi.org/10.1073/pnas.2522583123
  31. Front Neurosci. 2026 ;20 1731771
    Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.
    Yonghui Pang, Jiachen Yang, Jingjing Liu, Zhengyi Xie, Jin Wang.
      This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain's resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.
    Keywords:  astrocytes; disease; homeostasis; metabolism; microglia; neurons
    DOI:  https://doi.org/10.3389/fnins.2026.1731771
  32. Front Immunol. 2026 ;17 1758410
    Clinical and genetic spectrum of inborn errors of immunity: a retrospective study on outcomes at a single center.
    Hulya Kose, Akcahan Akalin.
       Introduction: Inborn errors of immunity (IEI) are particularly prevalent in regions with high rates of consanguinity, yet the genetic profiles in these populations are underreported. This study aims to describe the clinical and molecular characteristics of IEI in a highly consanguineous population and investigate the impact of genetic diagnosis on patient management.
    Method: This retrospective study included 52 patients with suspected IEI, as defined by the IUIS criteria. Clinical, immunological, and demographic data were recorded. Genetic analyses were performed primarily using next-generation sequencing (NGS) gene panels, and all pathogenic variants were confirmed by Sanger sequencing. Variants were interpreted in accordance with the ACMG guidelines.
    Results: A total of 52 patients were included in the study, with 92% of the individuals born to consanguineous parents, comprising 28 females and 24 males. The mean age at diagnosis was 4.63 ± 2.5 years. The median duration of follow-up was three years. The overall incidence was 0.3% representing the proportion of patients diagnosed with IEI among those referred to our center during the study period. A high rate of consanguineous marriage was observed, reported in 92% of the cases. The most frequently represented category was Predominantly Antibody Deficiencies (PAD), accounting for 20 patients (38.5%), including 12 cases (23%) of transient hypogammaglobulinemia of infancy (THI) and 7 cases (13%) of selective IgA deficiency. Among the 52 patients, 3 (5.8%) were diagnosed with severe combined immunodeficiency (SCID): 1 patient had ADA deficiency, and two patients had DNA ligase IV deficiency (LIG4). Additionally, 14 patients (26%) were diagnosed with combined Immunodeficiencies (CID). Thirty patients were treated with IVIG, and 3 patients underwent HSCT. A molecular diagnosis was established in 33 patients (63%). Genetic findings influenced clinical management in 82% of variant-positive cases, including decisions regarding HSCT, targeted therapy, and genetic counseling.
    Conclusion: This study highlights the distinctive genetic characteristics of IEI in a population with high consanguinity, emphasizing the need to incorporate molecular diagnostics into standard immunology practice, particularly in areas where recessive disorders are prevalent.
    Keywords:  ADA deficiency; IVIG; LIG4; gene; inborn errors of immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1758410
  33. Front Physiol. 2026 ;17 1747133
    Mitochondria: the central hub linking exercise to enhanced cardiac function.
    Jiaqin Cai, Tutu Wang, Shunchang Li.
      Sedentary lifestyle is a major risk factor for the occurrence and development of cardiovascular disease, which remains one of the leading contributors to global morbidity and mortality. Beyond inducing endothelial dysfunction, prolonged sedentary patterns trigger chronic inflammation and disrupt endogenous antioxidant defenses, resulting in mitochondrial dysfunction in cardiomyocytes and subsequent impairment of cardiac health. In contrast, regular physical exercise serves as an effective lifestyle intervention that mitigates sedentary-related cardiac damage and improves cardiac function. Mitochondria, as central organelles governing cellular survival and death, are thought to play a pivotal role in mediating the cardioprotective effects of exercise. However, the precise mitochondrial mechanisms underlying these benefits remain incompletely defined. This review aims to summarize current evidence on how exercise regulates mitochondrial function in the heart, with particular emphasis on recent advances linking mitochondrial respiration, dynamics, calcium homeostasis, inflammatory signaling, and oxidative stress to cardiac health. We further propose that exercise-induced improvements in mitochondrial function constitute a core mechanism underlying its cardioprotective effects. By comparing mitochondrial alterations under sedentary and exercise conditions, we provide a clearer mechanistic perspective on how lifestyle behaviors shape cardiac health. Furthermore, this paper also discusses signaling pathways that position mitochondria as key targets of exercise-induced cardiac protection.
    Keywords:  exercise; heart; inflammatory response; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2026.1747133
  34. Front Aging Neurosci. 2026 ;18 1689139
    Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
    Leah E Jamerson, Tara D Bradshaw, Patrick C Bradshaw.
      Changes in brain [NADPH]/[NADP+] and [NAD+]/[NADH] may contribute to aging. Anti-aging dietary restriction (DR) and intermittent fasting (IF) alter redox states that may contribute to their longevity effects. Pyruvate/lactate and acetoacetate/beta-hydroxybutyrate are indicators of the cytoplasmic and mitochondrial [NAD+]/[NADH], respectively, while the malate/pyruvate and isocitrate/alpha-ketoglutarate are indicators of the cytoplasmic [NADPH]/[NADP+]. Using these metabolite-pair ratios as redox indicators, the C57BL/6J mouse brain showed opposite redox changes with aging to the C57BL/6N mouse brain and human brain in the cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+]. Fasting caused universal reductive shifts in the brain cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+] and mitochondrial [NAD+]/[NADH]. The reductive shift in the cytoplasmic [NAD+]/[NADH] with fasting was opposite to that occurring with anti-aging ketone ester supplementation or ketogenic diet, which have been shown to cause an oxidative shift of the cytoplasmic [NAD+]/[NADH], but a reductive shift of the cerebral cortical cytoplasmic [NADPH]/[NADP+]. Several pathways that influence redox metabolism and aging are discussed, including fatty acid and cholesterol synthesis, the citric acid cycle, fatty acid beta-oxidation, glutaminolysis, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, the citrate-pyruvate shuttle, and the citrate-alpha-ketoglutarate shuttle. Brain proteome, brain single-cell RNA-Seq, and brain-region-specific bulk RNA-Seq data sets of aging and DR were examined, focusing on the pathways listed above to determine how they might contribute to the redox changes. Intermittent fasting has been shown to induce cyclic metabolic switching that contributes to neuroprotection and other health benefits resulting in delayed aging, while cyclic reductive redox shifts, especially in mitochondria, may be a driver of the beneficial effects.
    Keywords:  NAD+; NADPH; aging; astrocyte; brain; dietary restriction; fasting; redox
    DOI:  https://doi.org/10.3389/fnagi.2026.1689139
  35. Bioimpacts. 2025 ;15 33140
    Organoid-engineered neurovascular units for drug discovery and neurodegeneration research.
    Ailar Nakhlband.
      The highly selective permeability of the human blood-brain barrier presents a major obstacle to neurological disease modeling. Established 2D cell cultures and animal models are unable to accurately reproduce the physiological and molecular features of the human blood-brain barrier, limiting the translation of bench to bedside. Recent advances in the use of human induced pluripotent stem cells and organoid engineering have enabled the development of more physiologically relevant in vitro brain models for studying blood-brain barrier function. Blood-brain barrier organoids, mimic key structural and functional features of the blood-brain barrier. Moreover, integration of blood brain barrier organoids with brain organoids or microphysiological systems allows the formation of functional neurovascular units that better represent in vivo conditions. The development of scalable, reproducible, and partially vascularized blood-brain barrier organoid models holds promise for high-throughput drug discovery platforms, and the development of personalized therapeutic strategies for central nervous system disorders.
    Keywords:  BBB permeability assays; Blood–brain barrier (BBB) models; Brain organoids; Drug screening; Human stem cell–derived organoids; Neurovascular modeling; Precision medicine; Translational neuroscience
    DOI:  https://doi.org/10.34172/bi.33140
  36. Acta Physiol (Oxf). 2026 Mar;242(3): e70179
    N-Acetylglucosamine Selectively Attenuates Neuroinflammation in a Mouse Model of Mitochondrial Dysfunction.
    Laura Jiménez-Sánchez, Paula Ruiz-López, Pilar González-García, Janne Purhonen, Juan Manuel Martínez-Gálvez, Sergio López-Herrador, Julia Corral-Sarasa, María Elena Díaz-Casado, Carmen Venegas, Isaac Santos-Pérez, Enrica Olivieri, Adriana L Rojas, Luis Carlos López.
       AIM: Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characterize the progression of neurodegeneration in a mouse model of fatal mitochondrial encephalopathy and to evaluate the therapeutic potential of oral N-acetylglucosamine supplementation.
    METHODS: A mouse model of primary coenzyme Q deficiency was used to examine neurodegeneration at presymptomatic, symptomatic and terminal stages. Neuronal integrity, glial activation, myelination and inflammatory responses were assessed using histological, molecular and ultrastructural approaches, together with behavioral analysis of motor coordination. N acetylglucosamine was administered orally from 1 month of age, and its effects on neuroinflammation, myelin integrity and motor performance were evaluated.
    RESULTS: Astrocyte activation and neuronal loss were detected before the onset of clinical symptoms, whereas proinflammatory microglia appeared at later disease stages. Early myelin abnormalities were accompanied by an initial increase in oligodendrocyte precursor cells, suggesting a compensatory response to early myelin stress. Oral N-acetylglucosamine supplementation reduced glial activation and neuroinflammatory markers, likely through modulation of inflammatory signaling pathways. Although treatment did not fully reverse structural damage or restore myelin protein expression, it led to a significant improvement in motor coordination.
    CONCLUSION: These findings define a temporal sequence of early glial activation, neuronal loss, and myelin alterations in mitochondrial encephalopathy. Targeting glial responses and neuroinflammation at early disease stages may mitigate neurodegenerative progression and improve functional outcomes, highlighting a physiologically relevant therapeutic window for mitochondrial disorders.
    Keywords:  N‐acetylglucosamine; coenzyme Q; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.1111/apha.70179
  37. Brain. 2026 Feb 17. pii: awag066. [Epub ahead of print]
    Tiered modelling of a CACNA1A D1634N mutation linked to ataxia, epilepsy and cognitive deficits.
    Jacqueline Niu, Chi-Kun Tong, Ekniel Francois, Wayne N Frankel, Wendy K Chung, Henry M Colecraft.
      Missense mutations in CACNA1A, which encodes CaV2.1 voltage-gated calcium channels, underlie serious neurological diseases with inadequate treatment options. Developing new therapies for CACNA1A diseases is hindered by: 1) unknown biophysical impact of many mutations, 2) limited knowledge of genotype effects on channel function and behavioural phenotype, and 3) dearth of animal models mimicking the human disease. Here, we focus on a CACNA1A missense mutation (D1634N) identified in a patient with ataxia, epilepsy, moderate intellectual disability, and mild cerebellar loss. Heterologously expressed D1634N channels displayed a significantly decreased whole-cell current amplitude, a +25-mV shift in activation V1/2, and diminished single-channel open probability, indicating a loss-of-function (LoF). Patient-specific cortical neurons derived from induced pluripotent stem cells displayed enhanced intrinsic excitability compared to isogenic controls. Heterozygous knock-in mice with the analogous mutation (D1585N) displayed ataxia, absence epilepsy, and cognitive deficits, mirroring the human behavioural phenotype. Purkinje cell and cerebellar slice electrophysiology revealed a reduced whole-cell CaV2.1 current with a right-shifted V1/2 of activation, altered Purkinje cell excitability, and changes in presynaptic vesicle release probability at the parallel fibre to Purkinje neuron input. The results introduce a new CACNA1A LoF mutation and highlight the power of combined heterologous expression, iPSC neurons, and animal model studies to provide complementary insights into the molecular basis of disease with implications for developing therapies.
    Keywords:  CACNA1A; ataxia; calcium channel; cerebellum; channelopathy; epilepsy
    DOI:  https://doi.org/10.1093/brain/awag066
  38. Rejuvenation Res. 2026 Feb 15. 15491684261421863
    Breaking the Bonds of Aging: The Underappreciated Roles of Aberrant Cysteine Crosslinks and Protective Thiol Interventions.
    Sheila N Duong, Kristopher M Barnes, James H Frederich.
      Aging is a complex process characterized by the accumulation of molecular damage that leads to cellular dysfunction and tissue deterioration. Among the various types of contributing molecular damage, aberrant protein crosslinks are recognized as a key contributor to age-related pathologies. Crosslinks occurring at lysine and arginine residues, such as advanced glycation end-products (AGEs) and carbamylation, have attracted considerable attention of the aging research community. In contrast, the roles of cysteine-derived crosslinks in aging pathobiology remain underappreciated. While native disulfide formation is essential for protein structure and function, the same redox features that make cysteine indispensable to protein biochemistry also render it particularly susceptible to nonspecific disulfide crosslinking. The body exploits specialized protective thiols such as glutathione to maintain redox homeostasis and counteract the deleterious effects of aberrant disulfide formation. However, these endogenous protective measures decline with aging, resulting in the accumulation of oxidative cysteine modifications. In this review, we highlight the emergent roles of cysteine-related molecular damage in age-related disease. Drawing inspiration from endogenous protective thiols, we survey progress in the development of small-molecule therapeutic thiols that show promise in mitigating damage caused by the accumulation of cysteine-derived crosslinks. Understanding the relationship between these aberrant crosslinks and protective thiol interventions in aging diseases, as well as how therapeutic thiols can be improved, is critical for the development of comprehensive treatments.
    Keywords:  antioxidant; crosslinks; disulfide
    DOI:  https://doi.org/10.1177/15491684261421863
  39. Pediatr Rep. 2026 Jan 19. pii: 14. [Epub ahead of print]18(1):
    Integrating the Genomic Revolution into Newborn Screening: Current Challenges and Future Perspectives.
    Albina Tummolo, Emanuela Ponzi, Simonetta Simonetti, Mattia Gentile.
      In recent years, the development of new diagnostic technologies, such as tandem mass spectrometry (MS/MS) and next-generation sequencing (NGS), has caused a veritable revolution in the diagnosis of genetic diseases, reducing time, cost, and invasiveness associated with prior diagnostic techniques. While MS/MS laid the foundation for the development of numerous, usually institutionally based, neonatal screening programs, NGS has gained traction in newborn screening (NBS), primarily through pilot projects and private funding across different countries. As a result, the traditional Wilson and Jungner criteria have been supplemented by additional criteria, including considerations of equity and access, in response to emerging technologies. This review aims to provide an up-to-date overview of the global landscape of metabolic screening panels, highlight the major ongoing genomic screening projects, and outline the current models for integrating these two screening systems. Substantial differences exist across countries in the numbers and types of diseases included in national NBS programmes. In this context, Italy represents a prominent case, as its neonatal screening framework has seen significant expansion and development in recent years, reaching a particularly comprehensive metabolic screening panel. Nonetheless, a number of initiatives to incorporate genomic technologies into the NBS pathway are currently underway, primarily involving high-income countries. Nonetheless, unlike metabolomic-based NBS programs, no country has a government-mandated NGS program as first-tier testing for newborns. New evidence is emerging from ongoing models of integration of multi-omics approaches into NBS, including the use of AI and machine learning. Identifying the most appropriate system for this integration to reduce the false-positive and false-negative rates associated with both screening types, ensure more equitable access to screening, and facilitate faster access to treatment may represent a useful and foresightful way to conceptualize NBS in the future. This transitional phase should promote rigorous improvements before full-scale adoption.
    Keywords:  genomics; metabolic disorders; multiomics; newborn screening; next-generation sequencing; tandem mass spectrometry
    DOI:  https://doi.org/10.3390/pediatric18010014
  40. Clin Epigenetics. 2026 Feb 14.
    Genetic insights into biological aging and myasthenia gravis: a Mendelian randomization study of telomere length, epigenetic clocks, and mitochondrial DNA copy number.
    Wei Xiang, Yining Luan, Kangzhi Chen, Ting He, Qian Zhou, Huan Yang.
       BACKGROUND: Emerging epidemiological evidence shows myasthenia gravis (MG) is associated with age-related biological processes, but its mechanism of causality remains unexplained. This bidirectional Mendelian randomization (MR) study aimed to clarify the causal relationships between quantifiable biomarkers of aging and MG.
    METHODS: We extracted genetic instrumental variables for three aging biomarkers: telomere length, epigenetic clocks, and mitochondrial DNA copy number (mtDNA-CN) and MG from the public GWAS databases. The main causal effect estimates were obtained by the inverse variance weighted method, and supplementary sensitivity analysis was used to evaluate potential heterogeneity and pleiotropy effects.
    RESULTS: Overall, genetically predicted HannumAge and mtDNA-CN were associated with MG (OR = 0.909, 95% CI 0.834-0.991, P = 0.030; OR = 1.592, 95% CI 1.025-2.473, P = 0.039), though these associations did not survive false discovery rate (FDR) correction. Subgroup analyses showed a negative causal effect of HannumAge on early-onset MG (EOMG) (OR = 0.775, 95% CI 0.667-0.901, P = 0.001, PFDR =0.005), and a potential positive association of mtDNA-CN with late-onset MG (LOMG) (OR = 1.756, 95% CI 1.030-2.995, P = 0.039, PFDR =0.193). Reverse MR identified that EOMG causally increased epigenetic clocks (PhenoAge: OR = 1.056, 95% CI 1.004-1.111, P = 0.036; GrimAge: OR = 1.098, 95% CI 1.055-1.143, P < 0.001; HannumAge: OR = 1.100, 95% CI 1.058-1.144, P < 0.001), with the GrimAge and HannumAge association remaining significant after FDR correction. No evidence supported causal associations of MG/LOMG with aging biomarkers.
    CONCLUSION: Our findings demonstrate a bidirectional causality between EOMG and epigenetic aging clocks, which indicates that there is a self-reinforcing pathophysiological cycle. The epigenetic age acceleration is both a driver and a result of the progression of EOMG. The correlation between mtDNA-CN and LOMG suggests that there may be a potential compensatory adaptation mechanism to combat chronic oxidative stress in age-related autoimmunity. These results highlight the complex and subtype-dependent contributions of biological aging to the autoimmune-mediated pathology of MG, and provide key mechanistic insights into the subtype-specific aging in MG.
    Keywords:  Biological aging; Epigenetic clock; Genetics; Mendelian randomization; Myasthenia gravis
    DOI:  https://doi.org/10.1186/s13148-026-02083-3
  41. Commun Med (Lond). 2026 Feb 20.
    The clinical utility of genome sequencing is multi-dimensional: experience from the Hong Kong Genome Project.
    Annie Tsz Wai Chu, Claudia Ching Yan Chung, Ho Ming Luk, Shirley Sze Wing Cheng, Robin Hayeems, Stephanie Luca, Brian Hon Yin Chung.
       BACKGROUND: Assessing clinical utility of genome sequencing (GS) is essential for healthcare decisions. This study quantified the multidimensional utility of GS using the validated Clinician-reported Genetic testing Utility InDEx (C-GUIDE) within a diverse rare disease cohort at the Hong Kong Genome Project.
    METHODS: Adult and paediatric patients suspected of genetic disorders were recruited from the Hong Kong Children's Hospital. Clinical geneticists evaluated GS utility based on 17 items. Total C-GUIDE utility scores and global item scores were calculated, with individual item scores ranging from -2 to 2.
    RESULTS: Between March and July 2024, three clinical geneticists completed 247 C-GUIDE ratings for 245 probands, with 25% receiving positive, 7% inconclusive, and 69% negative GS results. Total C-GUIDE scores ranges from -1 to 30, with a mean of 6.1 (SD = 10.0). Multivariate regression analysis indicates that positive GS findings are associated with a 16.9-point increase in C-GUIDE scores compared to inconclusive or negative results (p < 0.001). Notably, the highest mean scores are observed in psychosocial benefits for patients and families, regardless of GS results. The mean global item score, representing overall assessment of clinical utility, is 0.53 (SD = 0.06). Baseline patient characteristics are not independently associated with C-GUIDE scores.
    CONCLUSIONS: This study represents the first and largest of its kind in the Asia Pacific region, highlighting the multidimensional benefits of GS and the importance of nationwide Genome Projects. By highlighting that clinical utility is primarily influenced by test results rather than patient characteristics, this study underscores the importance of equitable GS implementation across populations.
    DOI:  https://doi.org/10.1038/s43856-026-01441-9
  42. Mitochondrion. 2026 Feb 17. pii: S1567-7249(26)00026-7. [Epub ahead of print] 102136
    Phenotypic description and functional characterization of the mitochondrial disease associated with the SFXN4 gene.
    Sarah Courtois, Chloé Angelini, Juliette Preud'homme, Mégane Le Quang, Elodie Dumon, Stéphanie Dulucq, Nathalie Aladjidi, Caroline Kannengiesser, Pascal Barat, Sophie Naudion, Caroline Espil, Marie-Laure Martin-Negrier, Aurélien Trimouille.
      Sideroflexin 4 (SFXN4) is a transmembrane protein located in the inner membrane of the mitochondria. SFXN4 is also thought to be involved in the formation of iron-sulphur centres. Deleterious bi-allelic variants of the SFXN4 gene have been reported in only 3 patients, with a phenotype including intellectual disability and macrocytic anaemia. We describe here a patient carrying pathogenic variants of SFXN4, associated with a non-anaemic sideroblastic macrocytosis and a complex I deficiency.
    Keywords:  Macrocytosis; Mitochondrial disease; SFXN4
    DOI:  https://doi.org/10.1016/j.mito.2026.102136
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