bims-polgdi Biomed News
on POLG disease
Issue of 2026–09–06
63 papers selected by
Luca Bolliger, lxBio
  1. AI-augmented evidence as the next core competence in rare disease drug development: From snapshots to 360-degree movies.
  2. Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.
  3. Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
  4. How AI Is Speeding Up the Diagnostic Odyssey for Rare Diseases.
  5. Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
  6. Analysis of mtDNA Methylation.
  7. Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
  8. Mitochondria transfer research from cellular mechanisms to immune-inflammatory and translational frontiers: a bibliometric analysis from 2006 to 2026.
  9. Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.
  10. Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
  11. Exercise-Induced Intercellular Mitochondrial Transfer: Redox Signaling as a Candidate Regulatory Mechanism.
  12. Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.
  13. From consent to participatory governance: The need for multi-stakeholder alignment in iPSC-based drug repurposing.
  14. Reprogramming Autoimmune Immunity via Mitochondrial Quality Control: Mechanisms, Biomarkers, and Windows for Intervention.
  15. Identification of 2,4-dihydroxy-azaflavanone as an allosteric activator of SIRT1 and its potential role in cellular models of Parkinson's disease.
  16. Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study.
  17. Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
  18. Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.
  19. Mitochondrial Lipids in Cellular Adaptation.
  20. Gut microbiota-mitochondria-barrier-multiorgan axis: a network-based hypothesis for systemic injury.
  21. Understanding extracellular vesicles in antiaging.
  22. Phenotypic overlap masking MELAS in Turner syndrome: a diagnostic challenge.
  23. Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L Syndrome.
  24. Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
  25. Mitochondrial reprogramming of neutrophil extracellular traps in chronic obstructive pulmonary disease and asthma: toward a phenotype-driven therapeutic framework.
  26. "Tissue-Specific Mitochondrial Dysfunction in Keratoconus: An Integrated Structural, Genomic, and Functional Analysis".
  27. Rare disease benchmarks: Investment professionals' accuracy and beliefs.
  28. Facebook as a Lifeboat: An Interview Study Exploring the Role of Facebook in Supporting Parents of Children with Rare Diseases.
  29. Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases.
  30. Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
  31. Genetic testing practices across European epilepsy centers: An ERN EpiCARE survey.
  32. Algebraic Representation of Mitochondrial Dynamics.
  33. Form and function of actin impacts actin health and aging.
  34. An adult case of acute encephalopathy associated with general anaesthesia and the m.11232T > C MT-ND4 variant.
  35. Analysis of Relative Telomere Length and mtDNA Content in Individual Oocytes and Embryos by Quantitative Real-Time PCR (qPCR).
  36. Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.
  37. Mitophagy and Cellular Homeostasis in Kidney Diseases: Mechanisms and Potential Therapeutics.
  38. [Mitochondrial metabolism and the NADPH-cholesterol axis in hematopoietic stem cell fate determination].
  39. Mitochondrial molecular diversity in the brain.
  40. Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
  41. Experiences and Information Needs of Families of Children With Organic Acid or Fatty Acid Metabolism Disorders in Japan.
  42. Horizontal mitochondrial transfer: an emerging field in cell biology.
  43. A Call for Pediatric Magnetic Resonance Spectroscopy Harmonization in Neurometabolic Disorders with a Simple Approach for Diagnosis, Treatment Monitoring and Data Aggregation for Clinical Trials.
  44. Visual Detection and Stratification of Pathogenic mtDNA SNV Heteroplasmy by Balancing FnCas12a Signal Output and Allelic Discrimination.
  45. The Immunometabolic Architecture of Sepsis: Bridging Cellular Bioenergetics and Systemic Immune Dysregulation.
  46. [Interdisciplinary Research on Artificial Intelligence and Longevity Medicine: Global Landscape, Collaboration Networks, and Frontier Trends (2010-2025)].
  47. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  48. Septic Cardiomyopathy and Mitochondrial Quality Control.
  49. Immunosuppression in children with primary mitochondrial diseases after kidney transplantation: insight from case series of RMND1-related disease.
  50. Feto-Maternal Microchimerism and the Brain: Mechanisms, Neurological Implications, and Translational Perspectives.
  51. Pronuclear Transfer and Maternal Spindle Transfer in the Mouse.
  52. Characterization of mitochondria in trophoblast cells derived from control and early-onset preeclamptic pregnancies via induced pluripotent stem cells.
  53. Hypertensive mt. tRNAIle4263A>G mutation orchestrates vascular senescence and apoptosis by activation of mitochondria-ER interplay.
  54. Decision-Making in IVF: Restrictions on PGT-M Positive Embryo Transfers-A Qualitative Study.
  55. Phenotypic and transcriptomic characterization of biallelic RNU2-2 developmental and epileptic encephalopathy.
  56. T-rex: standardized analysis of germline variants in whole-exome sequencing trios.
  57. The Team Science Readiness Framework for scientific research collaboration.
  58. Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.
  59. Fluorescent Nanodiamond-Based Delivery Systems for Mitochondrial Targeting of Bioactive Peptides.
  60. Inborn Errors of Immunity and Hematopoietic Cell Transplantation: Recognition and Pretransplant Management.
  61. Artificial intelligence-assisted reinterpretation of preclinical progeria research suggests a hierarchical nuclear-vascular resilience framework with translational implications.
  62. ADSC-derived mitochondrial nanovesicles transplantation alleviates capsular fibrosis and inflammation and improves joint mobility in a rat model of adhesive capsulitis.
  63. Long-Term Follow-Up for Newborn Screening: A Roadmap and Guide With Programmatic Considerations.
  1. Drug Discov Today. 2026 Sep 03. pii: S1359-6446(26)00200-X. [Epub ahead of print] 104795
    AI-augmented evidence as the next core competence in rare disease drug development: From snapshots to 360-degree movies.
    Ning Lu.
      Rare disease drug development generates fragmented evidence that often fails health technology assessment (HTA) standards. This article sets out a 'snapshots to 360-degree movies' framework: Reconstructing a disease course from patients each seen once, through autoencoders, data-driven disease staging and optimal transport. Each component has been demonstrated elsewhere-ordering in rare neurodegenerative disease, the others outside rare disease-but not yet together at patient-population scale; the article states the conditions under which it would fail. The binding constraint is not regulatory: Regulators are increasingly receptive, but HTA bodies remain the bottleneck, and the European Union's Joint Clinical Assessment has put comparative evidence on the critical path-for most rare diseases, precisely what is missing. Building that capability may become a competitive advantage.
    Keywords:  artificial intelligence; digital twins; drug development strategy; evidence generation; health technology assessment; natural history models; rare diseases; real-world evidence; regulatory science; synthetic control arms
    DOI:  https://doi.org/10.1016/j.drudis.2026.104795
  2. J Vis Exp. 2026 Sep 03.
    Protocol for Duplex Sequencing of Mitochondrial DNA in Single Human Oocytes.
    Teresa Kloimboeck, Thomas Ebner, Kateryna Makova, Barbara Arbeithuber.
      Oocytes are densely packed with mitochondria, the energy-producing organelles that contain their own genome, mitochondrial DNA (mtDNA). Each cell contains multiple copies of mtDNA, with copy number varying among tissue types. Oocytes possess the highest mtDNA copy number, containing hundreds of thousands of mtDNA molecules per cell. Because mitochondria are inherited exclusively through the maternal lineage, accurate detection of mtDNA variants is essential for studies of inheritance, aging, and disease. The presence of multiple mtDNA copies allows wild-type and mutant molecules to coexist within the same cell, a condition known as heteroplasmy, in which low-frequency and de novo variants may occur at frequencies below 1%. Conventional next-generation sequencing (NGS) lacks sufficient accuracy to reliably distinguish these rare variants from errors introduced during library preparation and sequencing. Here, we present a protocol for enriching mtDNA from single human oocytes using Exonuclease V to remove linear DNA, followed by duplex sequencing library preparation for highly accurate mtDNA analysis. This workflow enables error-corrected sequencing of individual oocytes, facilitating reliable detection of low-frequency mtDNA variants and analysis of heteroplasmy and de novo mutagenesis. The protocol provides a reproducible approach for investigating mitochondrial genome variation in single oocytes using Illumina-compatible sequencing platforms.
    DOI:  https://doi.org/10.3791/73071
  3. Psychophysiology. 2026 Sep;63(9): e70383
    Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
    Darshana Kapri, Gabriel Sturm, Catherine Kelly, Ke Bo, Cynthia C Liu, Tor D Wager, Michio Hirano, Caroline Trumpff, Martin Picard.
      Time perception-the subjective sense of how quickly or consistently time passes-shows striking variability across individuals, yet its physiological basis remains poorly understood. We hypothesized that internal clock speed and trial-to-trial variability in time perception would be linked to physiological and behavioral states. In a cohort of healthy adults (n = 59) and individuals carrying rare mitochondrial DNA mutations affecting mitochondrial energy transformation (n = 36), we explored the associations between time perception (time estimation and production) with measures of immune mitochondrial bioenergetics, blood catecholamines, working memory, and structural and functional neuroimaging. We found weak evidence suggesting that internal clock speed and time perception variability correlated with age and physiological metrics including resting energy expenditure, serum and urine norepinephrine levels, mood and fatigue, working memory performance, and neuroimaging measures of brain structure and function. Individuals with mitochondrial disorders and those with healthy mitochondria exhibited no main difference in time perception. However, they exhibited differential relations with physiological and neural variables, suggesting that mitochondria may moderate how specific processes influence time perception. These results provide a foundation for future studies to examine how cellular bioenergetics relate to time perception in humans.
    Keywords:  mitochondrial disease; norepinephrine; resting energy expenditure; time perception
    DOI:  https://doi.org/10.1111/psyp.70383
  4. J Med Internet Res. 2026 Aug 27. 28 e109380
    How AI Is Speeding Up the Diagnostic Odyssey for Rare Diseases.
    Simon Spichak.
       Unlabelled: The road to diagnosis can be long and sometimes unending for rare diseases, requiring training and resources that many clinics do not have. In this News and Perspectives article, JMIR Correspondent Simon Spichak reports on how AI initiatives at a children's hospital in the United States and one in Canada are helping bridge that gap and could fundamentally reshape the diagnostic experience for children and families living with rare diseases.
    Keywords:  artificial intelligence; child; computerized medical records systems; differential diagnosis; genomics; machine learning; pediatric hospitals; rare diseases
    DOI:  https://doi.org/10.2196/109380
  5. J Inherit Metab Dis. 2026 Sep;49(5): e70247
    Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
    Lea Isermann, Aleksandra Trifunovic.
      Mitochondrial CLPP has emerged as an unusual therapeutic target because both increasing and decreasing its proteolytic activity can be beneficial, depending on the cellular and disease context. Pharmacological CLPP hyperactivation drives broad degradation of mitochondrial proteins and can selectively collapse mitochondrial fitness in susceptible tumor cells, an approach now clinically validated by the approval of dordaviprone for mutant diffuse midline glioma. Conversely, reduced CLPP activity can preserve respiratory-chain components and promote adaptive metabolic and redox remodelling in selected models of mitochondrial disease, neurodegeneration and metabolic dysfunction, with emerging potential in ischaemia-reperfusion injury. These opposing outcomes reflect the broader role of CLPXP in controlling mitochondrial translation, respiratory-chain integrity and metabolism rather than acting simply as a general protein quality-control system. In this review, we discuss the physiological functions and substrate selectivity of CLPXP, the mechanistic basis and clinical development of CLPP inhibitors and activators, and the growing evidence that therapeutic responses depend strongly on tissue identity, metabolic state and the nature of the underlying mitochondrial defect. Together, these findings position CLPP as a context-dependent therapeutic switch whose activity may need to be tuned in opposite directions to either preserve mitochondrial resilience or selectively dismantle mitochondrial fitness.
    DOI:  https://doi.org/10.1002/jimd.70247
  6. Methods Mol Biol. 2026 ;3038 295-307
    Analysis of mtDNA Methylation.
    Camila Bruna de Lima, Marc-André Sirard.
      Whole-genome methyl sequencing facilitates the characterization of DNA methylation profiles within a reference genome. Recent identification of mitochondrial DNA (mtDNA) as an additional regulatory pathway within embryos paves the way for examining the impact of assisted reproductive technologies and other environmental factors on gamete and embryo developmental programming. Here, we describe the protocol for preparing libraries tailored to detect cytosine methylation in mtDNA extracted from minimal input, typical of experiments involving reproductive samples such as oocytes and embryos.
    Keywords:  Cytosine methylation; Epigenetics; Mitochondria; mtDNA
    DOI:  https://doi.org/10.1007/978-1-0716-5292-3_17
  7. Sci Adv. 2026 Sep 04. 12(36): eaec8606
    Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
    Kristina Bubb, Giovanni Rigoni, Polyxeni Papadea, Gianluigi Pironti, Jelena Misic, Shan Jiang, David Alsina, Diana Rubalcava-Gracia, Daniel C Andersson, Roberta Filograna, Camilla Koolmeister, Patrick Giavalisco, Anna Wredenberg, Matthias Mann, Florian A Rosenberger, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8606
  8. Front Immunol. 2026 ;17 1898280
    Mitochondria transfer research from cellular mechanisms to immune-inflammatory and translational frontiers: a bibliometric analysis from 2006 to 2026.
    Peiwei Su, Wanyu Luo, Chao Zhu, Xudong Zhufu, Xianyi Zhang, Haoxin Wu, Rui Xu, Haijun Zhao.
       Background: Mitochondria transfer is an emerging mechanism of intercellular communication involved in mitochondrial homeostasis, metabolic remodeling, immune regulation, inflammatory responses, tumor progression, and mitochondrial transplantation-based therapy. However, the global research landscape and immune-inflammatory frontiers remain unclear.
    Methods: Publications on mitochondria transfer published between 1 January 2006 and 8 April 2026, were retrieved from the Web of Science Core Collection and Scopus. After deduplication and manual screening, 851 English-language articles and reviews were analyzed using bibliometrix, CiteSpace, VOSviewer, and Pajek.
    Results: The 851 publications included 566 articles and 285 reviews. They received 38,879 citations and an average of 45.69 citations per publication. Annual output increased markedly after 2018 and peaked in 2025. China and the USA were the leading contributors. Journal, co-citation, and keyword analyses showed that mitochondria transfer research has expanded from mitochondrial biology, stem cell-mediated repair, and cellular metabolism toward immune regulation, inflammation, tumor microenvironment remodeling, biomaterials, and translational medicine. Major knowledge bases and emerging hotspots included tunneling nanotubes, extracellular vesicles, mitochondrial transplantation, mitochondrial quality control, metabolic homeostasis, macrophages, T cells, B cells, immune evasion, macrophage polarization, and cGAS/STING-related mechanisms.
    Conclusion: Mitochondria transfer has developed into an interdisciplinary field connecting cellular mechanisms, immune-inflammatory regulation, disease microenvironment remodeling, and translational therapy. Future studies should clarify its molecular regulation and context-dependent consequences, particularly in immune cells, inflammatory diseases, tumor immune evasion, and mitochondrial transplantation-based interventions.
    Keywords:  immune regulation; inflammation; metabolic homeostasis; mitochondria transfer; mitochondria transplantation; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fimmu.2026.1898280
  9. Neurol Ther. 2026 Aug 31.
    Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.
    Shang Ma, Sushan Luo, Huahua Zhong.
      Neuromuscular diseases (NMDs) encompass over 800 distinct entities affecting approximately one in 1000 individuals worldwide, with progressive muscle weakness, atrophy, and motor impairment as primary clinical manifestations. The rarity of most NMDs creates fundamental challenges for artificial intelligence (AI) and machine learning (ML) applications that typically require large-scale datasets. In this narrative review we synthesize the literature published between 2018 and 2025 on AI applications across the NMD spectrum, organized by clinical application domain. We examine how AI has advanced diagnostic capabilities through genetic variant interpretation, muscle magnetic resonance imaging analysis, electromyography-based classification, and computational pathology. In disease monitoring and prognosis, wearable-derived digital biomarkers have achieved regulatory qualification (US Food and Drug Administration [FDA] and European Medicines Agency [EMA]) as clinical trial endpoints for Duchenne muscular dystrophy, while AI-driven survival models for amyotrophic lateral sclerosis (ALS) have been validated across 14 European centers. Proteomic and multi-omics analyses using ML have identified diagnostic panels for ALS. However, most reported models were developed and internally validated on single-center datasets, and few have undergone external or prospective validation or clinical implementation. Despite these achievements, research intensity varies dramatically across NMD subtypes, with ALS and Duchenne muscular dystrophy dominating while myotonic dystrophy, congenital myopathies, and metabolic myopathies remain virtually unexplored. Critical gaps persist in computational pathology, multi-center validation, and clinical translation. In this review, we discuss how federated learning, international collaborative networks (TREAT-NMD, Solve-RD, EURO-NMD), and foundation models can address these challenges, and propose directions for future AI-enhanced clinical studies in this data-scarce field.
    Keywords:  Artificial intelligence; Clinical decision support; Digital biomarkers; Federated learning; Machine learning; Neuromuscular diseases; Rare diseases
    DOI:  https://doi.org/10.1007/s40120-026-01017-8
  10. Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00380-0. [Epub ahead of print]97 104381
    Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
    Tanvi Chaudhary, Sharath Mohan Bhat, Priyadarshika Pradhan, Manjunath B Joshi, Devanjan Sinha.
      Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
    DOI:  https://doi.org/10.1016/j.redox.2026.104381
  11. Free Radic Biol Med. 2026 Sep 04. pii: S0891-5849(26)01137-8. [Epub ahead of print]
    Exercise-Induced Intercellular Mitochondrial Transfer: Redox Signaling as a Candidate Regulatory Mechanism.
    Mei Ma, Jinze Tian, Zhe Wang, Ziyi Zhang, Yong Zhang, Hai Bo.
      Intercellular mitochondrial transfer has been recognized as an important mechanism for maintaining tissue homeostasis and adapting to stress. Mitochondria can cross cellular boundaries through tunneling nanotubes, extracellular vesicles, and free mitochondrial release. However, the physiological signals coordinating these pathways remain poorly defined. Exercise is a potent inducer of transient redox signaling, generating superoxide and hydrogen peroxide while modulating mitochondrial dynamic remodeling. This review integrates exercise redox biology with redox regulation of transfer machinery characterized in non-exercise models, proposing that exercise-induced redox signaling may function as a candidate regulatory mechanism. The framework emphasizes bidirectional redox coordination, in which oxidant pulses may activate export in donor cells and prepare recipient cells for uptake and antioxidant defense. Exercise-induced mitochondrial transfer has been directly demonstrated in the brain, while observations in skeletal muscle, adipose tissue, and heart remain suggestive but have not been confirmed in exercise models. These findings support a framework in which intercellular mitochondrial transfer contributes to metabolic signaling, antioxidant defense, and distributed quality control across organs. This model represents a working hypothesis requiring direct experimental validation through lineage tracing, tissue-specific mitochondrial reporters, and intravital imaging.
    Keywords:  exercise; mitochondrial biogenesis; mitochondrial quality control; mitochondrial transfer; redox signaling; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.003
  12. Ann Hum Genet. 2026 Aug 30.
    Decoding the Genetic and Phenotypic Spectrum of MT-TI Mitochondrial Diseases.
    Enchi Yuan, Ning Zhang, Haoyu He, Tao Zhang, Enze Chen, Qidi Zhang, Dongmei Ji.
       BACKGROUND: Variants in the MT-TI gene, which encodes mitochondrial transfer RNA for isoleucine, have been associated with neuromuscular, cardiac, auditory, renal, and metabolic disorders, but their clinical interpretation remains difficult.
    OBJECTIVE: To integrate clinical, familial, heteroplasmy, and functional evidence across the reported MT-TI variant spectrum and clarify its implications for variant interpretation and diagnosis.
    METHODS: We conducted a narrative review of reported MT-TI variants, with detailed comparison of seven representative variants and synthesis of phenotypic, familial, tissue-specific heteroplasmy, and functional findings.
    RESULTS: Evidence was derived mainly from case reports and small pedigrees. Heteroplasmy differed markedly among blood, skeletal muscle, and myocardium, indicating that blood may not represent variant loads in energy-demanding tissues. Reported values generally reflected the lowest observed levels in affected individuals or family-specific boundaries rather than validated pathogenic cutoffs. Functional findings support a staged mechanism involving disturbed transfer RNA processing, structure, stability, or aminoacylation, followed by impaired mitochondrial protein synthesis and respiratory-chain dysfunction. Integrated mechanistic support was limited to a few variants, including m.4295A>G; evidence for most variants remained incomplete or indirect.
    CONCLUSION: Diagnosis requires tissue-informed heteroplasmy assessment integrated with phenotype, maternal family history, and functional evidence. Current treatment is supportive, and proposed reproductive and molecular strategies lack MT-TI-specific clinical-trial evidence.
    Keywords:  Ile; RNA; heteroplasmy; mitochondrial; mitochondrial diseases; oxidative phosphorylation; transfer
    DOI:  https://doi.org/10.1111/ahg.70056
  13. Stem Cell Reports. 2026 Sep 03. pii: S2213-6711(26)00273-0. [Epub ahead of print] 103062
    From consent to participatory governance: The need for multi-stakeholder alignment in iPSC-based drug repurposing.
    SIMPATHIC Consortium
      Induced pluripotent stem cells (iPSCs) are increasingly used as disease models to accelerate drug repurposing, especially for rare diseases. While ethical and regulatory issues in iPSC research have been widely discussed, little is known about how these challenges are addressed in practice. To provide insights into the current practice, challenges, and opportunities in the governance of research on iPSC-based drug repurposing for rare neurological disorders, semi-structured interviews were conducted with various experts from eight countries in the context of the SIMPATHIC project. The results indicate that this research context requires improved information provision for minors and individuals with cognitive impairment and more clarity regarding commercial use and reporting of findings. Uncertainty in governance procedures hinders collaboration, validation, and clinical translation in iPSC-based drug repurposing. Responsible (re)use of iPSCs requires dynamic, transparent, and participatory governance structures based on shared decision-making with all stakeholders involved.
    Keywords:  drug repurposing; governance; iPSC; multi-stakeholder; neurological; participatory; patient engagement; rare disease
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103062
  14. Int Immunopharmacol. 2026 Sep 01. pii: S1567-5769(26)01163-X. [Epub ahead of print]188 117316
    Reprogramming Autoimmune Immunity via Mitochondrial Quality Control: Mechanisms, Biomarkers, and Windows for Intervention.
    Xiao Chen, Jie Ding, Liu-Qing Meng, Shu-Fang Li, Yong Chen, Xin Wei, Wei-Rong Hu, Ke Wang, Feng Yao, Ying-Jie Zhao, Wei Hu, Ren-Peng Zhou.
       SIGNIFICANCE: In the case of heterogeneous autoimmune diseases (AIDs), the efficacy of single-pathway immunosuppression is limited, the toxicity is substantial, and the problem of cell type-specific metabolic vulnerability cannot be addressed.
    MECHANISM: New evidence highlights mitochondrial quality control (MQC) as an important regulatory axis of the immune set point. MQC is a coordinated network involving mitochondrial biogenesis, dynamics, mitophagy, proteostasis, protein import machinery, and selective removal of damaged mitochondrial components, including mitochondria-derived vesicles. Dysregulation across these interconnected MQC modules may contribute to key pathological events: impaired biogenesis compromises the metabolic fitness of regulatory T cells; an altered fission-fusion balance can influence macrophage inflammatory polarization; and defective mitophagy may increase the accumulation or release of immunostimulatory mitochondrial components, including mitochondrial DNA (mtDNA), triggering cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING)-driven type I interferon (IFN-I) amplification and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome hyperactivation. In parallel, impaired mitochondrial proteostasis, defective mitochondrial protein import machinery, dysregulated mitochondrial unfolded protein response (UPRmt) signaling, and altered Mitochondrial-derived vesicle (MDV)-mediated cargo disposal may further shape mitochondrial stress and immune-cell function.
    INNOVATION: We propose a conceptual shift from blanket immunosuppression to potential precision metabolic-immune reprogramming. This framework proposes that accessible MQC-related readouts, including transcription factor A (TFAM), Dynamin-related protein1 (Drp1) phosphorylation patterns, and Microtubule-associated protein 1A/1B-light chain 3 (LC3), may help inform treatment timing and therapeutic windows in future translational studies.
    FUTURE DIRECTIONS: To advance potential medicine in AIDs, prospective clinical studies should evaluate whether MQC-related biomarkers can identify treatment-responsive subgroups. For example, future studies should assess whether disease-stage and cell-specific modulation of mitophagy or mitochondrial dynamics improves treatment responses in rheumatoid arthritis (RA) patients stratified according to synovial Translocase of Outer Mitochondrial Membrane 7 (TOMM7) expression and metabolic state. These studies should test whether fission inhibition, restoration of regulated fission, or normalization of dysregulated fusion is beneficial in specific patient subgroups.
    Keywords:  Autoimmune diseases; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2026.117316
  15. Methods Enzymol. 2026 ;pii: S0076-6879(26)00199-0. [Epub ahead of print]734 121-149
    Identification of 2,4-dihydroxy-azaflavanone as an allosteric activator of SIRT1 and its potential role in cellular models of Parkinson's disease.
    Chitrakshi Pant, Vidya Jyothi Alli, Genji Sukumar, Abhijit Mohapatra, Surender Singh Jadav, Srihari Pabbaraja, Shasi V Kalivendi.
      Mitochondrial dysfunction is one of the significant aspects of Parkinson's disease (PD) pathophysiology, marked by a gradual decline in oxidative phosphorylation, an abnormal increase in free radical species, dysfunctional mitochondrial quality control, and faulty mitochondrial biogenesis. Sirtuin 1 (SIRT1), a NAD+-dependent class-III deacetylase, acts as a crucial metabolic sensor that orchestrates transcriptional programs related to mitochondrial biogenesis, respiratory chain assembly, and stress resilience, mainly by way of deacetylation and activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). While screening for the small molecule activators, we have identified that 2,4-dihydroxy-Azaflavanone allosterically activates SIRT1. This chapter outlines a detailed, multi-layered methodological framework for assessing the allosteric activation of SIRT1 by 2,4-dihydroxy-azaflavanone and its downstream effects in a cellular models of PD. The validation process involves synthesis of small molecules, molecular docking studies utilizing crystallographic SIRT1 coordinates (PDB: 5BTR), in vitro fluorometric deacetylase assays with recombinant enzyme, and cellular thermal shift assays (CETSA) to confirm direct, isoform-selective target engagement. The activation of downstream pathways is evaluated by immunoblotting and quantitative PCR for PGC-1α, TFAM, and quantification of mitochondrial DNA (mtDNA) copy number. Functional restoration of mitochondria in cells is analyzed by assessing the overall mitochondrial bioenergetics parameters using Seahorse extracellular flux analyzer. Overall, this integrated approach offers robust, reproducible results for exploring SIRT1-activators in the mechanisms mediating neurodegenerative disease models.
    Keywords:  Azaflavanone; CETSA; Mitochondrial biogenesis; Mitochondrial membrane potential; MtDNA copy number; PGC-1α; Parkinson’s disease; SIRT1; Seahorse assay
    DOI:  https://doi.org/10.1016/bs.mie.2026.06.011
  16. EBioMedicine. 2026 Sep 01. pii: S2352-3964(26)00342-7. [Epub ahead of print]131 106458
    Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study.
    GENOMIT study group
       BACKGROUND: Diabetes mellitus is a common but incompletely characterised manifestation of mitochondrial diseases (MD). Data on risk factors, clinical course, and treatment recommendations are lacking.
    METHODS: In this multinational cohort study, we analysed longitudinal data of patients with a genetically confirmed MD from the GENOMIT registry included at German, Austrian, and Italian sites between 07/2009-01/2025. Our objectives were to (1) expand the genetic spectrum of mitochondrial diabetes mellitus (mDM), (2) identify risk factors, (3) delineate the clinical course, and (4) characterise real-world use of antidiabetic therapies.
    FINDINGS: Of 2399 patients, 1225 (51%) were female, and 281 (12%; 172 female) had mDM. Diabetes occurred across 31 genotypes and exhibited marked genotype dependence, with the highest prevalence in m.3243A>G carriers (177/360 [49%]). Only the m.3243A>G variant was associated with a significantly increased risk of mDM (HR = 10.3; 95% CI 5.2-20.4, p < 0.0001), whereas single mtDNA deletions, multiple mtDNA deletions, and primary LHON variants, as well as sex, BMI, ethnicity, smoking, hypertension and dyslipidaemia did not show a significant association. Median diabetes onset in patients with the m.3243A>G variant was at 47.7 years (SD 45.2-52.0). Among patients with mDM, 140/281 (50%) used insulin, and 111/281 (40%) received non-insulin antidiabetic drugs, most commonly metformin, which was discontinued in 8/50 users. Literature review revealed neurological events temporally linked to metformin application in m.3243A>G carriers, though long-term use without adverse events was likewise reported.
    INTERPRETATION: mDM is frequent in patients with MD, and the individual risk is strongly genotype dependent. While caution is warranted, our data do not justify universal avoidance of metformin; prospective, genotype-informed studies are needed to guide management.
    FUNDING: German Ministry of Research, Technology and Space; Italian Ministry of Health; European Union.
    Keywords:  Diabetes mellitus; Metformin; Mitochondrial diabetes; Mitochondrial disease; m.3243A>G
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106458
  17. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123
    Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
    Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.
      Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.
    Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell
    DOI:  https://doi.org/10.1073/pnas.2531151123
  18. Exp Gerontol. 2026 Sep 02. pii: S0531-5565(26)00282-2. [Epub ahead of print]224 113303
    Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.
    Margaret-Jade Searles, Debanjali Dasgupta, Trace A Christensen, Gary C Sieck, Matthew J Fogarty.
      Declining aerodigestive neuromotor function is a major aspect of human aging, with impaired airway defense and swallow manoeuvres implicated in pneumonia and dysphagia. Hypoglossal motor neurons (MNs) innervate tongue muscles, essential for these behaviours. Their degeneration contributes to age-related aerodigestive dysfunctions. In neurodegenerative diseases, the ubiquitin-proteasome system (UPS) is altered, disturbing mitochondrial proteostasis. We have previously shown reduced mitochondrial abundance, dysfunction and mitochondrial fragmentation in aging hypoglossal MN somas and dendrites. However, the relationship between the UPS (pUBS65 and ubiquitinated proteins), mitochondrial fragmentation (pDRP1S616) and fusion promoting proteins (MFN2) in MN aging is unexplored. In other neurons, aging changes mitochondria within axons in an opposite way to somas and dendrites. We used Western blotting to show impairment in mitophagy-related pUBS65, increased fragmentation-promoting pDRP1S616 and unchanged MFN2. Serial Block-Face Scanning Electron Microscopy showed increased mitochondrial volume density and larger, more simplistic mitochondria in old, myelinated hypoglossal axons, while somas and dendrites showed reduced mitochondrial volume density and increased fragmentation. Our results suggest that a more nuanced compartment-specific evaluation of mitochondrial structure and function is required to fully elucidate the pathophysiology underlying age-related neuromotor dysfunction.
    Keywords:  Aging; Axon; Brainstem; Dendrite; Hypoglossal; Mitochondria; Motor neuron; Proteostasis
    DOI:  https://doi.org/10.1016/j.exger.2026.113303
  19. ACS Chem Biol. 2026 Aug 26.
    Mitochondrial Lipids in Cellular Adaptation.
    Mária Balážová, Lili Jiang, Cunqi Ye.
      Mitochondria serve as central hubs of cellular bioenergetics and signaling, yet the dynamic role of their lipid composition in cellular adaptation remains underappreciated. Unlike most organelles, mitochondria possess a unique dual-bilayer membrane architecture shaped by lipid transport and de novo synthesis. The mitochondrial lipidome, dominated by phosphatidylcholine, phosphatidylethanolamine, and the signature phospholipid cardiolipin, influences cristae organization, oxidative phosphorylation capacity, and metabolite transport, collectively determining whether mitochondria undergo stabilization, remodeling, or degradation. In this review, we explore how mitochondrial lipid dynamics sustain organelle-wide homeostasis while coordinating cellular adaptation across multiple temporal scales and how failure of lipid homeostasis drives rare monogenic disorders and complex pathologies. We propose that environmental shifts transiently disrupt the balance between phospholipid biosynthesis and utilization, generating changes in mitochondrial lipid homeostasis that promote cellular adaptation through complementary biophysical and biochemical signaling mechanisms. Specifically, membrane lipid remodeling rapidly alters membrane biophysical properties to regulate membrane protein activity, whereas bioactive phospholipid intermediates and side-products support long-term adaptive reprogramming. Mitochondrial lipids therefore function not merely as passive structural components but as active regulatory nodes that drive cellular plasticity, positioning lipid dynamics at the nexus of metabolic adaptation and human disease.
    DOI:  https://doi.org/10.1021/acschembio.6c00615
  20. Front Immunol. 2026 ;17 1885379
    Gut microbiota-mitochondria-barrier-multiorgan axis: a network-based hypothesis for systemic injury.
    Yachao Li, Huaijue Qiu, Xiang Gao, Yanling Zhang, Qin Xia.
      Intestinal barrier failure is considered a driver of multiple organ dysfunction syndrome (MODS) in critical illness; however, the precise molecular mechanisms linking altered gut microbes to systemic injury remain unclear. Here we propose a testable hypothesis: mitochondrial dysfunction within intestinal epithelial cells (IECs) acts as a mechanistic hub connecting microbial dysbiosis to barrier breakdown and eventual multiorgan damage. This system is not a unidirectional chain but a highly network-based process with bidirectional feedback loops, context-dependent interactions, and hypothetical cross-talk that require experimental validation. We review evidence that microbial metabolites-short-chain fatty acids, hydrogen sulfide, secondary bile acids-directly modulate mitochondrial respiration, membrane potential, and reactive oxygen species (ROS) production in the gut lining. Once mitochondrial quality control falters, the cell suffers adenosine triphosphate (ATP) depletion, excessive ROS, calcium-driven calpain activation, and leakage of mitochondrial damage-associated molecular patterns (mtDAMPs) like mitochondrial DNA (mtDNA) into the cytoplasm. These mtDAMPs ignite the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and the NLR family pyrin domain containing 3 (NLRP3) inflammasome, disrupting tight junctions and converting the intestinal barrier into an active inflammatory broadcaster. Critically, the inflammatory response is amplified by immune intermediary layers, including neutrophil extracellular trap (NET) formation, monocyte/macrophage metabolic reprogramming, endothelial activation, and complement activation, which bridge local barrier disruption to systemic organ injury. When mtDAMPs reach the circulation, they trigger sterile inflammation in distant organs through shared innate immune sensors (Toll-like receptor 9 [TLR9] and NLRP3) in liver, lung, and brain. A word of caution: circulating mtDNA originates from multiple tissues (e.g., immune cells, skeletal muscle, liver) and therefore represents a systemic DAMP, not a gut-specific signal; its interpretation requires contextual information on tissue origin and temporal dynamics. Human evidence still lacks clear answers on temporal order, directionality, epigenetic mediation, and quantitative thresholds. We discuss how circulating metabolites and mtDNA could serve as candidate monitoring biomarkers to turn this conceptual network into a testable, quantitative model. Finally, we outline a multi-dimensional research framework (metabolite replenishment, mitophagy enhancement, epigenetic tuning) while stressing that any clinical application must await prospective validation. For now, the "microbiota-mitochondria-barrier-multiorgan" axis should be seen as a well-grounded hypothesis, not an established fact.
    Keywords:  gut microbiota; intestinal barrier; mitochondrial damps; mitochondrial dysfunction; multiple organ dysfunction syndrome; systemic inflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1885379
  21. Periodontol 2000. 2026 Aug 31.
    Understanding extracellular vesicles in antiaging.
    Paras Ahmad, Nathan E Estrin, Anton Sculean, Richard J Miron.
       BACKGROUND: Aging is a multifactorial process marked by gradual cellular dysregulation, regulated by hallmarks, including genomic instability, mitochondrial dysregulation, and chronic inflammation. Extracellular vesicles (EVs), especially exosomes, have emerged as pivotal mediators of cell-to-cell communication with potential roles in both enhancing and alleviating aging. This review aimed to synthesize existing literature on the mechanistic and therapeutic role of EVs in aging and age-associated disorders.
    METHODS: A comprehensive narrative review was performed utilizing Web of Science, Scopus, and PubMed databases. Studies assessing EVs in aging, cellular senescence, regenerative biology, and age-related disorders were included. Both preclinical and clinical studies were qualitatively examined, emphasizing EV origin, molecular pathways, and treatment outcomes.
    RESULTS: EVs derived from young or stem cells show strong antiaging features across multiple systems, such as the immune, musculoskeletal, cardiovascular, and nervous systems. These impacts are regulated via mitigating cellular senescence, reestablishing mitochondrial activity, restoring mitophagic and autophagic signaling, regulating inflammatory signaling, and improving tissue regeneration. Contrarily, EVs from diseases or aged cells improve pro-aging phenotypes, such as inflammation, fibrosis, and metabolic dysregulation, underscoring their context-mediated duality. Preclinical evidence consistently supports EV-mediated therapies; nonetheless, clinical translation remains restricted owing to heterogeneity in EV subpopulations, lack of standardized isolation protocols, and variability in bioactive payload.
    CONCLUSION: EVs represent promising therapeutic agents and biomarkers in aging biology, with the potential to regulate multiple hallmarks of aging concurrently. Prospective research should prioritize standardization, targeted bioengineering, and rigorous clinical validation to allow successful antiaging interventions.
    Keywords:  biomarkers; cellular senescence; neurodegenerative diseases; regenerative medicine; stem cells
    DOI:  https://doi.org/10.1111/prd.70070
  22. Eur Heart J Case Rep. 2026 Sep;10(9): ytag578
    Phenotypic overlap masking MELAS in Turner syndrome: a diagnostic challenge.
    Tomoya Shinozaki, Hironobu Sumiyoshi, Daisuke Ueshima, Joe Onaka, Kazue Tajima.
       Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystemic disorder that can present with diverse clinical features, including cardiomyopathy and chronic intestinal pseudo-obstruction. However, diagnosing MELAS can be challenging when its manifestations overlap with other genetic syndromes, leading to diagnostic anchoring and potential mismanagement.
    Case summary: A 51-year-old woman with mosaic Turner syndrome presented with concentric left ventricular hypertrophy and mildly reduced systolic function (left ventricular ejection fraction 45%). Her medical history included childhood-onset hearing loss, hypothyroidism, and recurrent intestinal obstruction of unknown etiology, which had been previously attributed to Turner syndrome or its comorbidities. Despite resolution of bowel symptoms during prior hospitalizations, she exhibited persistent hyperlactataemia (4.55 mmol/L), a diagnostic red flag. Cardiac magnetic resonance imaging showed patchy mid-wall late gadolinium enhancement, suggesting a non-ischaemic process. Family history revealed a maternal pattern of cardiomyopathy and stroke-like episodes. Genetic analysis confirmed the m.3243A > G mitochondrial DNA mutation (heteroplasmy 23%), establishing a diagnosis of MELAS. Earlier recognition of mitochondrial dysfunction might have avoided a previous unnecessary laparotomy performed for suspected intestinal ischaemia.
    Discussion: This case illustrates the clinical challenge of phenotypic masking; features of Turner syndrome masked the underlying MELAS, resulting in a significant diagnostic delay. The coexistence of unexplained cardiomyopathy, recurrent pseudo-obstruction, and persistent hyperlactataemia should prompt consideration of mitochondrial disease, even in patients with an established genetic diagnosis. Clinicians must remain vigilant for multisystemic 'red flags' to avoid diagnostic anchoring and ensure appropriate metabolic and genetic evaluation.
    Keywords:  Cardiomyopathy; Case report; Chronic intestinal pseudo-obstruction; Hyperlactataemia; Left ventricular hypertrophy; MELAS; Mitochondrial disease; Turner syndrome
    DOI:  https://doi.org/10.1093/ehjcr/ytag578
  23. HGG Adv. 2026 Sep 04. pii: S2666-2477(26)00110-7. [Epub ahead of print] 100670
    Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L Syndrome.
    Alicia N Campbell, Kendall N Jung, Steven J Doyle, Ekaterina Lebayle, Barbara Corneo, Joanna Feng, Christopher L Ricupero, Jennifer M Bain, Randy Strich.
      The Mediator Kinase Module (MKM) coordinates transcriptional programs regulating cellular metabolism, stress responses, and differentiation. Heterozygous variants of MED13L, a core MKM component, cause a neurodevelopmental disorder characterized by variable intellectual disability, developmental delay, hypotonia and motor impairment, and congenital anomalies. However, the molecular basis underlying this clinical heterogeneity is poorly defined. Previously, we identified mitochondrial dysfunction and aberrant nuclear release of another MKM component, cyclin C (CCNC), in a single fibroblast line derived from an individual with MED13L syndrome. Here, we expand these studies across 12 fibroblast lines derived from individuals with 11 distinct MED13L variants. We identify mitochondrial dysfunction as a consistent feature of MED13L variation, characterized by reduced mitochondrial ATP production, decreased mitochondrial DNA abundance, elevated reactive oxygen species, and impaired transcription of genes involved in mitochondrial biogenesis. In parallel, all variant lines exhibit aberrant cytoplasmic CCNC localization, consistent with its established role in mitochondrial fission. Longitudinal analyses further reveal progressive declines in mitochondrial function along with markers associated with premature cellular aging. Importantly, the severity of mitochondrial dysfunction shows an association with variant position within MED13L and with clinical functional measures, suggesting that mutation location may partially predict disease severity. Together, these findings establish mitochondrial dysfunction as a consistent cellular feature of MED13L heterozygosity and identify CCNC mis-localization as a candidate biomarker of MKM disruption. More broadly, this work reveals an intersection between transcriptional control and mitochondrial homeostasis in MED13L syndrome, forming the framework for biomarker-driven therapeutic development in MED13L-associated and related neurodevelopmental disorders.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100670
  24. J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):
    Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
    Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.
      Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
    DOI:  https://doi.org/10.1172/JCI199847
  25. Front Immunol. 2026 ;17 1920684
    Mitochondrial reprogramming of neutrophil extracellular traps in chronic obstructive pulmonary disease and asthma: toward a phenotype-driven therapeutic framework.
    Pei Xu, Fen Xia.
      Chronic obstructive pulmonary disease (COPD), severe asthma, and asthma-COPD overlap (ACO) represent a major global burden of chronic airway inflammation, often remaining inadequately controlled by current corticosteroid and biologic therapies. Neutrophil extracellular traps (NETs) have emerged as a shared effector mechanism in these phenotypes, with neutrophil mitochondria acting as the upstream switch for sustained NET release and corticosteroid resistance. This review consolidates evidence that mitochondrial reprogramming of NETosis operates through four interlinked facets: mitochondrial reactive oxygen species (mtROS) production, the mitochondrial permeability transition pore, mitochondrial DNA release (mtDNA-DAMP), and PINK1/Parkin-PGC-1α-controlled mitophagy. These mechanisms drive a downstream spectrum including suicidal NETosis, vital mtDNA-NETosis, and gasdermin-mediated discharge. Disease-specific drivers (e.g., Nrf2-SLC7A11-GPX4 in COPD; IL-33/TSLP in asthma) reweight this common axis, resulting in distinct effector repertoires and steroid-response profiles. Therapeutically, the landscape is asymmetric: whilst NET-dissolution agents and type-2 biologics are approved, they address distal nodes. Conversely, mitochondrial-targeted antioxidants and metabolic regulators target the convergent root but remain in early development. We argue that translating this framework requires phenotype-enriched trials randomizing molecularly selected patients, coordinated bedside biomarker panels, and explicit inclusion of the ACO subgroup. A coherent framework, a set of candidate targets, and an explicit stratification logic are now defined, and the pivotal preclinical and early-phase clinical data needed to deliver such a programme are the necessary next step.
    Keywords:  chronic airway inflammation; corticosteroid resistance; mitochondrial reprogramming; neutrophil extracellular traps (NETs); phenotype-enriched trials
    DOI:  https://doi.org/10.3389/fimmu.2026.1920684
  26. Ocul Surf. 2026 Sep 01. pii: S1542-0124(26)00116-3. [Epub ahead of print]
    "Tissue-Specific Mitochondrial Dysfunction in Keratoconus: An Integrated Structural, Genomic, and Functional Analysis".
    Shivam Sharma, Lata Singh, Mithalesh Kumar Singh, Tapas Chandra Nag, Seema Kashyap, Anu Malik, Namrata Sharma.
       PURPOSE: Keratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning, conical protrusion, and irregular astigmatism, leading to visual impairment. Although oxidative stress is implicated in KC, the role of mitochondrial dysfunction remains unclear. We evaluated mitochondrial structural, genomic, and functional abnormalities in corneal tissues and blood from KC patients.
    METHODS: This prospective study enrolled 110 KC patients and 55 controls. Transmission electron microscopy (TEM) and immunohistochemistry (IHC) were performed on epithelial and stromal tissues from 10 KC and 5 control corneas assessing mitochondrial morphology, oxidative phosphorylation (OXPHOS) complexes and pro-apoptotic protein NOXA. Whole mitochondrial DNA (mtDNA) sequencing and relative mtDNA copy number analysis were performed on paired blood and corneal tissues from 50 KC patients and 35 controls including both epithelial and stromal samples. Gene expression of mitochondrial biogenesis and oxidative stress-related genes was analysed by qRT-PCR in corneal epithelium from independent 50 KC patients and 15 controls.
    RESULTS: TEM revealed cristolysis, membrane disruption, and reduced mitochondrial density in KC corneas. IHC showed reduced expression of OXPHOS complexes and increased NOXA expression (p<0.05). Sequencing identified 1,107 mtDNA variants, with more variants in corneal tissues than matched blood (929 vs. 576; p=0.0002). Recurrent likely pathogenic variants were enriched in complex I-encoding genes (ND4, ND5). KC corneas showed reduced mtDNA copy number, downregulated POLRMT, upregulated NOX4, and significant downregulation of multiple antioxidant genes (p<0.0001).
    CONCLUSION: KC patients exhibit tissue-specific mitochondrial abnormalities and impaired oxidative stress regulation, supporting a role for mitochondrial dysfunction in disease pathogenesis and highlighting potential therapeutic targets.
    Keywords:  Corneal pathology; Keratoconus; Mitochondrial DNA variants; Mitochondrial biogenesis; Mitochondrial dysfunction; Oxidative stress; Relative Copy number variation
    DOI:  https://doi.org/10.1016/j.jtos.2026.08.008
  27. Drug Discov Today. 2026 Aug 31. pii: S1359-6446(26)00197-2. [Epub ahead of print] 104792
    Rare disease benchmarks: Investment professionals' accuracy and beliefs.
    Jonathan Ilicki, Alexander J Spicer.
      Rare-disease assets account for a substantial and growing share of biopharmaceutical development and dealmaking, and published analyses provide benchmarks for their clinical, commercial and financial performance. Whether investment and business-development practitioners hold beliefs consistent with these benchmarks is largely unexamined. We surveyed 43 professionals across venture capital, pharmaceutical and biotechnology business development, asking them to estimate benchmarks for approval probability, acquisition timing, exit economics, time to peak sales and launch performance, and compared their responses with the published literature. Respondents were generally well calibrated on some structural characteristics visible through deal flow, such as the dominant modality for rare-disease assets, but systematically miscalibrated on specific magnitudes. Launch performance was the most underestimated, with 84% placing it below published levels, and most respondents underestimating how late acquisitions of rare-disease assets occur. Estimate accuracy was not associated with years of experience. These findings suggest a wide gap between published evidence and practitioner belief, which might lead some rare-disease assets to be assessed more conservatively than historical performance would justify.
    Keywords:  Rare diseases; business development; investment decision-making; orphan drugs; venture capital
    DOI:  https://doi.org/10.1016/j.drudis.2026.104792
  28. J Health Commun. 2026 Sep 03. 1-13
    Facebook as a Lifeboat: An Interview Study Exploring the Role of Facebook in Supporting Parents of Children with Rare Diseases.
    B Victor, N G Yilmaz, C Hoving, M Hillen, A J Linn.
      Parents of children with rare diseases face unique challenges due to scarce medical expertise and limited information sources. Social media, particularly Facebook, have become a vital (and sometimes the only) space for parents to access information, share experiences, and find emotional support. This study examined how parents of children with an ultra-rare genetic condition [FOXP1] engage with a Facebook group. Semi-structured interviews were conducted with 19 parents across eight countries and analyzed using thematic analysis. Based on the results, we developed the "Phased Social Media Engagement in Rare Disease Caregiving" model. The model illustrates how informational, emotional, and psychological needs may vary across the caregiving journey and under different circumstances. This model delineates three phases of engagement: (1) Frantic, characterized by intensive information seeking and urgent reassurance seeking commonly described around the time of diagnosis; (2) Selective and Saturated, in which parents, having surpassed an information threshold, used Facebook more strategically for targeted problem-solving and advocacy, while consciously avoiding distressing content; and (3) Mentoring, in which some parents guided and reassured newly diagnosed families, deriving meaning and identity through supporting others. Results highlight both the benefits and risks of online peer support groups, underscoring the need for healthcare providers to acknowledge these groups and help parents navigate information overload and emotional triggers.
    Keywords:  Facebook; caregivers; qualitative research; rare diseases; social support
    DOI:  https://doi.org/10.1080/10810730.2026.2723703
  29. Mol Genet Metab. 2026 Aug 27. pii: S1096-7192(26)00530-5. [Epub ahead of print]149(1-2): 110247
    Prescribing patterns of vitamin and cofactor therapies in genetically confirmed primary mitochondrial diseases.
    Merve Setenay Akyüzlüer Güneş, Merve Koç Yekedüz, Engin Köse, İlknur Sürücü Kara, Fatma Tuba Eminoğlu.
       BACKGROUND: Primary mitochondrial diseases (PMDs) comprise a genetically and clinically heterogeneous group of disorders for which evidence-based therapeutic options remain limited. Despite advances in molecular diagnosis and the identification of gene-specific therapeutic targets for selected conditions, vitamin and cofactor supplementation continues to be frequently prescribed. We aimed to evaluate prescribing patterns, dosing practices and the balance between PMDs with established genotype-directed metabolic therapy and PMDs managed with empirical supplementation in a genetically confirmed PMD cohort.
    MATERIALS AND METHODS: We retrospectively reviewed 62 patients with genetically confirmed PMDs followed at a tertiary pediatric metabolism center between 2015 and 2025. Demographic, genetic and treatment-related data were collected, including vitamin and cofactor use and dosing regimens. Patients were categorized as PMDs with genotype-directed therapies and PMDs managed with empirical supplementation.
    RESULTS: Sixty-two patients were included (43.5% female; mean age 10.7 years). Oxidative phosphorylation (OXPHOS) complex defects were the most common genetic category (35.5%). Overall, 71% of patients received at least one vitamin or cofactor supplement. Coenzyme Q10 (62.9%), carnitine (53.2%), riboflavin (48.4%), biotin (37.1%) and thiamine (35.5%) were the most frequently prescribed agents. Thirteen patients (21%) had PMDs with established targeted therapies and received genotype-directed treatment. Among the remaining 49 patients, who lacked a defined genotype-directed therapeutic option and were therefore classified as being managed with empirical supplementation, 63.2% (31/49) received at least one vitamin or cofactor supplement.
    CONCLUSION: Despite advances in molecular diagnosis, empirical vitamin and cofactor supplementation remains frequently used in patients with PMDs who lack established gene- or pathway-specific therapeutic options. These findings underscore the persistent gap between molecular diagnosis and evidence-based therapy and support the need for prospective multicenter studies to guide standardized treatment approaches in PMDs.
    Keywords:  Biotin; Carnitine; Coenzyme Q10; Primary mitochondrial disease; Riboflavin; Thiamine
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110247
  30. Pharmacol Res. 2026 Aug 31. pii: S1043-6618(26)00343-9. [Epub ahead of print]232 108428
    Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
    Ester Zito, György Hajnóczky.
      Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease pathogenesis. Here, we examine the molecular mechanisms that govern adaptive and maladaptive UPR signaling and discuss how these ER-centered responses impinge on mitochondrial and cellular physiology. We analyze three major drivers of coupling mitochondrial function to UPR signaling: (i) enhanced ERMCs, (ii) IP3R-mediated Ca²⁺ transfer from the ER to mitochondria, and (iii) bidirectional ROS/H₂O₂ exchange between the two organelles. We also discuss unresolved questions in the field and technological advances, including approaches to investigate ERO1-dependent redox nanodomains, ERO1 inhibitors and engineered ERMC linkers, that are advancing our understanding of ER-mitochondria crosstalk and revealing potential therapeutic opportunities. These insights may inform precision medicine strategies for diseases driven by chronic ER stress and mitochondrial dysfunction.
    Keywords:  CHOP; Ca²⁺ handling; ER stress; ERO1; ER–mitochondria contact sites (ERMCs); IP₃ receptor (IP₃R); Mitochondrial permeability transition pore (mPTP); Pharmacological therapy; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.phrs.2026.108428
  31. Epilepsia Open. 2026 Sep 02.
    Genetic testing practices across European epilepsy centers: An ERN EpiCARE survey.
    Sébile Tchaicha, Johanna Van Hulle, Eva Brilstra, Andreas Brunklaus, Gaetano Cantalupo, Martin Geroldinger, Amy McTague, Reetta Kälviäinen, Eulalia Turón-Viñas, Alexis Arzimanoglou, Rikke S Møller, Rima Nabbout.
       OBJECTIVE: Genetic testing plays an increasing role in the diagnostic pathway for rare and complex epilepsies. However, significant heterogeneity persists in access, implementation, and interpretation across Europe. This study aimed to assess genetic testing practices, accessibility, and challenges across expert epilepsy centers within the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE) and to identify key challenges and areas for harmonization.
    METHODS: A cross-sectional survey was developed by the ERN EpiCARE Clinical Genetics Working Group and distributed to 50 EpiCARE member centers across 27 European countries. The questionnaire collected quantitative and qualitative information on available genetic testing modalities, turnaround times, use of rapid testing, multidisciplinary team (MDT) organization, genetic counseling practices, and perceived challenges. Survey findings were complemented by a structured discussion held during the ERN EpiCARE General Assembly.
    RESULTS: Responses were received from 46 centers (51 responses). Most centers reported access to genetic testing, predominantly through in-house facilities. Whole-exome sequencing was available in 85% of centers, and gene panels were available in 78%. Whole-genome sequencing was available in 59% of centers, frequently restricted to research or performed externally. Turnaround times for standard genetic testing were most commonly between 1 and 6 months. Genetic testing strategies varied by epilepsy subtype, with gene panels most frequently used as first-tier testing, and exome sequencing preferentially applied in developmental and epileptic encephalopathies. Considerable heterogeneity was observed in MDT organization, access to genetic counseling, reimbursement, data-sharing and registry infrastructures.
    SIGNIFICANCE: Although genetic testing is widely available across ERN EpiCARE centers, substantial disparities persist in its organization, accessibility, and implementation. Addressing these gaps through strengthened multidisciplinary collaboration, harmonized diagnostic strategies, and enhanced European-level coordination will be essential to ensure equitable access to high-quality genetic care for individuals with epilepsy.
    PLAIN LANGUAGE SUMMARY: Genetic testing is increasingly integrated in the diagnostic pathway for rare and complex epilepsies and treatment decisions. An ERN EpiCARE survey assessed how genetic testing is implemented across specialist epilepsy centers in Europe and identified persistent organizational, financial, and clinical barriers. Although most centers had access to advanced genomic testing, important differences were identified in access, reimbursement, turnaround times, and multidisciplinary expertise. European collaboration and harmonized practices are needed to support equitable access to high-quality genetic care for people living with epilepsy.
    Keywords:  European reference networks; epilepsy; genetic testing; harmonization of care; multidisciplinary teams
    DOI:  https://doi.org/10.1002/epi4.70304
  32. Bull Math Biol. 2026 Sep 04. pii: 176. [Epub ahead of print]88(10):
    Algebraic Representation of Mitochondrial Dynamics.
    Raphael Mostov, Greyson Lewis, Gabriel Sturm, Wallace F Marshall.
      This paper addresses the increasing need for comprehensive mathematical descriptions of cell organization by examining the algebraic structure of mitochondrial network dynamics. Mitochondria are cellular structures involved in metabolism that take the form of a network of membrane-based tubes that undergo continuous re-arrangement by a set of morphological processes, including fission and fusion, carried out by protein-based machinery. Because of their network structure, mitochondria can be represented as graphs, and the morphological operations that take place in the cell, referred to as mitochondrial dynamics, can be represented by changes to the graphs. Prior studies have classified mitochondrial graphs based on graph-theoretic features, but an alternative approach is to focus not on the graphs themselves but on the set of morphological operations inducing mitochondrial dynamics, since this may provide a simpler representation. Moreover, the operations are what determine the graphs that will be generated in a biological system. Here we show that mitochondrial dynamics give rise to a category in which the objects are equivalence classes of graphs defined by one of the morphological operations and morphisms are mappings between these equivalence classes defined by the remaining morphological operations. For mitochondria consisting of a single component this gives rise to a particularly simple representation. Using these formalisms we define a distance metric for similarity between mitochondrial structures based on an edit distance, and demonstrate how this representation can be used for visualization and statistical analysis of biological data. In the course of defining these structures we provide a mathematical motivation for new experimental questions regarding mitochondrial fusion, the impacts of cell division on mitochondrial morphology, and the presence of a single giant component in some cell types. This work points to a general strategy for formulating a cell structure state-space, based not on the shapes of cellular structures, but on relations between the dynamic operations that produce them.
    Keywords:  Algebraic graph theory; Budding yeast; Cell representation; Mitochondrial fission; Mitochondrial fusion; Morpholomics; Planar graphs; Spatial statistics
    DOI:  https://doi.org/10.1007/s11538-026-01738-9
  33. iScience. 2026 Sep 18. 29(9): 117256
    Form and function of actin impacts actin health and aging.
    Maxim Averbukh, Hunter T Nelson, Tiffany Wang, Caitlin M Lange, Athena Alcala, Juri Kim, Daniella Suh, Matthew Vega, Shihong Max Gao, Naibedya Dutta, Khristina E Young, Rebecca Aviles Barahona, Aeowynn J Coakley, Joe A Gerke, Sofia F Odron, Jacqueline G Clarke, Navjot Singh, Matthew S Nickel, Jacob C Peterson, Hannah L Lam-Truong, Darius Moaddeli, Toni Castro Torres, Maria Oorloff, Melissa Peruch, Tripti Nair, Hemal H Mehta, Max A Thorwald, Shoichiro Ono, Sean P Curran, Meng C Wang, Bérénice A Benayoun, Cristal M Hill, Tyler A Johnson, Eileen M Crimmins, Thalida Em Arpawong, Caroline Kumsta, Gilberto Garcia, Ryo Higuchi-Sanabria.
      The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs)-arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin)-led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Actin dysfunction also displayed a more "aged" transcriptome using previously validated transcriptomics clocks, and broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting some links between aging and actin across organisms. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how changes in actin integrity correlate with diverse aging phenotypes across tissues. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics can potentially influence aging.
    Keywords:  actin; aging; healthspan; lifespan
    DOI:  https://doi.org/10.1016/j.isci.2026.117256
  34. Rev Esp Anestesiol Reanim (Engl Ed). 2026 Sep 02. pii: S2341-1929(26)00179-4. [Epub ahead of print] 502103
    An adult case of acute encephalopathy associated with general anaesthesia and the m.11232T > C MT-ND4 variant.
    I Arranz Chamorro, P Blanco-Schweizer, E Ruiz Pesini, M Busto Busto, T Ticona Espinoza, J Rodríguez Jiménez.
      We report the case of a 20-year-old woman who developed acute encephalopathy after uneventful general anaesthesia with sevoflurane, propofol, and opioids. The patient presented neurological impairment followed by metabolic acidosis and hyperlactatemia and neuroimaging findings involving the basal ganglia, brainstem, and cerebellum. Genetic testing confirmed the mitochondrial variant m.11232T > C in the MT-ND4 gene, previously described only in paediatric patients. This case could be one of the first cases described in the literature of acute encephalopathy associated with this mutation in an adult patient, possibly precipitated by exposure to volatile anesthetics. The patient's favorable clinical and radiological evolution after intensive neuroprotective management and suboccipital decompressive craniectomy highlights the importance of early diagnosis and individualized treatment. Mitochondrial dysfunction should be considered in atypical neurological presentations following general anesthesia, especially when accompanied by lactic acidosis and unusual neuroimaging findings.
    Keywords:  CHANTER syndrome; Encefalopatía tóxico-metabólica; Enfermedad mitochondrial; Mitochondrial DNA mutation; Mitochondrial disease; Mutación MT-ND4; Mutación del ADN mitochondrial; Perioperative metabolic disorders and lactic acidosis; Sevoflurane; Sevoflurano; Síndrome de CHANTER; Toxic–metabolic encephalopathy; Trastornos metabólicos perioperatorios y acidosis láctica; Variante m.11232T > C; m.11232T > C variant; mtND4 mutation
    DOI:  https://doi.org/10.1016/j.redare.2026.502103
  35. Methods Mol Biol. 2026 ;3038 249-263
    Analysis of Relative Telomere Length and mtDNA Content in Individual Oocytes and Embryos by Quantitative Real-Time PCR (qPCR).
    Yasmyn E Winstanley, Darryl L Russell, Rebecca L Robker.
      Oocytes and embryos are highly susceptible to intrinsic and extrinsic stressors, making assays for biomarkers of embryo quality of high importance. This has been technically challenging due to the very small amounts of material in embryos, leading to the use of assays requiring pooled embryos which mask inter-embryo variability. This protocol details a qPCR assay to analyze relative telomere lengths and mtDNA content in individual oocytes and embryos. Each is singly collected and lysed in a minimal volume, then qPCR is used to independently amplify two nuclear (telomere and Rn18S) and one mitochondrial DNA sequence for quantification of relative telomere length or mtDNA content that is normalized for cell number by the reference gene. This methodology enables robust and precise measurements of these molecular biomarkers in physiological contexts where tissue availability is limited. Importantly, this assay allows detection of the natural variability in mtDNA and telomeric DNA content between individual oocytes and embryos.
    Keywords:  Embryo; Mitochondrial DNA; Mouse; Oocyte; Telomere; qPCR
    DOI:  https://doi.org/10.1007/978-1-0716-5292-3_15
  36. Methods Enzymol. 2026 ;pii: S0076-6879(26)00237-5. [Epub ahead of print]734 29-53
    Experimental approaches for investigating sirtuin-mediated mitochondrial function, cellular metabolism, and epigenetic regulation.
    Karthick Chennakesavan, Thangavel Samikkannu.
      Cellular pathways for experimental discovery provide a comprehensive overview of sirtuin biology and its critical involvement in HIV-associated neurocognitive disorders (HAND) and related neurodegenerative diseases, highlighting the translational potential of sirtuin-targeted therapeutic strategies. As NAD+-dependent deacetylases and ADP-ribosyl transferases, sirtuins regulate diverse cellular processes, including stem cell maintenance, cellular proliferation, metabolic homeostasis, apoptosis, autophagy, oxidative stress responses, and genomic stability, all of which contribute to neuronal dysfunction and disease progression. This chapter focuses on key mammalian sirtuins, including SIRT1 and SIRT2, which are primarily localized within the nucleus and cytosol; mitochondrial sirtuins SIRT3, SIRT4, and SIRT5; and nuclear/nucleolar sirtuins SIRT6 and SIRT7. Here, a method with a detailed protocol to isolate compartment-specific sirtuin expression and activity was used: subcellular fractionation was performed using a subcellular fractionation kit to obtain cytosolic and nuclear fractions, while mitochondrial isolation was carried out using Tom20 antibody-conjugated magnetic microbeads. These approaches were applied to brain tissues from HIV-positive individuals, as well as to HIV-Tat-treated human microglial (HMC3) cells and astrocytes. This experimental framework enables accurate assessment of compartment-resolved sirtuin regulation in disease-relevant models. Collectively, the chapter highlights the protective roles of sirtuins in mitigating key pathogenic mechanisms underlying HAND and related neurodegenerative diseases. These findings support the emerging concept that sirtuins represent promising pharmacological targets for the development of novel therapeutic interventions in neurodegeneration and HIV-associated brain disorders.
    Keywords:  Epigenetics; HIV-associated neurodegenerative disorders; Histone deacetylases; Mitochondria; Sirtuins
    DOI:  https://doi.org/10.1016/bs.mie.2026.06.023
  37. Int J Biol Sci. 2026 ;22(13): 7332-7348
    Mitophagy and Cellular Homeostasis in Kidney Diseases: Mechanisms and Potential Therapeutics.
    Hao Lu, Shenyu Yan, Baoyi Shao, Jianbo Guo, Yifan Wang, Rui Hou, Shen Chen, Meicen Wu, Biao Wei, Fei Li, Xiaoming Meng, Haiyong Chen.
      Mitochondrial homeostasis has attracted increasing interest and is now recognized as playing a significant role in both kidney development and the progression of kidney disease. Among these, the latest approach, mitophagy, has been shown to be activated dynamically and reversibly under various physiological conditions, including reactive oxygen stress, nutrient deficiency, and cellular senescence, to maintain mitochondrial homeostasis and function. Moreover, findings indicate that mitophagy can also maintain mitochondrial quality through interactions and mutual regulation with mitochondrial dynamics. Crucially, a growing number of kidney diseases, such as acute kidney injury, diabetic kidney disease, and other chronic kidney diseases, are linked to abnormal levels of mitophagy. In this review, we comprehensively examined the vital role of mitophagy in kidney diseases, discussed the potential of mitophagy-targeted therapies, and described the detailed alterations in specific mitophagy-related proteins associated with kidney diseases.
    Keywords:  kidney disease; mitochondrial quality control; mitophagy; targeted therapy
    DOI:  https://doi.org/10.7150/ijbs.138435
  38. Rinsho Ketsueki. 2026 ;67(8): 945-949
    [Mitochondrial metabolism and the NADPH-cholesterol axis in hematopoietic stem cell fate determination].
    Kyoko Ito, Claudia Morganti, Haruhito Totani, Federica Zanotti, Ayşegül Erdem, Keisuke Ito.
      Mitochondrial metabolism actively and precisely contributes to hematopoietic stem cell (HSC) fate determination by ensuring proper segregation of mitochondria and by modulating fatty acid oxidation (FAO) activity and mitochondrial NADPH during asymmetric (or symmetric) cell division. Elevated NADPH levels in HSCs promote anabolic processes, notably cholesterol biosynthesis, redirecting acetyl-CoA away from the TCA cycle toward cholesterol production, which in turn supports multiple downstream biosynthetic pathways essential for HSC maintenance. The NADPH-cholesterol axis facilitates the biogenesis of extracellular vesicles (EVs) to sustain HSC properties. EVs from diverse cell types can influence HSC survival and clonogenic potential, contributing to the maintenance of HSC capacity, including autocrine and paracrine signaling that further reinforces intrinsic regulatory circuits. Targeting the mechanisms that regulate the fate of HSCs remains a central aim of ongoing research in HSC-based therapies, including ex vivo expansion, genetic editing strategies, and the treatment of hematological malignancies, with the potential to enhance transplantation outcomes and patient recovery.
    Keywords:  Cholesterol; Extracellular vesicles; Hematopoietic stem cell; Mitochondria
    DOI:  https://doi.org/10.11406/rinketsu.67.945
  39. Curr Opin Neurobiol. 2026 Sep 03. pii: S0959-4388(26)00106-6. [Epub ahead of print]101 103270
    Mitochondrial molecular diversity in the brain.
    Alva G Sainz, Xinnan Wang.
      Mitochondria are not uniform organelles. Across the brain, they exhibit profound molecular, biochemical, and functional diversity shaped by cell type, anatomical region, subcellular compartment, and lived experience. Recent advances in cell-type- and subcellular domain-targeted proteomics, transcriptomics, advanced live imaging, and functional biochemistry have begun to map this landscape with unprecedented resolution. Together, these findings challenge the conventional view of mitochondria as generic metabolic engines and position mitochondrial molecular diversity as a fundamental feature of brain organization, with direct relevance to behavior, aging, and neurological disease. This mini review synthesizes key recent studies in this field, highlighting their findings, methodological novelty, and significance, and formulates theories and hypotheses for future investigations.
    DOI:  https://doi.org/10.1016/j.conb.2026.103270
  40. Sci Adv. 2026 Sep 04. 12(36): eaef8132
    Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
    Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel.
      Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef8132
  41. J Genet Couns. 2026 Oct;35(5): e70281
    Experiences and Information Needs of Families of Children With Organic Acid or Fatty Acid Metabolism Disorders in Japan.
    Mikiko Kaneko, Kana Harada, Chisen Takeuchi, Hiroshi Kawame.
      Families of children with inherited metabolic disorders face a variety of medical, developmental, educational, and psychosocial challenges. However, little is known about how these families manage such issues within the Japanese healthcare and social support systems. This study explored the experiences and information needs of families of children with organic acid and fatty acid metabolism disorders. A cross-sectional questionnaire survey was conducted in Japan in June 2022 among 183 families of children with organic acid and fatty acid metabolism disorders recruited through a patient organization. Thirty-eight families responded to the survey. The questionnaire addressed the medical history, developmental concerns, support services, education, and psychosocial experiences. Most children (95%) were diagnosed within the first year of life. Two-thirds of the parents (66%) reported developmental concerns involving behavior, learning, or emotional regulation. Although many children attended regular schools, some required special needs education, and parents reported difficulties related to dietary management and school admission. Qualitative analysis of open-ended responses identified 10 categories describing parental experiences, including gratitude toward healthcare professionals, the need for information and support systems, and reflections on living with a chronic condition. Families of children with organic acid and fatty acid metabolism disorders face complex medical, educational, and psychosocial challenges. These findings highlight the importance of coordinated information sharing, multidisciplinary collaboration, and family-centered support to improve the quality of life of both children and their families.
    Keywords:  genetic counseling; metabolic disorders; natural history; parental experience; rare diseases
    DOI:  https://doi.org/10.1002/jgc4.70281
  42. Trends Cell Biol. 2026 Sep 04. pii: S0962-8924(26)00168-6. [Epub ahead of print]
    Horizontal mitochondrial transfer: an emerging field in cell biology.
    Michael V Berridge, Zuzana Nahacka, Katerina Komrskova, Minghao Zheng, Jiri Neuzil.
      The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.012
  43. AJNR Am J Neuroradiol. 2026 Sep 01. pii: ajnr.A9618. [Epub ahead of print]
    A Call for Pediatric Magnetic Resonance Spectroscopy Harmonization in Neurometabolic Disorders with a Simple Approach for Diagnosis, Treatment Monitoring and Data Aggregation for Clinical Trials.
    Kim M Cecil, Pierre Gilles Henry, Heidi Wallis, Audrey Thurm, Timothy P L Roberts.
       BACKGROUND: There is a pressing demand to implement a standard acquisition and post-processing approach for proton magnetic resonance spectroscopy performed in children within the clinical setting. Clinical magnetic resonance spectroscopy data is needed to characterize and understand phenotypes and track treatment response, especially in rare genetic disorders with distinct metabolite signatures. For instance, infants and children with cerebral creatine deficiency syndromes are too often misdiagnosed, which leads to delay in life-changing supplementation especially for those with synthesis deficiencies. Quantitative information about brain creatine concentrations is useful in characterizing these syndromes, potentially tracking relevant biomarkers in relation to treatment response, and guiding future clinical trial designs for patients.
    METHODS: Spectroscopists began discussions about the usage of magnetic resonance spectroscopy in late 2024 with the leadership of the Association for Creatine Deficiencies (ACD). The ACD is a charitable organization established by parents of children with creatine deficiencies to provide patient, family, and public education, to advocate for early intervention through newborn screening, and to promote and fund medical research for treatments and cures for Cerebral Creatine Deficiency Syndromes. The ACD hosts a patient registry where families complete surveys and upload medical reports. Upon review of radiologist reports, the group noted the variability in acquisition, post-processing and interpretation across patient studies and clinical imaging sites. A team of spectroscopists reviewed the literature, identified common parameters across vendors and developed a harmonized approach that can serve as a starting point for imaging sites adopting magnetic resonance spectroscopy or a supplement to those already using it.
    KEY MESSAGE: This paper is a call for the usage and provides a recommendation of a minimum standard single voxel proton magnetic resonance spectroscopy approach that can be implemented for rapidly evaluating pediatric patients with neurodevelopmental delays consistent with genetic etiologies.
    DOI:  https://doi.org/10.3174/ajnr.A9618
  44. Anal Chem. 2026 Aug 25. 98(33): 24507-24520
    Visual Detection and Stratification of Pathogenic mtDNA SNV Heteroplasmy by Balancing FnCas12a Signal Output and Allelic Discrimination.
    ShaoYu Yang, Yu Shen, Zhikang Zhang, LeYao Liu, Yizhen Han, Xiangyu Chen, HongYu Bao, Dongmei Ji, Pai Peng, Yi Du.
      Assessment of pathogenic mitochondrial DNA (mtDNA) single-nucleotide variant (SNV) heteroplasmy is important for molecular diagnostics, yet rapid visual profiling remains analytically challenging because an assay must combine single-nucleotide allelic discrimination, mutant-fraction-associated readout, and suitable target access. Herein, we report VISTA (visual identification and stratification of targeted mtDNA alleles), a broad-PAM FnCas12a assay that rebalances trans-cleavage signal output and mutant-wild-type discrimination for visual mtDNA SNV heteroplasmy analysis. VISTA uses unmodified FnCas12a with relaxed TTN PAM recognition and integrates crRNA spacer-length engineering with PEG8000/acBSA reaction tuning to improve the practical signal-discrimination balance without nuclease engineering. At the m.3243A>G model locus, spacer truncation enhanced mutant-wild-type discrimination, while molecular-dynamics simulations identified spacer-dependent differences between matched and mismatched complexes at the crRNA-DNA interface. The optimized assay resolved defined synthetic m.3243A>G heteroplasmy gradients by fluorescence imaging and was further adapted to lateral-flow detection. In locus-specific analyses of a deidentified collection of 74 peripheral-blood samples, fluorescence and lateral-flow readouts achieved ROC AUC values above 0.9 for mutant-allele classification after target-region amplification. Fluorescence supported heteroplasmy-associated profiling, whereas lateral flow provided a visual, semiquantitative readout for relative ranking based on the T/C ratio rather than absolute heteroplasmy measurement. VISTA therefore provides an accessible dual-readout analytical strategy for visual detection and heteroplasmy-associated profiling by tuning the FnCas12a signal output and allelic discrimination.
    DOI:  https://doi.org/10.1021/acs.analchem.6c04072
  45. Crit Care Clin. 2026 Oct;pii: S0749-0704(26)00038-2. [Epub ahead of print]42(4): 857-874
    The Immunometabolic Architecture of Sepsis: Bridging Cellular Bioenergetics and Systemic Immune Dysregulation.
    Valentim Rodrigues, Duarte Abecasis, Luis F Moita.
      Sepsis continues to be a leading public health challenge, accounting for almost 20% of annual global deaths. Here, we review the evolving pathophysiological understanding of this syndrome by highlighting the central role of immunometabolism. We move beyond the biphasic model to argue that hyperinflammation and immunosuppression coexist across different biological compartments. Recognition of danger through the signal triad of pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes induces profound intracellular metabolic reprogramming toward a predominantly aerobic glycolysis pattern. This shift supports early effector functions but leads to bioenergetic insufficiency, cytopathic hypoxia, and mitochondrial dysfunction.
    Keywords:  Immunometabolism; MODS; Mitochondrial dysfunction; PICS; Sepsis-3
    DOI:  https://doi.org/10.1016/j.ccc.2026.05.009
  46. Sichuan Da Xue Xue Bao Yi Xue Ban. 2026 Jul 20. 57(4): 966-973
    [Interdisciplinary Research on Artificial Intelligence and Longevity Medicine: Global Landscape, Collaboration Networks, and Frontier Trends (2010-2025)].
    Xinyan Huang, Jianshu Tan, Shuqin Cao, Longkang Di, Lunwei Kang, Zhuoli Zhu, Ga Liao.
       Objective: With the expansion of theories concerning aging and the rapid evolution of artificial intelligence (AI) methodologies, the integration of AI and longevity medicine has emerged as a critical pathway for extending human healthspan. This study is aimed at a systematic characterization of the research landscape, collaboration networks, and frontier trends in this interdisciplinary field, so as to inform clinical translation and the development of the health management industry.
    Methods: The Web of Science Core Collection, including Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI), was used as the data source. English-language publications in the interdisciplinary field of AI and longevity medicine between 2010 and 2025 were systematically retrieved, and 4170 valid records were included for a joint analysis using Bibliometrix and CiteSpace 7.0.
    Results: Annual publication output showed exponential growth. The global research landscape exhibited a China-US dual-core and a multipolar pattern, with institutional collaborations clustering into 3 major networks spanning Asia-Europe, the United States, and Continental Europe. Research topics were clustered into five major themes-the core concepts of aging and multimorbidity, AI-driven body composition and musculoskeletal assessment, deep-learning-based evaluation of brain aging through neuroimaging, wearable sensing and mobile health, and digital phenotyping and mental health. Marked differences in research priorities were observed among the three leading contributors, including China, the United States, and the United Kingdom. China demonstrated broad research coverage and clinically oriented multi-track development, the United States led in methodological innovation and digital phenotyping, and the United Kingdom concentrated on brain age research.
    Conclusions: This study systematically delineates the research landscape, collaboration networks, and frontier trajectories in the interdisciplinary field of AI and longevity medicine, providing data-driven evidence and decision-making support for advancing clinical translation and the development of the health management industry in this field.
    Keywords:  Aging biomarkers; Artificial intelligence; Brain age; CiteSpace; Digital phenotyping; Geroscience; Longevity medicine
    DOI:  https://doi.org/10.12182/20260760501
  47. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  48. Front Biosci (Landmark Ed). 2026 Jul 31. 31(8): 47390
    Septic Cardiomyopathy and Mitochondrial Quality Control.
    Xiangyi Pu, Zhaoqi Yan, Zhiming Liu, Xing Chang, Ruxiu Liu.
      Septic cardiomyopathy (SCM) is a prevalent and serious cardiac complication arising from sepsis-induced multiple organ dysfunction syndrome (MODS). The pathogenesis of SCM is complex and primarily involves immune-inflammatory responses, oxidative stress, programmed cell death, and mitochondrial dysfunction. In recent years, mitochondrial quality control (MQC) has attracted growing interest as a central mechanism for maintaining cellular homeostasis and myocardial energy metabolism in SCM. This review systematically summarizes recent advances in four key MQC mechanisms involved in SCM: (1) phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy; (2) mitochondrial dynamics, including dynamin-related protein 1 (Drp1)/fission protein 1 (FIS1)-driven fission and optic atrophy protein 1 (OPA1)/mitofusin (MFN)-regulated fusion; (3) mitochondrial biogenesis under the regulatory control of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) axis; and (4) the mitochondrial unfolded protein response (UPRmt), which maintains mitochondrial proteostasis through mediators such as C/EBP homologous protein (CHOP), YME1-like protease (YME1L), and Overlapping activity with m-AAA protease 1 (OMA1). These mechanisms have been shown to work synergistically to regulate mitochondrial clearance, renewal, and functional maintenance. Any imbalance among them can exacerbate myocardial injury. This review also emphasizes the redox crosstalk between oxidative stress and immune inflammation, with an emphasis on the pivotal contributions of NADPH oxidase 2 (NOX2), high mobility group box 1 (HMGB1), and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in vascular endothelial dysfunction and cardiac depression. In conclusion, preserving the dynamic equilibrium of MQC is crucial for preventing or reversing SCM and may present novel molecular targets and therapeutic strategies.
    Keywords:  cardiomyopathies; inflammation; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; oxidative stress; sepsis
    DOI:  https://doi.org/10.31083/FBL47390
  49. Pediatr Nephrol. 2026 Sep 04.
    Immunosuppression in children with primary mitochondrial diseases after kidney transplantation: insight from case series of RMND1-related disease.
    Sze Wa Wong, Fred Tomlin, Jelena Stojanovic.
      While successful kidney transplantation has been reported in pediatric patients with primary mitochondrial diseases, immunosuppression regimen and its effect on systemic disease were not described. We present four pediatric patients with genetically confirmed RMND1 disease in a quaternary nephrology center. They presented at a very young age and progressed rapidly to stage 5 chronic kidney disease. All underwent successful kidney transplantation. Their allograft function remained stable throughout the follow-up period, and they did not manifest any major systemic deterioration.
    Keywords:  Immunosuppression; Kidney transplantation; Primary mitochondrial diseases; RMND1 disease
    DOI:  https://doi.org/10.1007/s00467-026-07527-9
  50. Am J Reprod Immunol. 2026 Sep;96(3): e70317
    Feto-Maternal Microchimerism and the Brain: Mechanisms, Neurological Implications, and Translational Perspectives.
    Nosarieme O Abey.
       PROBLEM: Microchimerism in the brain is a common phenomenon, where in cells cross between mother and fetus during pregnancy, and persist for decades. It has been studied primarily within reproductive immunology and transplantation medicine. The relevance of microchimerism to central nervous system biology, neurological disease, and experimental chimeric modelling has received comparatively little systematic attention. This review sought evidence across the biology of feto-maternal microchimerism, its association with neurological disease, and the emerging field of experimental chimeric brain modelling, to extrapolate a cohesive mechanistic framework.
    METHOD: Research articles in reproductive immunology, neurodevelopment, and neurodegeneration were gathered to assess the potential roles of fetal microchimeric cells (FMc) in brain health and disease. By combining natural microchimerism with experimental chimeric models, a framework for understanding how nonself cells influence the maternal brain was extrapolated and critical mechanisms identified. Searches were conducted across PubMed/MEDLINE, Scopus, and Google Scholar using a dual-concept Boolean.
    RESULTS: The literature reviews show that microchimeric cells cross the blood-brain barrier (BBB), adopt neural and glial phenotypes in the maternal brain parenchyma, and exhibit injury-responsive recruitment in preclinical models. Reciprocally, maternal microchimeric cells (MMc) are present in the offspring brain, where they have been found adopting neural and immune-lineage phenotypes in experimental models. These findings raise the possibility that bidirectional microchimerism influences susceptibility to neurological disease, modulates neuroimmune signaling, and contributes to endogenous repair, although causal mechanisms remain unresolved. Experimental chimeric brain models have extended these principles into therapeutic contexts. Establishing the functional mechanism and directionality requires more prospective longitudinal cohort studies and transcriptional profiling at single-cell resolution in microchimeric brain-resident populations.
    Keywords:  BBB; fetal‐cells; feto–maternal; microchimerism; neuroimmunomodulations; neurological disease
    DOI:  https://doi.org/10.1111/aji.70317
  51. Methods Mol Biol. 2026 ;3038 477-493
    Pronuclear Transfer and Maternal Spindle Transfer in the Mouse.
    Ross Stocker, Jeffrey R Mann, John Carroll.
      Maternal Spindle Transfer (MST) and Pronuclear Transfer (PNT) are micromanipulation techniques that allow the transfer of the nuclear material from one oocyte or zygote to the cytoplasm of another. The application of these techniques has provided novel insights into nuclear-cytoplasmic interactions necessary for development, as well as fundamental discoveries such as genomic imprinting. Now, after extensive pre-clinical research, PNT and MST are starting to be used clinically for Mitochondrial Donation (also known as mitochondrial replacement therapy) and for patients with a history of repeated IVF failure. Here, we describe the methods for PNT and MST currently used in the mouse model. The techniques are readily adaptable for application to other mammalian species, including humans.
    Keywords:  Maternal spindle transfer; Mitochondrial disease; Mouse; Oocyte; Pronuclear transfer; Sendai virus; Zygote
    DOI:  https://doi.org/10.1007/978-1-0716-5292-3_25
  52. Biol Reprod. 2026 Aug 29. pii: ioag182. [Epub ahead of print]
    Characterization of mitochondria in trophoblast cells derived from control and early-onset preeclamptic pregnancies via induced pluripotent stem cells.
    Jessica Milano-Foster, Kameron Hahn, Juliann Leak, Grace Meers, Teka Khan, Megan A Sheridan, R Scott Rector, Danny J Schust, Toshihiko Ezashi, R Michael Roberts, Laura C Schulz.
      Early embryonic development occurs in a low oxygen environment, and mitochondrial morphology and function are distinct in embryonic cells and pluripotent stem cells (PSC), which rely less on oxidative phosphorylation than differentiated cells. Oxidative phosphorylation increases with differentiation to trophoblast (TB) and this process is reversed by reprogramming of adult cells to pluripotency, but the influence of oxygen conditions on this process has not been characterized. When PSC were differentiated to trophoblast by treatment with BAP (BMP4, A83-01 and PD173074), cellular ATP concentrations increased equally in 5% and 20% oxygen conditions. Although oxygen conditions in culture altered transcripts encoding mitochondrial proteins, particularly by suppressing COX4l2 at 20% oxygen, there were no consistent differences in mitochondrial morphology in either cytotrophoblast (CTB) or syncytiotrophoblast (STB) cells with changing oxygen. These results suggest that TB adapt to maintain mitochondrial function at high and low oxygen during differentiation. In a previous study, iPSCs were derived from both control and early onset preeclampsia (EOPE) pregnancies and differentiated with BAP; high oxygen conditions impaired TB invasion only in cells from EOPE pregnancies. Here, the increase in ATP concentration with TB differentiation was less robust in EOPE cells, and cytochrome C and ATPase subunit transcripts differed between EOPE and control cells at high oxygen. However, investigation of mitochondrial morphology revealed no excess damage in EOPE-derived lines, and no difference in mitochondrial respiration was detected. Collectively, these data provide limited support for the hypothesis that intrinsic differences in mitochondria underlie poor TB invasion in EOPE.
    Keywords:  early onset preeclampsia; induced pluripotent stem cell; mitochondria; oxidative stress; trophoblast differentiation
    DOI:  https://doi.org/10.1093/biolre/ioag182
  53. Redox Biol. 2026 Aug 20. pii: S2213-2317(26)00359-9. [Epub ahead of print]97 104360
    Hypertensive mt. tRNAIle4263A>G mutation orchestrates vascular senescence and apoptosis by activation of mitochondria-ER interplay.
    Nian Cao, Haijing Zhao, Zhengfeng Wu, Shuanglei Li, Wei Tong, Lihao Jin, Ming Wu, Jie Liu, Aihong Liu, Meng Wang, Changfu Liu, Yuqi Liu, Yundai Chen.
      The pathogenic mechanism underlying diseases caused by mitochondrial DNA (mtDNA) mutation, including hypertension, persists as an unresolved global challenge. Although mutation-induced mitochondrial defects have been well characterized, how these mito-perturbations are converted into critical intermediary signaling cascades and contribute to diseases remain unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived vascular organoids (VOs) and vascular cells, the hypertensive mt. tRNAIle4263A > G mutation was identified to induce vascular senescence, apoptosis and vascular-specific dysfunction through mitochondria-endoplasmic reticulum (ER) interaction. For the first time, this study mapped the transcriptional reprogramming landscape of human VOs carrying this mutation. Through systematic screening and functional validation, ER stress was screened out, together with downstream mitochondria-associated ER membranes-mitochondrial Ca2+ overload resulting in vascular abnormality. Pathological reactive oxygen species (ROS) elevation, driven by tRNAIle destabilization and bioenergetic failure, acts as the primary instigator of maladaptive ER stress activation in this cascade. Pharmacological targeting of this axis-using mito-Tempol (a mitochondria-targeted ROS scavenger), Tauro Ursodeoxycholic Acid (an ER stress inhibitor), or RU265 (a highly-selective mitochondrial calcium uniporter inhibitor)-rescues vascular abnormality. This study highlights mt. tRNAIle4263A > G mutation orchestrates vascular pathology through ROS induced activation of inter-organelle communication, resolving a long-standing knowledge gap between mtDNA mutations and diseases and establishing therapeutic nexuses for mtDNA mutation-related cardiovascular diseases.
    Keywords:  Hypertension; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial Ca(2+) overload; ROS; Vascular organoids; mt.DNA mutation
    DOI:  https://doi.org/10.1016/j.redox.2026.104360
  54. J Genet Couns. 2026 Oct;35(5): e70271
    Decision-Making in IVF: Restrictions on PGT-M Positive Embryo Transfers-A Qualitative Study.
    Elisheva Donath, Deena Dubrow, Allison Boyd, Katie Gallagher, Beth Georges Merin.
      This study employed an exploratory qualitative methodology to examine how IVF clinics in the United States develop and implement policies regarding the transfer of embryos that test positive for genetic conditions through preimplantation genetic testing for monogenic disorders (PGT-M). The study explored who is involved in creating these policies, and the key factors influencing these decisions. Semi-structured interviews were conducted with genetic counselors working in IVF clinics across the United States. Participants were asked about clinic policies regarding PGT-M positive embryos, their role in policy creation, and how patient requests are handled. Transcripts were analyzed thematically to identify patterns in clinic practices, policy rationales, and decision-making processes. Findings showed considerable variation in how clinics approach PGT-M affected embryo transfers. While one clinic follows strict guidelines that prohibit the transfer of embryos with pathogenic variants (including likely pathogenic variants or variants of uncertain significance [VUS]), others allow case-by-case consideration, particularly when patients face barriers to further IVF cycles. Common policy frameworks prioritize transfer of unaffected embryos, with affected embryos considered only after other options are exhausted. Key factors influencing policy decisions included ethical considerations, clinic values, provider discretion, legal and insurance frameworks, and concerns about the child's future quality of life. Despite formal protocols, many clinics still assess individual cases, underscoring the complexity of balancing standardization with patient-centered care. Genetic counselors often serve as intermediaries, advocating for patients while navigating institutional limitations. This study highlights the need for clearer, yet flexible, guidelines on PGT-M positive embryo transfer to ensure consistency while preserving patient autonomy. Greater integration of genetic counselors into policy development and clinical decision-making can support more ethically grounded and informed reproductive care.
    Keywords:  IVF policy; PGT‐M; clinical decision‐making; genetic counseling; patient autonomy; positive embryo transfer
    DOI:  https://doi.org/10.1002/jgc4.70271
  55. Epilepsia. 2026 Sep 01.
    Phenotypic and transcriptomic characterization of biallelic RNU2-2 developmental and epileptic encephalopathy.
    Olivia J Henry, Nadja Pekkola Pacheco, Irene Duba, Magnus Burstedt, Daniel Carlberg, Angelica M Delgado-Vega, Anna Hammarsjö, Sofie Ivarsson, Tord Jonson, Kristina Karrman, Nicole Lesko, Åsa Lindfors, Daniel Nilsson, Mia Olsson Engman, Lucía Peña-Pérez, Erik Stenund, Fulya Taylan, Malin Ueberschär, Samuel Wiafe, Sofia Ygberg, Anna Lindstrand, Anna Wedell, Ann Nordgren, Tommy Stödberg.
       OBJECTIVE: A significant proportion of individuals with suspected genetic developmental and epileptic encephalopathies (DEEs) remain unsolved following whole genome sequencing (WGS). Here we describe biallelic RNU2-2 variants causing a recently reported, severe, recessive DEE.
    METHODS: We screened individuals who have received WGS analyses at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic RNU2-2 variants. Deep phenotyping was performed through reviewing entire medical histories and phenotypic traits were transcribed to their corresponding Human Phenotype Ontology (HPO) term. HPO terms were used to generate pairwise phenotypic similarity scores and assess for significantly shared phenotype enrichment in the RNU2-2 sub-cohort. RNA sequencing analyses were performed in fibroblast and blood tissues to compare splicing events between RNU2-2 individuals and two independent control groups.
    RESULTS: We identified 14 individuals from nine families with 12 ultra-rare biallelic RNU2-2 variants clustering in the conserved 5' domains. Genotype data from 13 of 14 individuals has been reported previously as part of a larger cohort. All individuals presented with a highly concordant, severe DEE, characterized by severe to profound intellectual disability, inability to walk or communicate, hyperkinesia, and refractory seizures. Infantile spasms and tonic seizures were the predominant seizure types and a Lennox-Gastaut syndrome-like phenotype was common. These individuals had a significantly similar phenotypic signature when compared with 703 individuals with complex pediatric epilepsies (two-sided Monte Carlo permutation test, p = .005). RNA sequencing analyses showed aberrant splicing, with the most pronounced effects in fibroblast tissues in mutually exclusive exon and alternate 3' splice-site events, which were not detectable in blood.
    SIGNIFICANCE: We present deep phenotyping data and transcriptomic analyses that provide support for rare, 5' clustering biallelic RNU2-2 variants causing this novel, severe DEE. We propose an RNA sequencing methodology on fibroblast tissue for future validation of RNU2-2 variants.
    Keywords:  autosomal recessive disease; human phenotype ontology; small nuclear RNA genes; spliceosomopathies
    DOI:  https://doi.org/10.1002/epi.70473
  56. Sci Rep. 2026 08 31. pii: 27284. [Epub ahead of print]16(1):
    T-rex: standardized analysis of germline variants in whole-exome sequencing trios.
    Sara-Luisa Reh, Carolin Walter, Judith Lohse, Tabita Ghete, Markus Metzler, Julia Hauer, Franziska Auer.
      Whole-exome sequencing (WES) enables the identification of rare germline variants contributing to pediatric diseases. Trio-based sequencing, comparing affected children with their parents, is particularly effective for rare disease genetics. However, WES data analysis requires bioinformatics expertise, varies across institutions, and is often incompatible with clinical workflows. We developed T-Rex (Trio Rare variant analysis of EXomes), a cross-platform desktop application that enables the standardized and local analysis of WES germline Trio data without the need for programming knowledge. T-Rex integrates state-of-the-art tools for alignment, dual-variant calling (GATK HaplotypeCaller + VarScan2), annotation (SNPEff/SNPSift), rare-variant filtering based on population frequencies (gnomAD), and family-based statistical testing, including the Transmission Disequilibrium Test with multiple-testing correction. Benchmarking of the dual-caller strategy on the Genome in a Bottle Ashkenazim Trio demonstrates high precision (99.2%) while maintaining robust sensitivity (91.1%). User testing (n = 13) confirmed quick learning across clinicians and researchers. Application to a cohort of n = 121 pediatric cancer Trio datasets, filtering for rare protein-coding variants (MAF ≤ 0.1% in gnomAD v4.1), validated all assessable previously reported pathogenic variants. Overall, T-Rex enables clinicians to robustly analyze WES Trio data in compliance with data protection regulations without requiring additional software licenses. As one of the first platforms for comprehensive WES Trio analysis that requires no programming expertise while providing reproducible, end-to-end workflows for clinical genomics, T-Rex facilitates collaborative research between clinics and reduces reliance on external providers.
    Keywords:  Genetic predisposition; Germline variants; Rare disease; Trio-based sequencing; WES analysis platform
    DOI:  https://doi.org/10.1038/s41598-026-67762-w
  57. Front Psychol. 2026 ;17 1792280
    The Team Science Readiness Framework for scientific research collaboration.
    Molly P Kilcullen, Ibrahim Bukhari, Mia Terkowitz, Sarah Stevens, Cyd Lacanienta, Michael Rosen.
       Introduction: Multidisciplinary research teams need a practical structure for assessing and improving their readiness to collaborate effectively. We developed the Team Science Readiness Framework (TSRF) to address this need.
    Methods: Team science considerations were initially identified by team science and healthcare experts, including the authors and affiliated collaborators, and were supplemented through a literature review. The framework was iteratively refined, prioritizing practical relevance, robust empirical support, and actionable factors that could be targeted through feasible interventions for improvement or sustainment.
    Results: The resulting TSRF comprises tangible, evaluable, and actionable considerations for science teams and provides a structure for organizing existing tools and resources. It addresses the research process across three stages: building teams during the early phases of a research project; managing teams while executing the research plan; and sustaining, growing, or gracefully closing teams as individual projects conclude.
    Discussion: By emphasizing actionable and empirically supported constructs, the TSRF offers a practical approach to evaluating multidisciplinary research-team readiness and guiding interventions throughout the team lifecycle.
    Keywords:  framework; readiness; science teams; team science; teamwork
    DOI:  https://doi.org/10.3389/fpsyg.2026.1792280
  58. Immune Netw. 2026 Aug;26(4): e35
    Mitochondrial Metabolic Reprogramming and Skin Immune Homeostasis: From Basic Mechanisms to Therapeutic Perspectives.
    Nan Chen, Xiangping Xie, Shuangyan He, Lifen Liang.
      Mitochondria have long been viewed as the "powerhouses" of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells-glycolysis, oxidative phosphorylation, or fatty acid oxidation-determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the "dual identity" of mitochondria in skin immunity-as both metabolic regulators and signaling sensors-will lay the foundation for developing precise metabolic immunomodulatory therapies.
    Keywords:  Atopic dermatitis; Metabolic reprogramming; Mitochondria; Psoriasis
    DOI:  https://doi.org/10.4110/in.2026.26.e35
  59. ACS Appl Bio Mater. 2026 Aug 25.
    Fluorescent Nanodiamond-Based Delivery Systems for Mitochondrial Targeting of Bioactive Peptides.
    Dorna Akbarzadeh, Juan Carlos Calderón de la Rosa, Charles Fletcher, Arfaan A Rampersaud, Marie-Odile David, François Treussart, Nazanine Modjtahedi, Giorgia Urbinati.
      Mitochondria are recognized as key players affecting hallmarks of oncogenesis, tumor progression, and chemotherapy resistance, positioning this organelle as an important therapeutic target. We previously demonstrated that impairment of the AIF/CHCHD4-dependent protein import pathway disrupts mitochondrial bioenergetics and cell survival, highlighting this protein complex as a promising candidate for therapeutic intervention. Building on this concept, we identified a 27-residue peptide (N27) capable of perturbing the AIF-CHCHD4 interaction. However, its poor cellular uptake and inefficient mitochondrial localization have restricted its applicability. Here, we report on the development of a fluorescent nanodiamond (FND)-based nanosystem functionalized with a mitochondria-targeting peptide to transport and localize N27 at mitochondria. For this purpose, FNDs, as small as 40 nm, were doubly functionalized with polyethylene glycol (PEG) chains of two distinct lengths, providing covalent bonding for the mitochondria-targeting moiety and electrostatic interactions with the bioactive N27 peptide. FNDs were characterized before and after the addition of the peptides, with systematic assessment of the fraction of the bioactive peptide complexed as well as nanocarrier stability. Optimal conditions for copper-free click chemistry have also been defined in order to graft the mitochondria-targeting peptide without compromising the N27 loading or the stability of the nanosystem. Total internal reflection fluorescence and confocal microscopy demonstrated an increased cellular uptake of targeted FNDs. The FNDs colocalized with mitochondria, as well as the therapeutic peptide. This study provides the first description of dual-functionalized FNDs for mitochondria-targeted peptide delivery, establishing their potential as biocompatible and traceable nanoplatforms for subcellular delivery of bioactive peptides.
    Keywords:  AIF/CHCHD4 protein complex; drug vectorization; fluorescent nanodiamonds; inhibitory peptide; mitochondrial targeting
    DOI:  https://doi.org/10.1021/acsabm.5c02455
  60. Pediatr Ann. 2026 Sep;55(9): e341-e349
    Inborn Errors of Immunity and Hematopoietic Cell Transplantation: Recognition and Pretransplant Management.
    Alyssa M Greenwell, Avanti Gupte, Eman T Al-Antary.
      Primary immunodeficiencies, now more broadly termed as "inborn errors of immunity (IEI)," are rare genetic disorders associated with recurrent infections, immune dysregulation, autoimmunity, lymphoproliferation, and malignancy risk. Early recognition and diagnosis are essential to reduce infection-related morbidity, prevent organ damage, and identify children who may benefit from curative therapy. A comprehensive history, physical examination, targeted immune evaluation, and genetic testing can support diagnosis, while early supportive measures may reduce infection risk before definitive therapy. Treatment may include antimicrobial prophylaxis, immunoglobulin replacement, enzyme replacement, immune-modifying agents, gene-based therapies, and allogeneic hematopoietic cell transplantation (HCT), which can be curative for select IEI. However, HCT requires careful pretransplant evaluation, as outcomes are influenced by disease biology, infection burden, organ function, donor availability, graft-versus-host disease risk, and conditioning toxicity. This review focuses on recognition of IEI, initial evaluation, supportive care, and pre-HCT management for pediatricians.
    DOI:  https://doi.org/10.3928/19382359-20260628-02
  61. Int J Biol Sci. 2026 ;22(13): 7349-7357
    Artificial intelligence-assisted reinterpretation of preclinical progeria research suggests a hierarchical nuclear-vascular resilience framework with translational implications.
    Paolo Madeddu, Monica Cattaneo, Annibale Alessandro Puca.
      Preclinical research traditionally advances through hypothesis-driven experimentation that establishes mechanistic pathways to support translational development. While this approach has generated major biological insights, it may underemphasize alternative organizational patterns embedded within complex datasets, particularly in rare diseases where opportunities for experimental reiteration are limited. Recent advances in conversational artificial intelligence (AI) provide an opportunity to support structured analytical dialogue as a complementary approach for re-examining validated experimental observations. Here, we evaluated the feasibility and informative value of an investigator-led structured analytical dialogue to reinterpret a previously published preclinical study of Hutchinson-Gilford Progeria Syndrome (HGPS), a rare disorder characterized by accelerated cardiovascular aging. Investigators defined the analytical questions, established interpretative boundaries, and critically evaluated successive AI-generated outputs, while the AI platform functioned exclusively as an analytical support tool for exploring complementary conceptual organization of experimentally validated findings. The original study showed that delivery of the longevity-associated LAV-BPIFB4 gene preserved left ventricular diastolic function, reduced perivascular fibrosis, increased coronary arteriole density, and attenuated cellular senescence without modifying progerin accumulation. Structured analytical dialogue generated complementary hierarchical interpretations of these observations. By integrating graphical dispersion with individual-level numerical data, the investigator-led dialogue identified heterogeneous response trajectories and suggested that cardiovascular protection may be viewed as emerging from coordinated interactions between nuclear stress adaptation and vascular remodelling within a broader resilience framework. These interpretations are presented as hypothesis-generating conceptual extensions rather than new experimental findings. This study demonstrates the feasibility of structured investigator-led analytical dialogue as a complementary methodological approach for broadening interpretation of existing preclinical datasets while preserving the original experimental evidence. By making analytical reasoning more transparent and explicitly distinguishing validated observations from conceptual reinterpretation, this framework may assist prioritization of future mechanistic investigations, particularly in rare cardiovascular diseases where maximizing insight from existing datasets is especially important.
    Keywords:  Hutchinson-Gilford progeria syndrome; artificial intelligence-assisted reinterpretation; cardiovascular aging; human-AI analytical dialogue; translational medicine
    DOI:  https://doi.org/10.7150/ijbs.133754
  62. J Orthop Translat. 2026 Sep;60 101195
    ADSC-derived mitochondrial nanovesicles transplantation alleviates capsular fibrosis and inflammation and improves joint mobility in a rat model of adhesive capsulitis.
    Yiming Zhu, Zeyu Wang, Ziqi Huo, Dan Zhang, Yang Zhao, Jianhao Xie, Hao Li, Tianyuan Zhao, Pinxue Li, Zhi Wang, Chunyan Jiang, Xu Li.
       Background: Adhesive capsulitis (frozen shoulder) is a prevalent condition characterized by shoulder pain and progressive motion loss. Mitochondrial metabolic dysregulation is an underlying driver of chronic inflammation and fibrosis. This study aimed to characterize mitochondrial metabolic abnormalities in patient capsular tissue and evaluate a therapy using adipose-derived stem cell (ADSC) derived mitochondrial nanovesicles transplantation.
    Methods: Single-cell RNA sequencing was utilized to analyze the expression of nuclear-encoded genes related to mitochondrial metabolism in fibroblast subpopulations from human adhesive capsulitis capsular tissue. ADSC-derived membranes were extruded together with exogenous mitochondria to generate engineered mitochondrial nanovesicles (AD-Mito-NPs). An inflammatory fibroblast model was employed to assess the uptake of AD-Mito-NPs, along with associated transcriptomic and metabolomic changes, and their effects on apoptosis, inflammation, and extracellular matrix (ECM) remodeling. Finally, AD-Mito-NPs were locally injected into a rat model to evaluate joint movement and histopathology.
    Results: AD-Mito-NPs retained intact respiratory function, high fibroblast internalization efficiency, and stable physicochemical properties for up to 7 days. In vitro inflammatory models verified that AD-Mito-NPs reversed IL-1β-triggered mitochondrial injury and strengthened mitochondrial oxidative phosphorylation. Furthermore, AD-Mito-NPs alleviated intracellular reactive oxygen species accumulation and fibroblast apoptosis, mitigated inflammatory responses, and remodeled extracellular matrix homeostasis. In vivo, intra-articular administration of AD-Mito-NPs improved shoulder joint mobility, attenuated capsular thickening and disordered collagen arrangement, and suppressed local inflammation in a rat model of adhesive capsulitis.
    Conclusion: Mitochondrial metabolic imbalance is a factor driving capsular fibrosis in adhesive capsulitis. Engineered mitochondrial transplantation offers therapeutic benefits by enhancing mitochondrial energy production, mitigating oxidative stress and inflammation, and restoring ECM balance.
    The translational potential of this article: This article identifies mitochondrial metabolic dysregulation as a key driver of adhesive capsulitis-related capsular fibrosis and demonstrates that engineered AD-Mito-NPs are a safe platform for clinical translation. These NPs effectively enhance energy metabolism, reduce inflammation, and improve shoulder mobility in models, providing a promising alternative to existing treatments.
    Keywords:  Adhesive capsulitis; Adipose-derived stem cell; Capsular fibrosis; Joint inflammation; Mitochondrial dysfunction; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.jot.2026.101195
  63. Pediatrics. 2026 Sep 01. pii: e2026077357J. [Epub ahead of print]158(Suppl 2):
    Long-Term Follow-Up for Newborn Screening: A Roadmap and Guide With Programmatic Considerations.
    Marci K Sontag, Anthony Steyermark, Colleen McCauley Shannon, Lauren Barringer, Yvonne Kellar-Guenther.
      Long-term follow-up (LTFU) systems for newborn screening (NBS) are essential for evaluating access to care, outcomes, and treatment barriers. Following screening, infants with confirmed diagnoses are followed by care providers, but local, state, and national systems to assess outcomes are lacking. The objectives were to create a roadmap outlining stages for LTFU program development to assist jurisdictions in establishing systems that best fit their goals and resources. The initial roadmap was developed with input from jurisdictions developing NBS LTFU systems. Listening sessions were conducted, including experts who have published on NBS LTFU, federal agency and national association personnel, state NBS program representatives, family advocacy group leaders, and health informatics specialists. Revisions to the LTFU Roadmap were made based on feedback from each session. Programmatic considerations and tools were developed around key questions. Suggested changes were tracked, and theme saturation was assessed. The resulting LTFU Roadmap outlines 4 LTFU stages: (1) Connection to Care, assessing child-clinical care system connectivity; (2) Appropriate Treatment and Care, evaluating the adequacy of medical follow-up; (3) Developmental Milestone and Disease Outcomes, focusing on developmental outcomes; and (4) Family Well-Being and Health Outcome, assessing child thriving and family support. Each phase includes metrics to monitor progress, with considerations for data collection and storage. An LTFU Roadmap Guide was developed to provide a structured set of steps to assist in the development of systems. The LTFU Roadmap aims to enable more uniform implementation across NBS programs, while allowing customization, ultimately facilitating quality and system improvements.
    DOI:  https://doi.org/10.1542/peds.2026-077357J
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