bims-polgdi Biomed News
on POLG disease
Issue of 2026–07–26
fifty papers selected by
Luca Bolliger, lxBio
  1. Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
  2. Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.
  3. The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver.
  4. The long road to a rare diagnosis: A Malaysian case of childhood-onset progressive myoclonus, ataxia, and retinal dystrophy with biopsy features suggestive of mitochondrial dysfunction.
  5. Patient and Family Perspectives on Generative AI Tools in Rare Diseases: Exploratory Mixed Methods Online Survey.
  6. Variant Curation and Classification in Rare Disease Genomics: Standards and Emerging Tools for Single-Nucleotide Variant Analysis.
  7. Recommendations for the use of clinical outcome assessments in rare disease drug development.
  8. The Case for Master Protocols for Rare Neurological Diseases.
  9. Mito-interpreter: An online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of mitochondrial DNA variants.
  10. Mitochondrial carbonic anhydrases VA and VB: Metabolic roles and clinical significance.
  11. Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
  12. Psychological stress induced mitochondrial response in humans and its medial prefrontal biomarker correlates.
  13. Mitochondrial transfer: quality dictates immune-metabolic fate.
  14. Mapping Rare Disease Registries in Brazil: Situational Analysis and Proposal for National Unification.
  15. Mitochondrial capsules: A revolutionary organelle therapy for mitochondrial and neurodegenerative diseases.
  16. Quantum-Informed Perspectives on Mitochondrial Bioenergetics and Redox Signaling in Cardiovascular Disease.
  17. Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
  18. Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity.
  19. Mitochondrial dysfunction and the regulatory cell death crosstalk network in chronic obstructive pulmonary disease: from oxidative stress mechanisms to targeted therapeutic strategies.
  20. HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
  21. TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
  22. Mitochondrial DNA copy number in diabetic kidney disease: translational prospects and challenges.
  23. Diagnostic Performance of Large Language Models for Orthopedic-Related Rare Diseases and Their Impact on Physicians' Diagnostic Accuracy: 2-Stage Comparative Evaluation Study Based on the Chinese Rare Disease Catalog.
  24. Bioactive compounds from traditional Chinese medicine for mitochondrial dysfunction-oriented nanodelivery in neurodegenerative diseases.
  25. Accelerating Research on Brain Aging: Enabling Brain Imaging Data Sharing in the Open Science Landscape.
  26. APE1/Ref-1: multifunctional biology, selective inhibition, and the path to clinical translation.
  27. Mitochondria poor but capacity rich? The paradox of podocyte respiration.
  28. Initial-Visit Specialty Triage in Rare Diseases Using Large Language Models: Retrospective Benchmarking Study.
  29. The role of cytosolic mitochondrial DNA as a mitochondrial danger signal for stromal fibroblasts in forming the tumor-promoting microenvironment following radiation exposure.
  30. The power of one: The unexpected benefits of correcting a single tissue in multisystem mitochondrial disease.
  31. A Personal Health App and Wearable Co-Design Framework for Rare and Complex Diseases: User-Centered, Collaborative Co-Design Study.
  32. Launching a multi-level data strategy for rare eye diseases: a methodological case study from national to European scale.
  33. Persona-Driven Data Augmentation for Disease Name Recognition Across Rare and General Disease Corpora: Comparative Evaluation Study.
  34. Accelerating Pediatric Oncology Drug Development: Advances in Clinical Pharmacology, Trial Design, Non-Clinical Evidence, and Regulatory Science.
  35. From Variant Interpretation to Biomarker Translation: Multi-omics Integration in Inherited Neuromuscular Diseases.
  36. From Models to Meaning: The Integrator Pharmacologist's Role in Advancing Health Equity Across the Drug Development Continuum.
  37. Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
  38. SIRT Family: Biological Functions and Therapeutic Targets.
  39. Sperm Mitochondrial DNA Copy Number and Nuclear DNA Methylation Across Clinical and Non-Clinical Preconception Cohorts.
  40. ER-mitochondria contact sites and organelle stress in asthma.
  41. Mitochondrial tRNA biogenesis, modifications and disease relevance.
  42. Outcome strategies for clinical trials in Neuropaediatric rare diseases.
  43. Mitochondrial dysfunction in intervertebral disc degeneration: Linking oxidative stress, altered cell fate, and Matrix degeneration.
  44. Integrating remote testing and machine learning to identify markers of cerebellar ataxia at home.
  45. Integrating care across the life course supports goal-aligned end-of-life care.
  46. Zebrafish as a versatile model in biomedical research, from disease modeling to regenerative medicine: a review.
  47. The emerging role of trace elements in epilepsy and metabolic disorders: a new frontier in neurotherapeutics.
  48. Continuity and discontinuity in Native American populations: Insights from ancient and modern mitochondrial DNA.
  49. Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
  50. "Overlap" Syndromes in Autoimmune Liver Disease: Definitions, Clinical Challenges and Future Directions.
  1. JCI Insight. 2026 Jul 22. pii: e199182. [Epub ahead of print]11(14):
    Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
    David Alsina, Diana Rubalcava-Gracia, Kristina Bubb, Rodolfo Garcia-Villegas, Akos Vegvari, Roberta Filograna, Florian A Rosenberger, Camilla Koolmeister, Nils-Göran Larsson.
      Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.
    Keywords:  Cell biology; Metabolism; Mitochondria; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.199182
  2. Mitochondrion. 2026 Jul 22. pii: S1567-7249(26)00085-1. [Epub ahead of print] 102195
    Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.
    Ismail Gouiza, Aymane Bouzidi, Meriem Hechmi, Majida Charif, Abir Zioudi, Nadia Kheriji, Hela Boudabous, Mouna Zribi, Safa Khatrouch, Raoudha Kebaili, Ilhem Ben Youssef-Turki, Mediha Trabelsi, Slim Abdelmoula, Ichraf Kraoua, Amel Ben Chehida, Rym Kefi, Guy Lenaers.
      Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.
    Keywords:  Bioinformatic analysis; Genetic diagnosis; Leigh syndrome; Mitochondrial diseases; North Africa; Tunisia
    DOI:  https://doi.org/10.1016/j.mito.2026.102195
  3. Biochem Biophys Res Commun. 2026 Jul 16. pii: S0006-291X(26)01068-5. [Epub ahead of print]831 154304
    The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver.
    Ruoyi Zhang, Zhijie Song, Qimeng Xin, Wenbin Xing, Wenlan Zhang, Yanmei Yang.
      Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by sustained immune activation and profound metabolic dysregulation. Accumulating evidence indicates that mitochondrial DNA (mtDNA) plays an active role in linking mitochondrial stress to innate immune signaling in RA. This review synthesizes current findings within a unifying mechanistic framework centered on the mtDNA damage-release-immune activation axis. Owing to limited chromatin protection and constrained repair capacity, mtDNA is highly susceptible to oxidative injury in the inflammatory microenvironment of RA, leading to copy number alterations and mutational accumulation. Damaged or oxidized mtDNA can translocate to the cytosol or extracellular space, where it acts as an immunostimulatory danger signal and amplifies innate immune activation. Persistent mtDNA-related signaling, together with oxidative stress and impaired mitochondrial quality control, contributes to immunometabolic reprogramming in key effector populations. Clinically, circulating cell-free mitochondrial DNA has emerged as a dynamic biomarker associated with disease activity and therapeutic response. Collectively, this framework integrates mitochondrial dysfunction with immune activation in RA and highlights mtDNA-centered pathways as rational targets for mechanism-based intervention. Further standardization of mtDNA assays and mechanism-informed clinical studies will be essential to advance mtDNA-focused precision strategies in RA.
    Keywords:  Immunometabolism; Mitochondrial DNA; NLRP3 inflammasome; Rheumatoid arthritis; TLR9; cGAS-STING
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154304
  4. J Int Med Res. 2026 Jul;54(7): 3000605261467202
    The long road to a rare diagnosis: A Malaysian case of childhood-onset progressive myoclonus, ataxia, and retinal dystrophy with biopsy features suggestive of mitochondrial dysfunction.
    Kishwen Kanna Yoga Ratnam, Jun Fai Yap.
      ObjectiveMyoclonus is a hyperkinetic movement disorder characterized by sudden, involuntary jerks due to muscle contraction or brief lapses of muscular activity and may arise from diverse conditions. When accompanied by cerebellar dysfunction and retinal involvement, it suggests a heterogeneous spectrum of disorders, including mitochondrial, repeat-expansion, and other inherited neurogenetic disorders. In Malaysia, the diagnosis of rare diseases remains challenging because of phenotypic overlap and resource limitations. We illustrate the diagnostic dilemma of a possible mitochondrial disorder when definitive testing is not readily accessible.MethodsWe describe a woman in her early 40s with childhood-onset myoclonic jerks, progressive gait instability, cerebellar signs, and cognitive decline.ResultsOphthalmic assessment showed reduced visual acuity, optic disc pallor, and electroretinographic findings consistent with cone-rod dystrophy. Audiometry demonstrated bilateral sensorineural hearing loss. Brain computed tomography showed cerebral and cerebellar atrophy. Muscle biopsy revealed preserved architecture without ragged-red fibers, but oxidative enzyme histochemistry showed subsarcolemmal mitochondrial aggregates suggestive of mitochondrial dysfunction. Whole-exome sequencing did not identify a causative variant. Given the combination of cerebellar features and retinal dystrophy, a repeat-expansion disorder, particularly spinocerebellar ataxia type 7, remained a key differential diagnosis. Targeted repeat-expansion testing and mitochondrial deoxyribonucleic acid analysis were not performed because of patient-centered considerations. Despite disease progression, multidisciplinary follow-up was maintained, including structured physiotherapy and annual ophthalmologic surveillance.ConclusionThis case highlights the importance of pragmatic care planning in resource-limited settings and maintaining comprehensive care for patients without a definitive molecular diagnosis. It also emphasizes the need to strengthen rare disease diagnostic pathways to support shared decision making.
    Keywords:  Case report; cerebellar ataxia; cone-rod dystrophy; mitochondrial dysfunction; rare disease
    DOI:  https://doi.org/10.1177/03000605261467202
  5. J Particip Med. 2026 Jul 24. 18 e93720
    Patient and Family Perspectives on Generative AI Tools in Rare Diseases: Exploratory Mixed Methods Online Survey.
    Charlotte Blease, James Jones, Catherine E Blease, Anna Kharko, Carolina Garcia Sanchez, Kenneth D Mandl.
       Background: Generative artificial intelligence (GenAI) tools are widely accessible to the public, who are engaging with them for a wide range of health care applications. Existing research has focused predominantly on clinician-facing adoption. Far less is known about how patients and family members use GenAI tools, particularly in rare disease contexts, where diagnostic delay, limited specialist access, and unmet informational needs are common.
    Objective: This study aimed to examine the experiences and opinions of adult patients with rare diseases and parents or guardians of children with rare diseases regarding the use of GenAI tools.
    Methods: Between November 2025 and January 2026, we conducted an exploratory mixed methods web-based survey using convenience sampling through rare disease community organizations in the United States. The survey included closed-ended items assessing prior GenAI use, purposes of use, perceived influence on medical decisions and diagnoses, trust, concerns, communication with clinicians, and experiences of harm, alongside open-text questions capturing qualitative reflections. Descriptive statistics were used to summarize quantitative data. Inductive qualitative analysis was applied to the open-text responses.
    Results: A total of 115 respondents completed the survey. A majority of respondents were parents or guardians of a child with a rare disease (n=74, 64.3%), and the remaining respondents were patients with a rare disease (n=41, 35.7%). Slightly more than half of respondents (n=63, 54.8%) reported prior use of GenAI tools in the context of rare disease. Common purposes included exploring new treatments or clinical trials (n=53, 46.1%), interpreting medical tests or clinical notes (n=37, 32.2%), locating specialists or care centers (n=29, 25.2%), and suggesting possible diagnoses (n=28, 24.3%). Nearly one-third of respondents (n=37, 32%) reported some degree of influence of GenAI on their medical decisions. Nearly 10% (n=12) reported contributions of GenAI to a formal diagnosis. Concern about GenAI accuracy was widespread; 71 of 115 (61.8%) respondents reported moderate to extreme concern. Most respondents (n=90, 78.3%) had not discussed AI-generated information with a clinician. Few respondents (n=7, 6.1%) reported experiencing harm. Qualitative analysis identified 3 themes: (1) GenAI as a practical tool for augmenting patient and caregiver expertise and advocacy, (2) conditional trust and bounded use of GenAI with an emphasis on verification and human oversight, and (3) perceived risks, harms, and structural concerns, including inaccuracies, genetic misinterpretation, and privacy and commercialization issues.
    Conclusions: In this exploratory study, patients and families affected by rare diseases were actively experimenting with GenAI tools to support information seeking, preparation, and advocacy while simultaneously expressing substantial caution and concern about the reliability, safety, and appropriate boundaries of use. Our findings contrast sharply with clinician concerns that patients lack the capacity to use GenAI tools judiciously. Notwithstanding, the sample was skewed toward highly educated participants. Future research should prioritize more representative samples to better capture the range of patient and caregiver experiences with GenAI in rare disease care.
    Keywords:  education; general practice; generative AI; large language models; online survey questionnaire; primary care; qualitative research; training
    DOI:  https://doi.org/10.2196/93720
  6. Arch Med Res. 2026 Jul 24. pii: S0188-4409(26)00114-1. [Epub ahead of print]57(8): 103492
    Variant Curation and Classification in Rare Disease Genomics: Standards and Emerging Tools for Single-Nucleotide Variant Analysis.
    Jimena Barraza García, Marta García, Leire Echepare Olivera, Carlos Iván Rivera Pedroza, Víctor Del Nogal Soler.
      The widespread adoption of next-generation sequencing (NGS) for rare disease diagnosis has transformed clinical genomics. Multiple approaches have been proposed to standardize and improve the analysis, classification, interpretation, and reporting of genetic variants in clinical settings. This review provides a focused, practical overview of variant curation and current classification frameworks, particularly for single-nucleotide variants (SNVs) and small insertions/deletions within coding regions. These variant types remain the most frequent findings in clinical sequencing and are the primary targets of existing classification guidelines. While highly relevant, other variant types and analytical approaches fall outside the scope of this focused review and are addressed elsewhere in the literature and within this special issue. We distinguish between three related yet conceptually distinct processes: variant curation, defined as the systematic collection and evaluation of evidence; variant classification, defined as the standardized assignment of pathogenicity categories according to established guidelines; and clinical interpretation, which contextualizes a classified variant within an individual patient's phenotype to inform medical decision-making. We will examine advances in the field of variant classification that contribute to improving molecular diagnosis of rare diseases, highlighting the achievements, limitations, and challenges present in each aspect addressed. Key developments in variant classification are reviewed, including the 2015 guidelines and subsequent refinements, population databases, computational predictors, multiplexed functional studies, reanalysis efforts, and collaborative initiatives. Many challenges remain to be addressed, such as the interpretation of non-coding variants, the transition to updated classification frameworks, the diversity in population databases, and the development of new predictors, among others.
    Keywords:  ACMG/AMP guidelines; Pathogenicity predictors; Rare diseases; Variant classification
    DOI:  https://doi.org/10.1016/j.arcmed.2026.103492
  7. EClinicalMedicine. 2026 Aug;98 104073
    Recommendations for the use of clinical outcome assessments in rare disease drug development.
    LifeArc Accelerating Rare Disease Trials (ARDT) centreaf
      There are over 10,000 rare diseases collectively affecting an estimated 250-450 million people globally. While these diseases are rare individually, their cumulative impact on patients, families, healthcare systems, and society is substantial. The incorporation of clinical outcome assessments (COAs) in clinical trials can facilitate patient-focused drug development and treatment evaluation by generating meaningful evidence on how patients feel and function. This work was conducted in three phases: a targeted literature review (searched Aug 2025; updated Feb 2026), a multistakeholder workshop (online, Sept 2025) and, finally, an online survey to ratify final recommendations (responses by March 3, 2026). Of 43 individuals invited, 35 (81%) attended the virtual workshop: 11 researchers (including clinical trialists); 12 patients/caregivers; seven industry experts; four individuals from regulatory agencies and one HTA expert. All were based in the UK or USA. Across three sessions, the workshop explored stakeholder perspectives on considerations and appropriate methodological approaches to COA assessment for rare disease drug development to facilitate the generation of recommendations for future use. A threshold of at least 70% votes was chosen, a priori, for inclusion in the final set of recommendations. Here, we describe the potential benefits of COAs, summarise the key challenges, and provide recommendations to facilitate their effective and consistent integration in drug development for rare diseases.
    Keywords:  Clinical outcome assessment; Clinical trials; PRO; Patient-focused drug development; Patient-reported outcome; Rare diseases
    DOI:  https://doi.org/10.1016/j.eclinm.2026.104073
  8. Ann Neurol. 2026 Jul 21.
    The Case for Master Protocols for Rare Neurological Diseases.
    Jennifer Vermilion, Sabrina Paganoni, Scott R Plotkin, Melanie Quintana, Sara B Calvert, Ineka T Whiteman, Raymond Y Wang, Nadia Moore, Erika F Augustine.
      Master protocol trials allow for simultaneous multiple hypothesis testing within a common framework and might be applicable for rare diseases. In May 2025, the Network for Excellence in Neuroscience Clinical Trials convened a multistakeholder conference to discuss master protocol trials in rare neurological disorders. In this paper, we explore how master protocol trial designs may apply to rare neurological disorders, using the neuronal ceroid lipofuscinoses as an example. Through shared protocol elements and trial infrastructure, master protocols may decrease cost and improve efficiency in testing potential therapeutics in rare disease, accelerating the delivery of urgently needed therapies to patients. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78311
  9. Mitochondrion. 2026 Jul 22. pii: S1567-7249(26)00084-X. [Epub ahead of print]91 102194
    Mito-interpreter: An online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of mitochondrial DNA variants.
    Ning Zhang, Yang Yang, Haoyu He, Qihan Wang, Dongmei Ji.
      Mito-interpreter is an online tool developed to implement the ACMG/AMP standards and guidelines for mitochondrial DNA (mtDNA) variant interpretation. Manually applying these specialized guidelines is time-consuming and error-prone due to mtDNA complexities. This tool streamlines the process by systematically organizing evidence categories and integrating key data sources, including population frequencies from MITOMAP and Helix, as well as pre-computed scores from the APOGEE and expert-validated evidence from ClinGen. By automating data aggregation and rule-based logic, Mito-interpreter enables clinicians and researchers to focus on evidence evaluation, thereby enhancing efficiency and accuracy in clinical diagnostics and research. The tool is freely available at https://www.mtdna-interpreter.com.
    DOI:  https://doi.org/10.1016/j.mito.2026.102194
  10. Enzymes. 2026 ;pii: S1874-6047(26)00007-7. [Epub ahead of print]59 105-130
    Mitochondrial carbonic anhydrases VA and VB: Metabolic roles and clinical significance.
    Stanislav Kalinin, Seppo Parkkila, Ashok Aspatwar.
      Mitochondrial carbonic anhydrases VA and VB (CA VA and CA VB) are localized within the mitochondrial matrix. These zinc-containing enzymes catalyze the reversible hydration of carbon dioxide to bicarbonate and protons, thereby providing bicarbonate for essential mitochondrial metabolic reactions and contributing to intracellular pH balance. CA VA is predominantly expressed in the liver and plays a key role in supplying bicarbonate for pathways such as gluconeogenesis, ureagenesis, and lipogenesis. In contrast, CA VB shows a broader tissue distribution and supports mitochondrial metabolism across multiple organs, although its physiological role is less clearly defined. Mitochondrial CAs are directly linked to metabolic processes required for energy homeostasis. Deficiency of CA VA is associated with metabolic disorders, particularly those involving impaired ammonia detoxification and disruption of intermediary metabolism. This chapter summarizes current knowledge on CA VA and CA VB, including their molecular and structural features, biochemical properties, tissue distribution, and roles in mitochondrial metabolism. In addition, evidence from experimental models, clinical findings related to CA5A mutations, and emerging therapeutic perspectives are discussed.
    Keywords:  Bicarbonate metabolism; CA VA; CA VB; Gluconeogenesis; Metabolic disorders; Mitochondrial carbonic anhydrase; Mitochondrial metabolism; Ureagenesis
    DOI:  https://doi.org/10.1016/bs.enz.2026.05.002
  11. Nucleic Acids Res. 2026 Jul 17. pii: gkag720. [Epub ahead of print]54(14):
    Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
    Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.
      Accurate replication of the mitochondrial genome (mtDNA) depends on DNA polymerase γ (Pol γ), yet its strand-displacement activity has been reported with varying outcomes across studies. Here we show that human Pol γ carries out robust, processive strand-displacement synthesis under physiological divalent metal-ion concentrations. We identify two functional classes of metal-binding sites: high-affinity sites that support DNA synthesis and unwinding, and low-affinity sites that selectively suppress unwinding without impairing polymerase activity. Pol γ efficiently displaces DNA/DNA duplex and RNA/DNA hybrids, supporting a role in RNA primer removal during mtDNA replication. Cryo-EM structures of Pol γ bound to fork-mimicking DNA reveal conformational states corresponding to progressive duplex unwinding and identify structural elements that facilitate strand displacement. These findings establish a metal-dependent mechanism for Pol γ activity and reconcile previous discrepancies in its reported unwinding capacity.
    DOI:  https://doi.org/10.1093/nar/gkag720
  12. Transl Psychiatry. 2026 Jul 20.
    Psychological stress induced mitochondrial response in humans and its medial prefrontal biomarker correlates.
    A Ankeeta, Ashutosh Tripathi, Yizhou Ma, Bindu Pillai, Joshua J Chiappelli, Jennifer N Jernberg, Alia Warner, Keiko Kunitoki, Bhim M Adhikari, Si Gao, Xiaoming Du, Loise Kabui, Francisco Pallares Solano, Oluwabunmi Akindona, Zhenyao Ye, Shuo Chen, Mohammad Milad, Peter Kochunov, Anilkumar Pillai, L Elliot Hong.
      Stress response obligates increased mitochondrial activities to meet stress-induced high energy requirement. This stress-mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top-down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress-mitochondrial response paradigm to study the process in humans. We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf-mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress-induced cf-mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS, N = 16), as well as high-resolution brain imaging based cortical thickness focusing on the mPFC (N = 30). We found that salivary cf-mtDNA was significantly elevated immediately after the psychological stress challenge (p = 2.0 × 10-7) and gradually declined after. Exploratory analyses indicated that the cf-mtDNA response was only nominally associated with the cortisol response and was not substantially driven by changes in cortisol. Instead, we found that higher baseline mPFC/dACC lactate+ levels, which may partly reflect mitochondrial dysfunction were significantly associated with the cf-mtDNA response (r = 0.80, p < 0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r = -0.52, p = 0.003). Age had a U-shape effect such that cf-mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct-mtDNA response variance (p = 0.003). This stress challenge-salivary cf-mtDNA assay paradigm may offer a new, non-invasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.
    DOI:  https://doi.org/10.1038/s41398-026-04246-5
  13. Trends Mol Med. 2026 Jul 23. pii: S1471-4914(26)00172-3. [Epub ahead of print]
    Mitochondrial transfer: quality dictates immune-metabolic fate.
    Kai Liu, Quazi T H Shubhra, Hui Zhang.
      Horizontal mitochondrial transfer (HMT) outcomes are shaped by donor fitness and transfer context. We propose a post-transfer quality checkpoint that integrates membrane potential, oxidative damage, mitophagy, fusion, and fission to determine the recipient-cell's response. Depending on donor quality and recipient thresholds, HMT may drive bioenergetic restoration, inflammation, or tumor immune escape. This framework extends route-centered accounts of HMT toward a testable, quality-governed model for therapeutic intervention.
    Keywords:  immune-metabolic fate; mitochondrial quality; mitochondrial transfer; quality checkpoint
    DOI:  https://doi.org/10.1016/j.molmed.2026.07.002
  14. J Med Syst. 2026 Jul 20. pii: 115. [Epub ahead of print]50(1):
    Mapping Rare Disease Registries in Brazil: Situational Analysis and Proposal for National Unification.
    Filipe Andrade Bernardi, Bibiana Mello de Oliveira, Natan Monsores de Sá, Domingos Alves, Têmis Maria Félix.
      Rare disease registries in Brazil remain fragmented across federal, state, and local initiatives, limiting the availability of reliable epidemiological information to support diagnosis, care planning, research, and public policy. This study aimed to map existing rare disease registry entities and registry-related initiatives in Brazil and to propose practical guidelines for their unification into an integrated national registry. We conducted a descriptive, exploratory mapping study combining a structured literature search with documentary analysis of public policies, health information systems, registry portals, institutional reports, and legislative documents related to rare diseases in Brazil. PRISMA-S was used to report the search component, and a PRISMA-style flow diagram documented source identification and selection. We identified a rapidly evolving legislative landscape, including federal bills proposing a national monitoring system or registry and recent state-level statutes related to identification and observatories. Using an expanded, auditability-oriented inventory definition, we mapped 28 registry entities and registry-related initiatives. Of these, 24 are implemented, three are legislative proposals, and one is under development. Among the 24 implemented initiatives, 16 are national or multicentre, Brazil-based initiatives; three are state-level; four are regional/local; and one is a transnational registry with documented participation of a Brazilian cohort. Registry creation and registry-related activity accelerated after 2018, particularly between 2020 and 2026. We conclude that Brazil exhibits substantial data fragmentation across uncoordinated systems. A unified approach should integrate epidemiological data from existing networks, state notification systems, specialised hospital registries, and technology appraisal information under coordinated governance, while embedding privacy-by-design and information security safeguards.
    Keywords:  Epidemiology; Health information systems; Health registries; Public health policy; Rare diseases; Unified Health System
    DOI:  https://doi.org/10.1007/s10916-026-02442-w
  15. Mol Ther. 2026 Jul 20. pii: S1525-0016(26)00590-3. [Epub ahead of print]
    Mitochondrial capsules: A revolutionary organelle therapy for mitochondrial and neurodegenerative diseases.
    Yaguang Zhang, Xuyang Yang, Mingtian Wei.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.022
  16. Am J Physiol Heart Circ Physiol. 2026 Jul 24.
    Quantum-Informed Perspectives on Mitochondrial Bioenergetics and Redox Signaling in Cardiovascular Disease.
    Francesco Tona.
      
    Keywords:  Bioenergetics; Cardiovascular disease; Heart failure; Mitochondria; Redox signaling
    DOI:  https://doi.org/10.1152/ajpheart.00308.2026
  17. Aging Cell. 2026 Aug;25(8): e70639
    Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
    Heng Zhang, Guangyu Liang, Anding Liu.
      During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age-related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post-translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence-associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver-brain, liver-muscle, and liver-gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia-lowering agents, senotherapeutics, and microbiota-directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.
    Keywords:  aging; ammonia; liver
    DOI:  https://doi.org/10.1111/acel.70639
  18. Front Immunol. 2026 ;17 1902029
    Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity.
    Enli Xie, Yushan He, Yongjun Sun.
      Traditionally recognized as "cellular powerhouses", mitochondria have gained relevance as pivotal nodes in the integration of metabolism, stress signaling, and innate immunity. In this context, the present work seeks to answer the following question: Does the continuous, exercise-induced mitochondrial stress contribute towards training of innate immune cells by promoting the generation of DAMPs such as mtDNA and succinate? Exercise can be considered as a form of controllable mitochondrial stressor. Mechanistically, the temporary release of mtDAMPs through exercise results in activation of pattern recognition receptors (NLRP3, TLR9, cGAS-STING). Subsequently, there is a metabolic reprogramming event favoring switch from oxidative phosphorylation to aerobic glycolysis along with epigenetic changes (H3K4me3, H3K27ac) priming pro-inflammatory genes for enhanced secondary response. Moderate-intensity exercise develops an immune homeostatic condition with reduced low-grade inflammation and increased reactivity, while sedentary behavior fosters chronic low-grade inflammation, and excessive high-volume exercise can temporarily reduce immune competency. Herein, we present an integrative model where exercise-induced mitochondrial stress as a physiological "training vaccine" to enhance immune surveillance via trained immunity principles. The current model helps differentiate the immune status of elite athletes from sedentary subjects and paves the way for understanding the immunological benefit of exercise prescription in infection prevention, metabolic health, and cancer immunotherapy.
    Keywords:  DAMPs; epigenetic reprogramming; exercise immunology; metabolic reprogramming; mitochondrial stress; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1902029
  19. Front Immunol. 2026 ;17 1856853
    Mitochondrial dysfunction and the regulatory cell death crosstalk network in chronic obstructive pulmonary disease: from oxidative stress mechanisms to targeted therapeutic strategies.
    Hongyan Fan, Juandi Xue, Jianghua Si.
      The sustained progression of chronic obstructive pulmonary disease (COPD) may not be independently driven by a single process such as chronic inflammation, oxidative stress, or cell death, but rather originates from a cross-amplification network among "mitochondrial dysfunction-oxidative stress-regulated cell death." In the context of mitochondrial damage, excessive generation of reactive oxygen species (ROS), damage and release of mitochondrial DNA (mtDNA), and dysregulation of mitochondrial quality control (MQC) collectively promote airway epithelial injury, sustained inflammation, alveolar destruction, and tissue remodeling. Furthermore, regulated cell death modalities such as apoptosis, necroptosis, pyroptosis, and ferroptosis are not isolated from each other but are coupled under a shared context of mitochondrial stress, exhibiting different dominant patterns across various cell types and disease stages. Adopting an integrated perspective encompassing mitochondrial dysfunction, amplified oxidative stress, and the regulated cell death (RCD) cross-network, this article synthesizes current research regarding COPD-related mechanisms, with a focus on mitochondrial damage markers, RCD activity indicators, mechanism-oriented patient stratification, and potential therapeutic strategies targeting mitochondrial homeostasis and cell death pathways. This framework facilitates the transition of COPD understanding from the traditional chronic inflammation model to a more stratified and translationally promising mitochondrial-cell death network model.
    Keywords:  chronic obstructive pulmonary disease (COPD); mitochondrial dysfunction; mitochondrial quality control; oxidative stress; pyroptosis; regulated cell death (RCD)
    DOI:  https://doi.org/10.3389/fimmu.2026.1856853
  20. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2619864123
    HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.
    Jiamin Yi, Qin Yang, Chunzhuang Zhou, Yunfei Zhu, Yingfeng Tu, Lin Zhao, Min Tang, Junhong Qin, Tao Long, Tianxing Li, Ping Li, Zikang Gong, Qilin Wang, Xin Yong, Da Jia.
      The HECT-type E3 ubiquitin ligase HUWE1 is a critical regulator of protein homeostasis, genome stability, and neurodevelopment. Variants in HUWE1 are linked to X-linked intellectual disability (XLID), yet a significant number of HUWE1 variants are noncatalytic, leaving their disease mechanisms unresolved. Here, we identify an AMBRA1-RMC1-HUWE1 signaling axis that directs HUWE1-mediated ubiquitination to mitochondria to regulate neural development. In zebrafish, noncatalytic HUWE1 variants found in XLID patients (M375I, G660R, and H669Q) recapitulate key neurodevelopmental deficits, including impaired brain growth and motor neuron defects. Global ubiquitin profiling reveals that these variants selectively disrupt the ubiquitination of mitochondrial proteins without affecting nuclear substrates. Mechanistically, AMBRA1 acts as a mitochondrial scaffold that recruits RMC1, enabling HUWE1 localization to mitochondria through direct interaction with RMC1. Disruption of this recruitment by disease-associated HUWE1 variants prevents mitochondrial targeting and impairs mitochondrial substrate ubiquitination. Notably, Urolithin A treatment ameliorates neurodevelopmental phenotypes in HUWE1-deficient zebrafish. Together, our findings define an AMBRA1-organized mitochondrial recruitment pathway in which RMC1 links HUWE1 to mitochondria, explain noncatalytic HUWE1-associated XLID, and suggest mitochondrial quality-control enhancement as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1073/pnas.2619864123
  21. Mol Genet Metab. 2026 Jul 19. pii: S1096-7192(26)00503-2. [Epub ahead of print]149(1-2): 110220
    TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
    Claire-Marine Bérat, Giulia Barcia, Pauline Gaignard, Zahra Assouline, Elisa De La Cruz, Marie-Céline François-Heude, Agathe Roubertie, Claude Cances, Louis Dufour, Marianne Alison, Olivier Patat, Aurélien Trimouille, Samira Ait-El-Mkadem Saadi, Agnès Rötig, Marie Hully, Cécile Rouzier, Isabelle Desguerre, Nathalie Boddaert, Manuel Schiff.
       BACKGROUND: TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management.
    OBJECTIVE: To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes.
    METHODS: We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease.
    RESULTS: The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes.
    CONCLUSION: TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
    Keywords:  Dystonia; Leigh syndrome; Mitochondrial disease; Mitochondrial respiratory chain complex III; Spastic paraparesis; TTC19
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110220
  22. Arch Physiol Biochem. 2026 Jul 19. 1-29
    Mitochondrial DNA copy number in diabetic kidney disease: translational prospects and challenges.
    Lixia Lu, Yongtong Cao, Liang Ma, Xiaomu Kong.
      Context: Diabetic kidney disease (DKD) presents substantial challenges in early detection and clinical monitoring. Mitochondrial dysfunction plays a pivotal role in DKD pathogenesis, and mitochondrial DNA copy number (mtDNA-CN) reflects this dysfunction. Objective: To evaluate the translational potential of mtDNA-CN as a biomarker for DKD, focusing on its diagnostic, prognostic, and monitoring utility across biological specimens, and examine the critical challenges of its clinical translation. Materials and Methods: We systematically synthesize evidence from cellular experiments, animal models, and clinical studies that assess mtDNA-CN alterations in DKD, with a comparative analysis of specimen types and methodologies. Results: Studies demonstrated that mtDNA-CN in blood and urine are correlated with the onset and progression of DKD. Rigorous standardization must be implemented across specimen collection, pre-analytical processing, analytical testing, detection and data reporting. Conclusion: MtDNA-CN is a promising and measurable biomarker for DKD. Combined with conventional markers, it could enhance clinical utility.
    Keywords:  Diabetic kidney disease; biomarker; clinical translation; mitochondrial DNA copy number
    DOI:  https://doi.org/10.1080/13813455.2026.2702001
  23. J Med Internet Res. 2026 Jul 24. 28 e92931
    Diagnostic Performance of Large Language Models for Orthopedic-Related Rare Diseases and Their Impact on Physicians' Diagnostic Accuracy: 2-Stage Comparative Evaluation Study Based on the Chinese Rare Disease Catalog.
    Tusheng Li, Ziqian Ma, Baodong Wang, Ning Fan, Aobo Wang, Lei Zang.
       BACKGROUND: Orthopedic-related rare diseases are difficult to diagnose because of their low prevalence, heterogeneous phenotypes, and fragmented knowledge. Large language models (LLMs) can serve as dynamic knowledge-support tools, but their diagnostic performance and effect on physicians' decision-making remain unclear.
    OBJECTIVE: This study aims to compare the diagnostic performance of advanced LLMs for orthopedic-related rare diseases and to evaluate the effect of a 2-stage LLM-assisted diagnostic workflow on physicians' diagnostic accuracy and subjective acceptance.
    METHODS: We selected 40 orthopedic-related rare diseases from the Chinese Rare Disease Catalog. A total of 4 general-purpose LLMs each generated 1 primary diagnosis and 5 differential diagnoses per case. Diagnostic accuracy, defined as a correct primary diagnosis, was compared using the Cochran Q test and pairwise McNemar tests with Bonferroni correction. A representative LLM was integrated into a 2-stage workflow involving 27 intermediate and 15 senior orthopedic physicians. Physicians first diagnosed all cases independently and then rediagnosed the same cases after reviewing nonauthoritative LLM suggestions. Physician diagnostic data were primarily analyzed using mixed-effects logistic regression at the individual-diagnosis level. Case-level group accuracy was additionally assessed using >50% and ≥2/3 accurate-physician thresholds. After both rounds, physicians completed an 8-item Likert-scale questionnaire assessing subjective acceptance and workflow perceptions.
    RESULTS: Claude Sonnet 4.5, ChatGPT-5.0, and Gemini 2.5 Pro each achieved 90% (36/40) primary-diagnosis accuracy, whereas DeepSeek-V3.2 achieved 67.5% (27/40; Cochran Q P<.001). Before LLM assistance, mean physician-level accuracy was 42.22% for intermediate physicians and 58.67% for senior physicians; after assistance, it increased to 68.80% and 83.33%, respectively. In the primary mixed-effects logistic regression analysis, physician seniority group and LLM assistance stage were significantly associated with diagnostic correctness (both P<.001), whereas the group-by-stage interaction was not significant (P=.10). Secondary case-level analyses using the >50% threshold showed improvement from 40% (16/40) to 67.5% (27/40) for intermediate physicians and from 57.5% (23/40) to 82.5% (33/40) for senior physicians, with similar findings using the ≥2/3 threshold. Cases accurately diagnosed by all 3 agents increased from 16 to 27. The questionnaire showed high internal consistency (Cronbach α=0.902) and generally positive attitudes, with no significant differences between physician groups (P=.11 to P=.78).
    CONCLUSIONS: LLMs achieved high diagnostic accuracy for orthopedic-related rare diseases. In the 2-stage LLM-assisted workflow, LLM assistance was associated with higher diagnostic correctness in both physician groups, although seniority-related differences in the magnitude of benefit require evaluation in larger studies. Senior physicians retained higher diagnostic correctness than intermediate physicians. Secondary case-level analyses suggested attenuation of group-level gaps in case-recognition patterns. Physicians reported broadly positive workflow perceptions. Given the same-day repeated-case design and potential short-term recall bias, these exploratory findings should be interpreted cautiously and warrant prospective randomized, crossover, washout-period, independent-case, or real-world evaluations of LLM-assisted diagnostic workflows in orthopedics.
    Keywords:  LLM; clinical decision support systems; diagnostic accuracy; large language model; orthopedics; rare diseases
    DOI:  https://doi.org/10.2196/92931
  24. Phytomedicine. 2026 Jul 14. pii: S0944-7113(26)00821-4. [Epub ahead of print]159 158590
    Bioactive compounds from traditional Chinese medicine for mitochondrial dysfunction-oriented nanodelivery in neurodegenerative diseases.
    Ting Cheng, Wenjie Hao, Mingwei Li, Yulong Yang, Zhihong Rao, Wenming Yang.
       BACKGROUND: Bioactive compounds from traditional Chinese medicine (TCM) have shown therapeutic potential in neurodegenerative diseases (NDDs), particularly through the regulation of mitochondrial function. Recent studies indicate that encapsulating these TCM bioactive compounds in nanodelivery systems significantly enhances their bioavailability, improves their ability to target the central nervous system, and offers more precise drug delivery.
    PURPOSE: This review aims to synthesize current evidence on how TCM bioactive compounds modulate mitochondria-related pathological nodes in NDDs and discuss how nanodelivery systems can be rationally engineered for blood-brain barrier (BBB) traversal, neuronal uptake, and mitochondrial or mitochondrial dysfunction-responsive delivery.
    METHODS: This is a structured narrative review. Relevant literature on TCM bioactive compounds, mitochondrial dysfunction, and nanodelivery systems for NDDs was retrieved from PubMed, Web of Science, and Scopus through April 2026. After applying predefined inclusion criteria, studies published between 2014 and 2025 were selected for analysis. The emphasis was placed on mechanistic studies, representative nanoformulations, and recent translational evidence.
    RESULTS: Current evidence indicates that bioactive compounds from traditional Chinese medicine, particularly polyphenols, alkaloids, flavonoids, saponins, and terpenoids, converge on several shared mitochondrial pathological nodes in neurodegenerative diseases, including oxidative stress, impaired bioenergetics, disrupted mitochondrial dynamics, defective mitophagy, and mitochondria-mediated apoptosis. Nanodelivery systems consistently improve the physicochemical properties, pharmacokinetic stability, blood-brain barrier transport, and intracellular exposure of these compounds, thereby enhancing their therapeutic potential. Mechanistically, rational integration of disease-responsive nanocarriers with mitochondria-regulating compounds enables spatiotemporal modulation of mitochondrial function rather than merely increasing drug accumulation. However, current evidence remains predominantly preclinical, with most formulations achieving brain targeting rather than verified mitochondrial subcellular targeting. Standardized evaluation of multistage BBB-neuron-mitochondria delivery efficiency, long-term safety, and translational performance is still lacking.
    CONCLUSION: Mitochondrial dysfunction-oriented nanodelivery of TCM bioactive compounds represents a promising strategy for NDD intervention. Future progress depends on more rigorous quality control from the herbal materials to the final nanoformulations, improved pharmacokinetic and safety evaluations, better disease-relevant animal models, and regulatory science frameworks tailored for botanical nanomedicines.
    Keywords:  Bioactive compounds; Mitochondrial dysfunction; Nanodelivery neurodegenerative diseases; TCM
    DOI:  https://doi.org/10.1016/j.phymed.2026.158590
  25. Eur J Neurol. 2026 Jul;33(7): e70672
    Accelerating Research on Brain Aging: Enabling Brain Imaging Data Sharing in the Open Science Landscape.
    Kathrin Giehl, Thilo van Eimeren.
      The global burden of age-associated diseases continues to grow. In particular, the accelerating impact of neurodegenerative diseases on individuals, communities and societies necessitates more effective approaches to diagnosis, prognosis and treatment of such disorders. Hence, the establishment of imaging biomarkers for early detection of disease, progression monitoring, and therapeutic evaluation is of utmost importance. Yet, despite the scientific consensus on the benefits of scientific collaboration and consequently medical innovation including biomarker development, substantial barriers for sharing neuroimaging data remain, demanding a transformation in how scientific data are generated, made accessible, re-used and valued. These barriers range from technical and infrastructural limitations to legal and motivational challenges that hinder widespread adoption of open science practices. Here, we present a comprehensive overview of the current landscape of brain imaging data sharing in neurodegenerative disease research. We explore the status of preregistration, data harmonization and storage standardization, legal compliance, and researcher incentives. We highlight best practices before, during and after data generation and the pressing need for a coordinated strategy regarding simplified and unified legal frameworks compliant with the General Data Protection Regulation of the European Union. Finally, we advocate for the establishment of an academic credit system designed to reward data stewardship. Only with a combined effort from researchers, stakeholders and funding agencies including a sustained infrastructure investment and community education, the field can fully overcome inertia and move towards much-desired open science, thereby fully leveraging shared data to improve patient outcomes and scientific discovery.
    Keywords:  BIDS; European Health Data Space; GDPR; brain health; neuroimaging
    DOI:  https://doi.org/10.1111/ene.70672
  26. Expert Opin Ther Targets. 2026 Jul 21. 1-16
    APE1/Ref-1: multifunctional biology, selective inhibition, and the path to clinical translation.
    Jessica A Occhiuto, Silpa Gampala, Melissa L Fishel, Mark R Kelley.
       INTRODUCTION: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional stress-response regulator that coordinates genome maintenance, redox signaling, RNA biology, and cellular metabolism. Its expression and subcellular localization further determine disease states and severity. The growing appreciation of its biological complexity and clinical relevance makes APE1/Ref-1 an increasingly attractive therapeutic target for redox-stress-related diseases.
    AREAS COVERED: In this review, we aim to consolidate information on the structural and mechanistic basis of APE1/Ref-1 redox and repair functions, while recognizing emerging evidence in DNA/RNA-forming G-quadruplex (rG4) biology, RNA metabolism, protein homeostasis, and mitochondrial function. We discuss mechanisms regulating APE1/Ref-1 expression, activity, and trafficking, which dynamically influence function in physiological and disease contexts. We specifically emphasize therapeutic strategies including redox-specific inhibition, endonuclease-targeted approaches, and genetic perturbations that result in distinct effects across disease models.
    EXPERT OPINION: Evolving understanding of APE1/Ref-1 biology has accelerated therapeutic development, particularly through redox-selective targeting strategies. Small-molecule inhibitors such as APX3330 and new-generation analogs like APX2009 and APX2014 have advanced into therapeutic applications spanning cancer, inflammatory disorders, and ocular diseases. Continued investigation into the context-dependent and multifunctional roles of APE1/Ref-1, together with the progression of mechanism-informed therapeutic design, is steadily strengthening the translational potential of APE1/Ref-1-directed therapies.
    Keywords:  APE1/Ref-1; cancer therapeutics; diabetic retinopathy; inflammation; inflammatory bowel disease; mitochondrial function; redox-selective inhibition; transcriptional regulation
    DOI:  https://doi.org/10.1080/14728222.2026.2706465
  27. Kidney Int. 2026 Aug;pii: S0085-2538(26)00427-8. [Epub ahead of print]110(2): 291-293
    Mitochondria poor but capacity rich? The paradox of podocyte respiration.
    Antonio S Novaes, Ilse S Daehn.
      Campbell et al. show that podocyte mitochondria, isolated using a cell-specific MITO-Tag approach, possess high intrinsic respiratory capacity despite their low abundance. The study demonstrates that conventional culture conditions suppress mitochondrial respiration and increase oxidative stress, suggesting that current experimental systems may underestimate mitochondrial function in podocytes. The authors provide evidence that mitochondrial respiratory capacity in podocytes declines in male mice with aging, indicating that mitochondria could play a role in age-associated glomerular injury.
    DOI:  https://doi.org/10.1016/j.kint.2026.05.008
  28. J Med Internet Res. 2026 Jul 23. 28 e101711
    Initial-Visit Specialty Triage in Rare Diseases Using Large Language Models: Retrospective Benchmarking Study.
    Jie Song, Zhichuan Xu, Meng Xiao, Cheng Bi, Yuxin Zhang, Xin Zheng, Xiaoran Li, Qiongfang Cao, Ziyu Lu, Hao Yang, Bairong Shen.
       Background: Specialty triage at first contact is an overlooked step in early diagnostic pathways for rare diseases. Patients often present with overlapping, multisystem, and atypical manifestations, making first-visit specialty selection challenging and potentially prolonging diagnostic pathways.
    Objective: The aim of this study is to evaluate the accuracy, response time, and consistency of large language models (LLMs) for initial-visit specialty triage in rare diseases across multiple datasets, and to compare their performance with registered nurses and nonmedical participants.
    Methods: In this retrospective benchmarking study, we used 5 rare disease datasets: a publication-derived case set, 3 RareBench-derived datasets, and a Facial phenotype-Gene-Disease Dataset-derived set. Fourteen LLMs were evaluated over 5 independent runs per case. Performance was assessed using accuracy, response time, and consistency, with subgroup analyses by model accessibility, reasoning mode, parameter scale, and phenotype count. Human comparison was conducted on the publication-derived case set using registered nurses and nonmedical participants.
    Results: Across datasets, model accuracy ranged from 0.4378 to 0.7141. Claude-opus-4-5 achieved the highest accuracy (0.7141) and consistency (0.9653), averaging 10.79 seconds per case. GPT-5.1 had the shortest response time (3.39 s/case) and high accuracy (0.6948). Proprietary models had numerically higher average accuracy than open-weight models (0.6973 vs 0.6365). Nonthinking models achieved higher average accuracy than thinking models (0.6789 vs 0.5826) and had shorter response times, although this exploratory comparison was based on a small number of thinking models. Accuracy varied by phenotype count, with higher performance in cases with 1 to 2 or more than 14 phenotypes. On the publication-derived case set, LLMs achieved higher average accuracy than registered nurses and nonmedical participants (0.5978 vs 0.4914 and 0.4573).
    Conclusions: LLMs showed potential as assistive tools for initial-visit specialty triage in rare diseases. Model choice, reasoning mode, and phenotype information density influenced performance, but subgroup findings should be interpreted cautiously. Future work should evaluate LLM-based specialty triage in prospective clinical settings and develop clinician-supervised workflows with traceable evidence support.
    Keywords:  artificial intelligence; digital health; large language models; rare diseases; specialty triage
    DOI:  https://doi.org/10.2196/101711
  29. J Radiat Res. 2026 Jul 21. pii: rrag054. [Epub ahead of print]
    The role of cytosolic mitochondrial DNA as a mitochondrial danger signal for stromal fibroblasts in forming the tumor-promoting microenvironment following radiation exposure.
    Tsutomu Shimura.
      Inflammation plays an essential role in detecting foreign pathogens, which triggers a defensive response, eliminates infected tissue and facilitates tissue repair. However, when acute inflammation progresses to chronic inflammation, it contributes to the development of diseases, such as cancer. Both the inflammatory response and gene mutations are key elements of radiation-induced carcinogenesis; however, the molecular mechanisms underlying the initiation of the inflammatory response following radiation have not been fully understood yet. We hypothesize that cytosolic mitochondrial DNA is a mediator of the inflammatory response in radiation-induced tumor microenvironment formation. Using normal human fibroblasts and mice, we recently demonstrated that radiation fragmented mitochondrial DNA, which was subsequently released into the cytoplasm. Unlike nuclear DNA, cytosolic mitochondrial DNA is considered foreign by the DNA sensor cyclic GMP-AMP synthase, cGAS, and triggers an immune response similar to that evoked by viral DNA. Thus, cytosolic mitochondrial DNA is a mediator of inflammation in various physiological and pathological contexts. In addition, mitochondrial DNA fragments are released into the extracellular matrix. Such mitochondrial danger signals generated by fibroblasts in response to radiation exposure contribute to inflammation. Here, this review discusses the manner in which mitochondrial danger signals alter the microenvironment of tissue stem cells, or the stem cell niche, and contributes to the formation of the tumor microenvironment. In addition, the mechanisms underlying radiation-induced carcinogenesis are addressed.
    Keywords:  cytosolic mitochondrial DNA; inflammation; mitochondria danger signal; radiation-induced carcinogenesis; tumor microenvironment
    DOI:  https://doi.org/10.1093/jrr/rrag054
  30. Mol Ther. 2026 Jul 20. pii: S1525-0016(26)00594-0. [Epub ahead of print]
    The power of one: The unexpected benefits of correcting a single tissue in multisystem mitochondrial disease.
    Carlos T Moraes.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.025
  31. JMIR Mhealth Uhealth. 2026 Jul 20. 14 e85425
    A Personal Health App and Wearable Co-Design Framework for Rare and Complex Diseases: User-Centered, Collaborative Co-Design Study.
    Sarah Margaret Goodday, Emma Karlin, Madeleine Sorensen, Robin Yang, Paul Gordon, Caresse Opoku, Daniel Vuong, Jenee Wilson, Diane McKenzie, Jules Piccotti, Massimiliano Tavanti, Megan Fitzgerald, Yochai Re'em, Hannah Wei, Megan Golden, Daniel Morgan, Michele Manion, Ricardo Mosquera, Tricha Shivas, Elise Hoover, Allison Peck, Nathan Peck, Zollie Yavarow, Heidi Bjornson-Pennell, Andra Stratton, Samali Anova Sahoo, Douglas Arbittier, Elizabeth Arbittier, Renee Goff, Donna Harvin-Graham, Nancy Howard, Camille Knudsen, Mary Oldham, Stephen Friend.
       BACKGROUND: End user co-design in the personal digital health technology space is underdeveloped. Clinical uptake of personal digital health technologies has been poor, highlighting a need to cocreate solutions with end users.
    OBJECTIVE: The study aimed to describe an "end user" co-design framework in the development of 5 prototype personal health apps for patients with different rare or complex diseases.
    METHODS: A patient-led, user-centered, collaborative personal health app plus wearable plug-in co-design methodology was developed. Five prototype apps were developed for end users with long COVID-19, pancreatitis, primary ciliary dyskinesia, sarcoidosis, and valosin-containing protein disease by a multidisciplinary partnership including patients, app design and development experts, user experience experts, clinicians, and patient-driven organizations. Phase 1 involved a 6-month co-design process with 5 modules involving patient-driven organizations that included the codevelopment of specifications through group workshops and independent exercises that defined the goals, content, features, and user experience of each app. Phase 2 involved app build-out, internal alpha testing, and beta study preparations. Phase 3 involved a usability beta testing study in which end users used the app and associated wearable/smart devices (Oura ring, Lumia ear device, Empatica EmbracePlus, and MIR Spirobank Spirometer) for up to 5 months. Participant feedback was documented continuously and systematically, centering on the following themes: functionality, usability, harms, benefits, self-explorations, and beta testing study details related to retention and adherence.
    RESULTS: While unique app goals were codeveloped by each disease group, a central goal across groups was to develop a personal health app enabling users to track subjective, self-reported symptoms, objective measures of health, and unique modifiers of symptoms. A total of 239 end user participants participated in the beta testing pilot study. Enrollment and retention rates were high, ranging from 94% to 100% and 92.2% to 100%, respectively. All active participants gave some form of feedback: there were 257 unique participant suggestions of how to specifically modify or improve the study app experience. Participant feedback themes commonly centered around customization to reduce daily burden and improve personal tailoring of the app. Participants' desires surrounding symptom displays were heterogeneous.
    CONCLUSIONS: Personal health app co-design is rooted in a complex digital landscape that requires a significant amount of up-front effort and time. However, the up-front investment of time can result in rich and diverse end user feedback that could save time in the app development trajectory to implementation. This paper provides a co-design framework and the building blocks of 5 prototype personal health apps with publicly available open-source code on GitHub. These prototypes could be leveraged for improving understanding of, communicating symptoms of, and providing n-of-1 suggestions for rare or complex diseases, providing benefit to patient communities and individual patients.
    Keywords:  PCD; VCP disease; co-design; digital health; l ong COVID-19; mobile health; pancreatitis; primary ciliary dyskinesia; sarcoidosis; user-centered; valosin-containing protein; wearables
    DOI:  https://doi.org/10.2196/85425
  32. Orphanet J Rare Dis. 2026 Jul 21.
    Launching a multi-level data strategy for rare eye diseases: a methodological case study from national to European scale.
    Camille Beluffi-Marin, Marilyne Oswald, Isabella Anna Vacchi, David Keegan, Bart Peter Leroy, Hélène Dollfus.
      Rare eye diseases bring unique challenges in clinical research and patient care due to their heterogeneity, low prevalence, and dispersed expertise. To address these challenges, an integrated multilevel data strategy has been developed in France and Europe, enabling structured, interoperable data collection and reuse across national and transnational initiatives. In this paper, we present a methodological framework using the metaphor of a spaceship to illustrate the vertical articulation of this ecosystem, from national infrastructures to European platforms. At the base of the spaceship lies BaMaRa, France's national registry for rare diseases, which ensures the systematic collection of core clinical data at the point of care. The next stage is FREDD, a disease-specific data warehouse dedicated to rare eye conditions, developed by the SENSGENE network thanks to the France 2030 RaReTiA project. FREDD integrates granular phenotypic and genotypic data, allowing for in-depth research and cohort building. FREDD is fully interoperable with BaMaRa, ensuring data consistency and minimizing redundancies. The third level of the spaceship is REDgistry, the European registry for rare eye diseases coordinated by ERN-EYE. REDgistry allows for cross-border data harmonization and aligns with FAIR principles to facilitate data sharing and secondary use in international research. At the top of the structure is the European Health Data Space, a future platform enabling secure and standardized access to health data for research and policy-making at the EU level. At the core of this architecture remains the patient, whose data is the very foundation of the system. Although not always actively involved in data collection, the patient remains central to the purpose and structure of each data layer. Building and sustaining such a complex infrastructure requires the coordination of a wide range of stakeholders, including clinicians, research networks, data stewards, hospital IT departments, national authorities, and European institutions. The success of this multilevel model depends on shared standards, transparent governance, and sustained collaboration across all actors. Together, they form the propulsion system of the spaceship, enabling the structured reuse of high-quality data to accelerate research and improve care in the field of rare eye diseases.
    Keywords:  BNDMR; BaMaRa; Data governance; ERN-EYE; Health care data secondary use; Health data warehouse; Interoperability; Rare eye diseases; SENSGENE
    DOI:  https://doi.org/10.1186/s13023-026-04505-0
  33. JMIR Med Inform. 2026 Jul 24. 14 e87831
    Persona-Driven Data Augmentation for Disease Name Recognition Across Rare and General Disease Corpora: Comparative Evaluation Study.
    Jude Crener Junior Pierre, Tomohiro Nishiyama, Shaowen Peng, Shoko Wakamiya, Eiji Aramaki.
       BACKGROUND: Medical information extraction requires automatically identifying disease names and related terms in text. This task, known as named entity recognition (NER), relies on expert-annotated data that are costly to produce and often available only in limited quantities. Data augmentation (DA) aims to expand available training data; however, standard techniques such as synonym replacement and back-translation may introduce inappropriate substitutions or fail to preserve entity-label alignment, which is critical for sequence-labeling tasks. Although large language models can generate fluent text, their outputs may also contain factual inconsistencies or unintended changes if not carefully controlled.
    OBJECTIVE: This study investigated whether persona-driven, document-level DA using a large language model could improve biomedical disease NER performance by generating diverse rephrasings of medical documents while preserving annotated entities.
    METHODS: We designed a DA framework using multiple personas that varied in medical expertise, personality, tone, and narrative style. Using prompting constrained by XML tags, each persona rephrased training documents while aiming to preserve annotated entity spans. We evaluated the framework on 2 biomedical disease NER datasets with complementary roles: RareDis, a low-resource rare disease corpus, and National Center for Biotechnology Information (NCBI) disease, a more general disease benchmark. Semantic fidelity and lexical diversity were measured using BERTScore and Bilingual Evaluation Understudy (BLEU-4), respectively, and personas were grouped into high-, balanced-, and low-fidelity subsets. Biomedical pretrained BioBERT models were fine-tuned and evaluated under multiple settings, including gold-standard (GS) data only, synonym replacement, single-persona augmentation, curated persona subsets, and all-persona augmentation. Performance was assessed using microaveraged entity-level precision, recall, and F1-score, and results were examined at both the overall and individual entity-type levels. Performance values are reported as mean (SD).
    RESULTS: Persona-driven DA improved NER performance over GS-only training in both datasets, with the strongest gains obtained by combining multiple persona-generated variants with GS data. In RareDis, the best result was achieved by the low-fidelity subset (mean F1-score 73.35, SD 0.19 vs baseline 71.22, SD 0.45), while in NCBI disease, the all-personas setting performed best (mean F1-score 89.32, SD 0.26 vs baseline 87.82, SD 0.18). In low-resource experiments, the all-personas and high-fidelity persona settings in NCBI disease exceeded the performance of the model trained on 100% GS data using only 60% of the training data, whereas gains in RareDis were more modest. Entity-level analysis showed improvements across RareDis categories, particularly for symptom, and confusion analysis indicated reduced symptom-sign confusion under augmentation.
    CONCLUSIONS: Persona-driven DA improved biomedical disease NER by introducing controlled linguistic variation while largely preserving annotated entities. The strongest gains were obtained when multiple persona-generated variants were combined with GS data, although the benefit varied across datasets. These findings suggest that this approach is a promising strategy for low-resource biomedical NER.
    Keywords:  LLM; NER; NLP; data augmentation; disease; large language model; low-resource; named entity recognition; natural language processing; persona; rare disease
    DOI:  https://doi.org/10.2196/87831
  34. J Clin Pharmacol. 2026 Jul;66(7): e70242
    Accelerating Pediatric Oncology Drug Development: Advances in Clinical Pharmacology, Trial Design, Non-Clinical Evidence, and Regulatory Science.
    Ya-Feng Wen, Xiaoning Wang, Sarandeep Boyanapalli, Lee Anderson, Thao Dang, Guan Xing, Marianna Calvet, Tiffany Hart, Sreeneeranj Kasichayanula, Xiaochen Zhao.
      Pediatric oncology drug development remains uniquely challenging due to the rarity and biological heterogeneity of childhood cancers, ethical considerations in trial conduct, and the limited feasibility of large, randomized studies. Despite these barriers, recent years have seen a notable acceleration in the approval of oncology therapies for pediatric populations, driven by advances in molecularly targeted treatments, evolving regulatory requirements, and innovation in trial design. Reducing nonclinical data requirements and increasing the adaptation of model‑informed drug development approaches are also contributing to advances in pediatric oncology treatment by supporting dose selection, optimizing study design, and reducing unnecessary patient burden. In this review, recent regulatory requirements from the United States, the EU, and other key regions on pediatric oncology drug development are discussed. Thirty-three drugs with oncology indications in pediatric populations approved by the US FDA between 2018 and 2025 are reviewed. These approvals provide examples of how nonclinical and clinical data were generated with a focus on strategies for dose-finding and justification. Common challenges and considerations related to clinical operations and formulation development in pediatric populations and the emerging use of real-world data, external controls, and artificial intelligence/machine learning are also discussed.
    Keywords:  clinical pharmacology; clinical trial design; model‐informed drug development; oncology; pediatric; real‐world evidence
    DOI:  https://doi.org/10.1002/jcph.70242
  35. Hum Mutat. 2026 ;2026 9236120
    From Variant Interpretation to Biomarker Translation: Multi-omics Integration in Inherited Neuromuscular Diseases.
    Suming Zhang, Xiaoling Lang, Lunxin Liu.
      Genetic neuromuscular diseases are highly heterogeneous disorders characterized by diagnostic challenges and limited therapeutic options, underscoring an urgent need for precise biomarkers. The rapid advancement of multi-omics technologies has broadened biomarker discovery from single genomics to multidimensional integrative analyses encompassing transcriptomics, proteomics, and metabolomics. This progression offers opportunities to improve disease diagnosis, subtyping, prognosis assessment, and treatment monitoring. However, translational gaps persist between multi-omics discoveries and clinically applicable biomarkers. This review systematically examines the current application of multi-omics biomarkers in genetic neuromuscular diseases. It provides an in-depth analysis of the multifaceted barriers encountered during the translation process, including technical hurdles, clinical validation complexities, data interpretation challenges, and health system-level obstacles. Furthermore, the review explores emerging solutions including artificial intelligence-assisted decision-making, ethical governance, and policy preparedness. The review aims to offer a framework for constructing a potentially responsible and efficient multi-omics translation in genetic neuromuscular diseases.
    Keywords:  artificial intelligence; biomarkers; clinical translation; genetic neuromuscular diseases; multi-omics integration; variant of uncertain significance
    DOI:  https://doi.org/10.1155/humu/9236120
  36. Clin Pharmacol Ther. 2026 Jul 20.
    From Models to Meaning: The Integrator Pharmacologist's Role in Advancing Health Equity Across the Drug Development Continuum.
    Rajesh Krishna.
      Modeling and simulation strategies have evolved from supportive analytical tools to central decision-making engines across drug discovery, development, and regulatory science. By integrating data, models, and stakeholder perspectives, integrator pharmacologists ensure that early discovery decisions translate into robust clinical strategies, meaningful benefit-risk assessments, and ultimately, patient access. This reflection underscores how equity-focused quantitative thinking will pave the path for the next generation of translational science.
    DOI:  https://doi.org/10.1002/cpt.70398
  37. Smart Med. 2026 Jun;5(3): e70043
    Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
    Yixiang Zhang, Yawei Du, Shifeng Ling, Hanqi Wang, Jiahao He, Jiahong Li, Kaifeng Huo, Baikun Liu, Qingfeng Li, Jiao Wei, Wenguo Cui.
      Adipose-derived stem cells (ADSCs) are central regulators of adipose tissue homeostasis and regenerative capacity. Accumulating evidence indicates that aging and obesity profoundly impair ADSC function, through progressive mitochondrial dysfunction and disrupted mitochondrial-nuclear communication. Emerging studies reveal that defects in nuclear-mitochondrial crosstalk constitute a key driver of ADSC senescence and adipose tissue aging. In this review, we synthesize recent advances in understanding the mitochondrial mechanisms underlying ADSC aging, with particular emphasis on how mitochondrial dysfunction reshapes stem cell fate decisions, metabolic plasticity, and inflammatory signaling within aged adipose niches. We further highlight mitochondria targeting therapeutic strategies that hold promise for reversing ADSC senescence. Collectively, this framework positions mitochondrial regulation as a unifying axis for ADSC rejuvenation, offering new opportunities to restore adipose tissue homeostasis and mitigate age-related metabolic dysfunction.
    Keywords:  adipose derived stem cell; aging; cellular communication; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/smmd.70043
  38. MedComm (2020). 2026 Aug;7(8): e70866
    SIRT Family: Biological Functions and Therapeutic Targets.
    Jia-Yi Wang, Feng-Li Jiang, Fang-Yuan Zhang, Dong-Hui Huang, Xiao-Ying Li, Song Gao, Hua You, Qi-Jun Wu, Huan-Huan Chen, Ting-Ting Gong.
      Sirtuins (SIRT1-SIRT7) are nicotinamide adenine dinucleotide (NAD+) dependent deacylases that serves as metabolic sensors, coupling cellular energy status to chromatin structure, mitochondrial function, and stress responses. Dysregulated SIRT activity has been extensively studied in aging, metabolic syndrome, cardiovascular disease, neurodegeneration, cancer, and immune disorders. However, robust human evidence and SIRT-targeted therapies are lacking. Transgenic mouse models serve as key platforms to study gene function and guide therapeutic development. This review synthesizes evidence from Sirt1-7 transgenic mouse models regarding the core cellular processes governed by SIRTs: metabolism, genome integrity, stress resistance, immunity, and autophagy, and illustrates their operation across different organ systems. By comparing global, tissue-specific, and inducible knockout (KO) and overexpression (OE) models of cardiovascular, respiratory, digestive, nervous, endocrine, urogenital, musculoskeletal, malignant, and immune diseases, we identified central regulatory SIRTs (SIRT1, SIRT3, and SIRT6), context-dependent modifiers (SIRT2, SIRT4, SIRT5, and SIRT7), and their organ- and cell type-specific functions. We also summarize representative small-molecule SIRT activators, inhibitors, and degraders, covering both clinical and preclinical studies, and highlight where contradictions and knowledge gaps remain. Together, these analyses help clarify which aspects of SIRT modulation are most promising and under what isoform, tissue, and disease contexts they should be pursued for the development of SIRT‑targeted therapies in human disease.
    Keywords:  Sirtuins; inflammation; metabolism; therapeutic targets; transgenic mouse model
    DOI:  https://doi.org/10.1002/mco2.70866
  39. Andrology. 2026 Jul 20.
    Sperm Mitochondrial DNA Copy Number and Nuclear DNA Methylation Across Clinical and Non-Clinical Preconception Cohorts.
    Savni Sawant, Karolina Nowak, Amanda L Paskavitz, Emily Houle, Ricardo P Bertolla, Lidia Minguez-Alarcon, Russ Hauser, J Richard Pilsner.
       BACKGROUND: Sperm mitochondrial DNA copy number is an emerging marker of male fertility, with elevated mtDNAcn associated with poor semen quality across various populations. Sperm DNA methylation has also been previously demonstrated to be negatively correlated with semen parameters in IVF cohorts.
    OBJECTIVE: To determine whether mtDNAcn is associated with nuclear DNA methylation across three population-based and clinical fertility cohorts.
    DESIGN: The association between sperm mtDNAcn and genome-wide DNA methylation was investigated in 748 men from a general population cohort (LIFE; n = 379) and two infertility cohorts (SEEDS; n = 170 and EARTH; n = 199). Sperm DNA methylation and mtDNAcn were quantified by the Illumina EPIC (v1) array and triplex probe-based digital PCR, respectively. Covariate-adjusted linear regressions were conducted within each cohort and then meta-analyzed using METAL. Gene ontology analyses explored the biological relevance of differentially methylated CpGs (DMCs) and regions (DMRs).
    RESULTS: Using a Holm-Bonferroni significance threshold, our analyses identified 1351, 224, and 258 DMCs and 2582, 1536, and 1284 DMRs in LIFE, SEEDS, and EARTH, respectively, indicating that higher sperm mtDNAcn was associated with DNA hypermethylation. In meta-analysis, 576 DMCs were associated with mtDNAcn. Notably, the genes corresponding with DMCs and DMRs are known critical regulators of male fertility and were enriched in the regulation of male meiosis, germline protection, spermatogenesis pathways, and early embryonic development.
    DISCUSSION AND CONCLUSION: Our results, observed across three independent cohorts and supported by meta-analysis, indicate a consistent association between the sperm mitochondrial genome and nuclear DNA methylation, suggesting that mtDNAcn and methylation patterns may be linked during spermatogenesis. Further research is warranted to elucidate the mechanisms underlying these associations and to evaluate their relevance for reproductive outcomes.
    Keywords:  epigenome wide association studies; male infertility; meta‐analysis; sperm DNA methylation; sperm mitochondrial DNA copy number
    DOI:  https://doi.org/10.1111/andr.70320
  40. Mol Biol Rep. 2026 Jul 22. pii: 1236. [Epub ahead of print]53(1):
    ER-mitochondria contact sites and organelle stress in asthma.
    Sihao Zhu, Xinxin Xing, Jia Zheng, Hai Wang.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.
    Keywords:  Asthma; ER–mitochondria contact sites; Mitochondria-associated endoplasmic reticulum membranes; NLRP3 inflammasome; Organelle stress
    DOI:  https://doi.org/10.1007/s11033-026-12441-2
  41. Nat Rev Mol Cell Biol. 2026 Jul 24.
    Mitochondrial tRNA biogenesis, modifications and disease relevance.
    Wen-Yu Zhu, Ilias Skeparnias, Athanasios-Nasir Shaukat, Jinwei Zhang, Ru-Juan Liu.
      The biogenesis, modifications and function of mitochondrial transfer RNAs (mt-tRNAs) reflect the symbiotic relationship and coordinated evolution between the domesticated organelle and the outer cell. Through evolution, mt-tRNA structures have been severely degenerated, and mt-tRNA-associated proteomes have acquired additional domains and interfaces, leveraging post-transcriptional modifications to maintain functional affinity and specificity. Considerable progress has been made in the past decade in elucidating mt-tRNA structure, biogenesis, modifications and functions. In this Review, we outline how mt-tRNAs are excised from polycistronic transcripts and mature through coordinated actions of mitochondrial processing enzymes. We then examine how mitochondrial aminoacyl-tRNA synthetases and mitoribosomes have coevolved to recognize degenerated mt-tRNAs and support a streamlined genetic code. The roles of post-transcriptional modifications in mt-tRNA structure stabilization, mt-tRNA decoding and the coupling of metabolism to translation are also discussed. Moreover, we review mt-tRNA-associated pathologies and emerging therapeutic strategies, highlighting unifying principles that inform efforts to restore coherence of mitochondrial translation.
    DOI:  https://doi.org/10.1038/s41580-026-00999-5
  42. Neurosci Appl. 2026 ;5 107021
    Outcome strategies for clinical trials in Neuropaediatric rare diseases.
    Maria Teresa Acosta, José Ángel Aibar, Celso Arango, Estibaliz Arce Cirauqui, Cristina Baeza, Elizabeth Berry-Kravis, Kim I Bishop, Joan Busner, Chere Chapman, Boris Chaumette, Inés Del Cerro, John Carlos Diaz, Georg Dorffner, Chris J Edgar, Simona Giorgi, Sabine M Hölter, Sarah Kittel-Schneider, Robert D Latzman, Carmen Moreno, Stefano Pallanti, Carlotta Colzi, Carme Plasencia, Franziska Radtke, Kenneth Rockwood, Antonella Santuccione Chadha, Gunes Sevinc, Manpreet K Singh, Suzanne H Smith, P K Tandon, Daniella Tinoco, Eleonora Broggi, Sara Fontecha Morgan, Igor Magaraggia, Silvia Zaragoza Domingo.
      Neuropaediatric Rare Diseases (NRDs) impose a profound and multidimensional burden on patients, families, and healthcare systems. Persistently low clinical trial success rates reflect an unmet methodological need as much as a therapeutic one. A fundamental bottleneck is the absence of fit-for-purpose clinical outcome assessments. In fact, instruments validated for non-rare or adult populations fail to capture clinically meaningful change in heterogeneous, small, and developmentally complex NRD populations. Building directly on a systematic catalogue of methodological challenges in NRD outcome research published by our group (Acosta et al., 2025), this paper presents a structured set of actionable outcome strategies proposed by a large multidisciplinary expert group convened under the auspices of the European College of Neuropsychopharmacology (ECNP) and the International Society for CNS Clinical Trials and Methodology (ISCTM). Using a structured, iterative expert-opinion approach, each identified challenge served as a prompt for developing one or more candidate strategies, each mapped one-to-one to its corresponding barrier. Strategies are presented across four thematic domains: (1) innovative methodologies to enhance ecological validity and reduce rater context effects; (2) novel or adapted outcomes and endpoints that preserve clinical meaningfulness under conditions of high heterogeneity and limited sample sizes; (3) the purposeful use of natural history resources; and (4) approaches to support comparability and synthesis across programmes. Additional considerations address caregiver expectancy bias and recruitment, stakeholder alignment, maturational confounding, and preclinical-clinical connectivity. Collectively, these strategies constitute a practical, challenge-mapped "living" toolbox for clinical scientists designing NRD trials. Each strategy is already in use or validated in analogous rare-disease contexts. Realising their potential at scale requires institutional programmes, pre-competitive co-validation platforms, systematic stakeholder co-design, and early engagement with regulatory agencies as scientific partners in endpoint development.
    Keywords:  Clinical outcome assessments; Clinical trials; Digital health technologies; Natural history data; Neuropaediatric rare diseases; Outcome measures
    DOI:  https://doi.org/10.1016/j.nsa.2026.107021
  43. Cell Signal. 2026 Jul 23. pii: S0898-6568(26)00411-0. [Epub ahead of print] 112754
    Mitochondrial dysfunction in intervertebral disc degeneration: Linking oxidative stress, altered cell fate, and Matrix degeneration.
    Cong Zhang, Zuolong Wu, Rui Ran, Guanghai Zhao, Wei Song, Yongqiang Shi, Weiwei Ma, Haihong Zhang.
      Intervertebral disc degeneration (IVDD) is a major pathological basis of chronic low back pain and is closely associated with disrupted cellular homeostasis, extracellular matrix (ECM) imbalance, and chronic inflammation. In recent years, mitochondrial dysfunction has emerged as a key upstream event linking multiple degenerative changes in the disc. Impaired mitochondrial homeostasis, characterized by energy metabolism disorder, mitochondrial membrane potential loss, excessive mitochondrial reactive oxygen species (mtROS) production, Ca2+ imbalance, and mitochondrial DNA damage, can promote abnormal cell fate decisions, suppress ECM synthesis, and enhance matrix catabolism. In parallel, mechanical overload, inflammatory stimulation, hypoxia, nutrient deprivation, acidic stress, aging, and oxidative stress further aggravate mitochondrial injury, forming a self-amplifying cycle of microenvironmental stress, mitochondrial dysfunction, oxidative damage, cell fate dysregulation, and ECM degeneration. Although previous reviews have discussed mitochondrial dysfunction in IVDD from the perspectives of small-molecule interventions, ER stress-mitochondrial crosstalk, mitochondrial quality control (MQC), or mitophagy, a unified framework connecting mitochondrial injury with oxidative stress, regulated cell fate programs, inflammatory amplification, and ECM degeneration remains insufficiently defined. By integrating mitochondrial pathology, cell fate regulation, biomarker development, and therapeutic implications, this review provides a systematic framework for understanding IVDD pathogenesis and developing future disease-modifying treatments.
    Keywords:  Cell fate; Extracellular matrix; Intervertebral disc degeneration; Mitochondrial dysfunction; Nucleus pulposus cells; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112754
  44. Commun Med (Lond). 2026 Jul 20.
    Integrating remote testing and machine learning to identify markers of cerebellar ataxia at home.
    Penina Ponger, Yael De Picciotto, Daniela Maisel, Hanna Liandres, Sarah Brisman, William Saban.
       BACKGROUND: In-person assessments face accessibility, scalability, and geographic diversity challenges, especially for rare diseases. Additionally, Cerebellar Ataxia (CA) non-motor symptoms(NMS) are often overlooked. We aimed to address these gaps by leveraging the Internet and machine-learning.
    METHODS: In a bi-center study, we assessed 100 participants: 30 CA, 45 neurotypically healthy(NH), and 25 Parkinson's disease(PD), recruited from 57 geographical locations across two countries. We evaluated multiple domains-cognition, anxiety, depression, social support, and personality-using accessible online tools. We applied leave-one-out cross-validation and feature importance analysis to examine the machine-learning model's ability to distinguish between groups and identify the most sensitive and specific CA predictors.
    RESULTS: Machine-learning models trained on these remote non-motor features alone, yield AUCs of 0.74/0.76(CA vs. NH) and 0.78/0.79 (CA vs. PD) using leave-one-out cross-validation, demonstrating classification power exceeding 20%.
    CONCLUSION: These findings highlight the value of integrating digital-health technologies and machine-learning models for CA NMS evaluation, potentially serving as scalable digital-markers.
    DOI:  https://doi.org/10.1038/s43856-026-01794-1
  45. Commun Med (Lond). 2026 Jul 20.
    Integrating care across the life course supports goal-aligned end-of-life care.
    M Courtney Hughes.
      As global populations age and lifespan increases, health systems too often conceptualize "healthy aging" and "end-of-life care" as distinct phases. Yet emerging evidence from geroscience, palliative care, and health systems science suggests that aging and dying lie on a continuum of adaptation and care. This Perspective proposes a framework that treats system-supported, goal-aligned end-of-life care as a public health outcome of integrated life-course care and argues for system redesign to introduce earlier palliative approaches, align care models across the life-course, and reduce health disparities. This article outlines key mechanisms, evidence for integration, a conceptual model, and implications.
    DOI:  https://doi.org/10.1038/s43856-026-01807-z
  46. Fish Physiol Biochem. 2026 Jul 23. pii: 124. [Epub ahead of print]52(4):
    Zebrafish as a versatile model in biomedical research, from disease modeling to regenerative medicine: a review.
    Seyede Fatemeh Heydari, Azam Abedi, Amir Mohammad Mirnejad, Hamid Kooshki, Mehrdad Moosazadeh Moghaddam.
      Zebrafish are an effective animal model widely utilized in biomedical research. They are known for their rapid reproduction and substantial genetic similarity to humans. Their transparent embryos directly enable the visualization of developmental processes and disease progression. This makes zebrafish invaluable for studying a broad range of human diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Compared with other vertebrate models, zebrafish offer several advantages, including ease of genome editing, cost-effective maintenance, and suitability for high-throughput drug screening. Recent advancements have expanded the use of zebrafish in disease modeling and regenerative medicine, providing deeper insights into the genetic and cellular mechanisms underlying human pathologies. Zebrafish provide a robust platform for evaluating the safety, efficacy, and regenerative potential of both natural and synthetic biomaterials, including hydroxyapatite, bioactive glass nanoparticles, and bioceramics. This capability facilitates the creation of artificial tissues that closely resemble native structures. Additionally, integrating artificial intelligence technologies has improved automated data analysis and phenotyping in zebrafish studies, enhancing both accuracy and throughput. This review highlights current applications of zebrafish in disease modeling, drug discovery, regenerative medicine, and biomaterial assessment, emphasizing their evolving role as a versatile preclinical platform supported by advanced genetic and computational tools.
    Keywords:  Animal model; Artificial intelligence; Disease modeling; Drug screening; Patient-derived xenograft; Regenerative medicine; Zebrafish
    DOI:  https://doi.org/10.1007/s10695-026-01748-3
  47. Biometals. 2026 Jul 21.
    The emerging role of trace elements in epilepsy and metabolic disorders: a new frontier in neurotherapeutics.
    Sana El Foutat, Abdelaati El Khiat, Naima Fdil.
      Studies investigating the relationship between trace element status and disease variability in humans are steadily increasing. Experimental and clinical data suggest that normal brain function critically depends on the homeostasis of several trace elements, and that disturbances in this balance may contribute to epileptogenesis. Trace elements in epilepsy have therefore emerged as a growing field of research, with numerous studies exploring the mechanisms by which different metal ions influence epileptic seizures in both animal models and patients. This review summarizes current evidence on the trace elements most frequently associated with epilepsy, including selenium, iron, copper, zinc and manganese, and highlights inherited metabolic disorders Menkes diseases and Congenital Hypomagnesemia, as well as selected mitochondrial syndromes, in which profound trace element imbalances converge with epileptic phenotypes. In addition, we discuss how antiepileptic drugs and the ketogenic diet can modify trace element levels in serum and other biological matrices. We performed a bibliographical synthesis to examine the correlation between epilepsy and abnormal concentrations of trace elements; namely zinc, copper, iron, selenium, manganese, magnesium and phosphorus, in blood and brain. Overall, available evidence suggests that trace element dysregulation may influence epileptogenesis, seizure susceptibility, and response to antiepileptic therapies.
    Keywords:  Element trace; Epilepsy; Epileptogenesis; Inherited metabolic disorders; Therapeutic
    DOI:  https://doi.org/10.1007/s10534-026-00852-4
  48. Genet Mol Biol. 2026 ;pii: S1415-47572026000500122. [Epub ahead of print]49Suppl 1(Suppl 1): e20250248
    Continuity and discontinuity in Native American populations: Insights from ancient and modern mitochondrial DNA.
    Gustavo Medina Tavares, Bastien Llamas, Rafael Bisso-Machado.
      Ancient DNA research has expanded dramatically in recent years, transforming reconstructions of how and when humans settled the American continent. In this review, we synthesize evidence for genetic temporal continuity and discontinuity in Native American population history using mitochondrial DNA (mtDNA) from ancient and contemporary individuals. We systematically surveyed studies indexed in PubMed, ResearchGate, and Google Scholar, extending earlier compilations with publications through October 2025. For each population, we compiled sample sizes, mtDNA haplogroup frequencies, geographic coordinates, and associated archaeological and chronological information. These data were used to map the spatial distribution of founding mtDNA lineages, examine regional trajectories of haplogroup frequencies, and characterize patterns of mitochondrial population structure. Geographic distance showed a statistically detectable but limited association with mtDNA differentiation. Time-ordered haplogroup frequency series revealed region-specific dynamics, including long-term persistence of maternal lineages as well as marked episodes of turnover, some coincident with major cultural transitions. Genetic data were obtained from 315 studies. The dataset for contemporary populations included 23,315 individuals from 322 populations, while ancient DNA data included 4,192 individuals associated with 211 archaeological populations. Together, these data provide a comprehensive synthesis of mtDNA-based temporal and spatial patterns relevant to the peopling of the American continent.
    DOI:  https://doi.org/10.1590/1678-4685-GMB-2025-0248
  49. Gene. 2026 Jul 20. pii: S0378-1119(26)00328-8. [Epub ahead of print]1010 150318
    Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
    Priyanka Priyadarshini Pattnaik, Shakti Ketan Prusty, Sanghamitra Pati, Kiran Anjum Jew, Anirban Kumar Bora, Jyotirmaya Sahoo, Pratap Kumar Sahu.
      Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.
    Keywords:  Biomarkers; Gene interplay; Multi-omics; Neurodegeneration; Neuroinflammation; Precision medicine; Protein aggregation
    DOI:  https://doi.org/10.1016/j.gene.2026.150318
  50. Clin Liver Dis. 2026 Aug;pii: S1089-3261(26)00042-5. [Epub ahead of print]30(3): 751-760
    "Overlap" Syndromes in Autoimmune Liver Disease: Definitions, Clinical Challenges and Future Directions.
    Roie Tzadok, Inbal Houri.
      Autoimmune liver diseases, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are rare chronic conditions characterized by immune-mediated hepatobiliary injury. While traditionally viewed as distinct entities, they exist along a continuous spectrum, manifesting in some cases as "overlap" or "variant" syndromes. These variants are considered phenotypic variations of shared pathways rather than unique diseases. The rarity of these conditions and an incomplete understanding of their underlying pathophysiology have prevented standardized definitions, and ultimately hinder the development of robust, evidence-based clinical protocols for these patient populations. This review aims to offer a pragmatic clinical approach to these complex cases.
    Keywords:  Autoimmune hepatitis (AIH); Overlap; Primary biliary cholangitis (PBC); Primary sclerosing cholangitis (PSC); Variant
    DOI:  https://doi.org/10.1016/j.cld.2026.04.008
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