bims-polgdi Biomed News
on POLG disease
Issue of 2026–08–09
forty-six papers selected by
Luca Bolliger, lxBio
  1. Targeting mitochondria for the treatment of neurodegenerative diseases.
  2. Drug safety in patients with mitochondrial disease: an observational cohort study.
  3. Rare Pyloric Stenosis in Mitochondrial Disease Treated with Hand-Assisted Laparoscopic Pyloromyotomy.
  4. Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
  5. Mitochondria with (distinct) personality.
  6. Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.
  7. Exploring cell-type associations of rare disease phenotypes using non-diseased cell atlases.
  8. Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.
  9. The Microbiome-Mitochondria Axis in aging: a self-reinforcing vicious cycle linking metabolic dysregulation, mitochondrial quality control failure, and inflammaging.
  10. Clarifying the complex: New guidance for rare disease care.
  11. Intercellular mitochondrial exchange shapes tumor evolution, microenvironment adaptation, and therapeutic vulnerabilities.
  12. Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
  13. Stepwise Diagnostic Evaluation of Chinese Large Language Models: Comparative Study of Common and Rare Diseases.
  14. Mechanistic pathways linking gut microbial metabolites, microbial structural products, and host-microbe co-metabolites to mitochondrial function.
  15. Rett syndrome: The Natural History Study journey.
  16. Designing an integrated data model for prospective genotype-phenotype in inborn errors of immunity research.
  17. Organ-specific mitochondrial heterogeneity: An under-recognized variable in preclinical drug toxicity screening.
  18. Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
  19. Neurons Die Not by One Hit, but by Signaling Convergence.
  20. Evolution and synergy of healthcare security policies for rare diseases in China: a quantitative content analysis.
  21. Mitochondrial quality control in acute liver injury and its therapeutic implications (Review).
  22. Developing consensus on rare disease care pathways and ERN integration across Europe: insights from stakeholder workshops and a Delphi study.
  23. Beyond the Pump: Unravelling Immunometabolic Crosstalk and Organelle Dynamics in Sepsis-Induced Cardiomyopathy.
  24. Reconceiving orphan drug market exclusivity as a conditional public-law entitlement: a sustainable regulatory governance model with comparative lessons for China.
  25. Clinical Development of Therapies for Charcot-Marie-Tooth Disease: Recommendations for Trial Design, Endpoints, and Regulatory Pathways.
  26. Mitochondria-targeted therapeutic strategies in assisted reproduction: challenges and potential solutions.
  27. Lamotrigine-induced Stevens-Johnson syndrome in the setting of mitochondrial encephalomyopathy: A case report.
  28. The (European) protein homeostasis network.
  29. The microbiome-mitochondria axis: the context-dependent role of urolithin A in aging and cancer via mitophagy.
  30. Astrocytes in Genetic Epilepsies: Supporting Actor or Key Player?
  31. Brain aging clocks: From methodological advances to cellular mechanisms.
  32. Foundation models for low-data drug discovery: mining heterogeneous public and proprietary data in neglected indications.
  33. Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.
  34. Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
  35. Microswimming as a mechanism for mitochondrial wiggling.
  36. Can agentic AI dent Eroom's Law? Large reasoning models across the drug discovery and development pipeline.
  37. Accelerating AI-Driven Neuroimaging Research in Dementia.
  38. Challenges in the care of rare vascular liver diseases: Insights from patients, health care providers, and patient organizations.
  39. Multilevel impairment of mitochondrial respiration in inclusion body myositis.
  40. Caenorhabditis elegans in neuroscience: from neural communication to neurodegenerative disease modeling.
  41. Calreticulin as a stress-responsive integrator of ER proteostasis, calcium homeostasis, and immune clearance.
  42. Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.
  43. Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
  44. KBG syndrome: A scoping review of electroclinical features of patients with epilepsy.
  45. Building data science capacity in the public health workforce: a Public Health Data Science Life Cycle framework.
  46. Data Governance Transformation: Now is the time to revisit Data Governance Policy.
  1. Front Neurosci. 2026 ;20 1835506
    Targeting mitochondria for the treatment of neurodegenerative diseases.
    Qian Li, Ming You.
      Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.
    Keywords:  blood–brain Barrie; mitochondrial dysfunction; mitochondrial targeting; nanocarrier delivery system; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnins.2026.1835506
  2. Neurol Sci. 2026 Aug 06. pii: 683. [Epub ahead of print]47(9):
    Drug safety in patients with mitochondrial disease: an observational cohort study.
    Oskar Järvinen, Mika H Martikainen.
       BACKGROUND: Mitochondrial diseases are common inherited neurometabolic disorders and frequently involve the nervous system, yet their multisystem nature often necessitates complex pharmacological management. Many commonly prescribed medications have off-target effects on mitochondrial function, and patients with mitochondrial disease may be particularly vulnerable to such effects due to impaired energy metabolism. However, systematic data on medication safety in this patient group remain scarce.
    METHODS: In this retrospective, single-centre, cohort-based study at Turku University Hospital (Turku, Finland), we reviewed the medication data from all hospital stays and outpatient prescriptions of 44 mostly adult (20 women; mean age 50 years, range 12-83 years) patients with genetically and clinically confirmed mitochondrial disease for years 2010-2022. We used the Anatomical Therapeutic Chemical system for drug classification. Potential drug-drug interactions and potential adverse drug reactions were investigated. Special focus was on potential mitochondrial toxicity of drugs and clinically relevant drug-drug interactions.
    RESULTS: Altogether ~ 1000 individual medication entries were reviewed. We identified several common drugs with potentially adverse effects on mitochondria, including metformin, beta-blockers, statins, ciprofloxacin, fluoxetine, ibuprofen, and certain anti-seizure drugs. Medications generally considered contraindicated in mitochondrial disease were not observed. No high-risk drug interactions were detected. Additional finding of clinical relevance was the frequent use of analgesics.
    CONCLUSIONS: Further research regarding mitochondrial safety of several drug classes is needed for more evidence-based safety evaluations. Pain in the context of mitochondrial disease merits increased attention.
    Keywords:  Drug safety; Medication; Mitochondria; Mitochondrial disease; Pharmacological treatment
    DOI:  https://doi.org/10.1007/s10072-026-09298-5
  3. CRSLS. 2026 Jul-Sep;13(3):pii: e2026.00033. [Epub ahead of print]13(3):
    Rare Pyloric Stenosis in Mitochondrial Disease Treated with Hand-Assisted Laparoscopic Pyloromyotomy.
    Francis S Lee, Christina W Lee, Clare H Lee, Vincent Hunley.
      Mitochondrial diseases are rare genetic disorders that affect the body's ability to produce energy at the cellular level. Because many organs rely heavily on mitochondrial function, these diseases can cause a wide range of symptoms involving the nervous system, muscles, heart, and gastrointestinal tract. Gastrointestinal complications are common and may include difficulty swallowing, gastroparesis, and intestinal motility disorders. Although pyloric stenosis has rarely been reported, mitochondrial dysfunction affecting gastrointestinal smooth muscle and enteric neuronal function provides a plausible mechanism for the development of gastric outlet obstruction and pyloric dysfunction, leading to severely limited nutritional intake, weight loss, and malnutrition. We present the case of a young woman with a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) variant who developed severe pyloric stenosis resulting in chronic gastric outlet obstruction and profound malnutrition. Her condition progressed to complete dependence on total parenteral nutrition (TPN) and was complicated by recurrent septicemia related to central line-associated bloodstream infections (CLABSI). After failing conservative treatment, she underwent laparoscopic hand-assisted pyloromyotomy with intraoperative esophagogastroduodenoscopy. Following surgery, her gastric emptying improved significantly, allowing her to regain weight and discontinue TPN. With her nutritional status and strength restored, she was able to resume normal activities and successfully complete her college education. This case demonstrates the significant gastrointestinal complications that can occur in mitochondrial disease and highlights the potential benefit of surgical intervention in selected patients with severe pyloric dysfunction.
    Keywords:  Central line-associated bloodstream infection (CLABSI); Gastrointestinal dysmotility; Gastroparesis; Hand-assisted laparoscopy; Intraoperative esophagogastroduodenoscopy (EGD); Laparoscopic pyloromyotomy; Malnutrition; Metabolic disorder; Mitochondrial disease; Mitochondrial encephalomyopathy; Pyloric stenosis; Septicemia; Total parenteral nutrition (TPN); and stroke-like episodes (MELAS); lactic acidosis
    DOI:  https://doi.org/10.4293/CRSLS.2026.00033
  4. J Transl Med. 2026 Jul 31. pii: 988. [Epub ahead of print]24(1):
    Impaired NADH-linked mitochondrial respiration disrupts ventral midbrain neuronal programs in POLG disease.
    Anbin Chen, Tsering Yangzom, Gareth John Sullivan, Kristina Xiao Liang.
       BACKGROUND: POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined.
    METHODS: Using patient-derived midbrain organoids and single-cell RNA sequencing, we investigated how POLG mutations alter mitochondrial and neuronal programs at subtype resolution. We analyzed dopaminergic neuronal populations and ventral midbrain neurons to define disease-associated transcriptional changes. To evaluate therapeutic improvement, POLG organoids were treated chronically with nicotinamide riboside (NR), followed by single-cell transcriptomic profiling and pathway enrichment analysis.
    RESULTS: POLG mutations induced a coordinated downregulation of genes associated with oxidative phosphorylation and synaptic signaling, particularly in terminally differentiated dopaminergic neurons. This transcriptional alteration involved genes encoding respiratory chain complexes I-V, mitochondrial translation machinery, and ATP synthase components, suggesting disruption of mitochondrial bioenergetic programs at the transcriptomic level. Among dopaminergic subtypes, DA2 neurons and ventral midbrain neurons showed the most pronounced transcriptional alterations, indicating maturation-dependent vulnerability. NR treatment was associated with altered expression of genes involved in oxidative phosphorylation, NADH dehydrogenase activity, respiratory chain assembly, and synaptic pathways. Following NR exposure, dopaminergic subpopulations exhibited changes in cell-type proportions and partial normalization of mitochondrial- and synaptic-related transcriptional programs.
    CONCLUSIONS: These findings identify transcriptional alterations in pathways related to mitochondrial respiration. The data further suggests that modulation of NAD⁺ metabolism is associated with transcriptional changes in mitochondrial and neuronal pathways in this disease context.
    Keywords:  Dopaminergic vulnerability; Midbrain organoids; NADH-dependent respiration; POLG disease; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12967-026-08706-w
  5. Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923
    Mitochondria with (distinct) personality.
    Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.
      Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.044
  6. Front Neurol. 2026 ;17 1882474
    Targeting mitochondrial ribosomal proteins: a functional and translational framework for neurodegenerative disease research.
    Luigi Del Giudice, Marco Guida, Maria Rosaria Aletta, Paola Pontieri.
      Mitochondrial dysfunction is a central feature of neurodegenerative diseases, yet the molecular mechanisms governing mitochondrial protein synthesis remain insufficiently understood. Mitochondrial ribosomal proteins (MRPs), essential for the translation of mitochondrial-encoded components of the oxidative phosphorylation system, are emerging as critical regulators of neuronal homeostasis and survival. In this mini-review, we examine current knowledge on mitochondrial ribosomes with a focused analysis of three mitochondrial ribosomal proteins-MRPL44, NAM9, and GEP3-highlighting their structural and functional roles in maintaining mitochondrial integrity. We discuss evidence linking alterations in these proteins to key pathogenic processes relevant to neurodegeneration, including impaired oxidative phosphorylation, increased oxidative stress, and defective mitochondrial quality control. Importantly, we propose an integrative research perspective that positions these MRPs as potential modulators of tissue-specific vulnerability in neurodegenerative disorders. By synthesizing available data and identifying critical knowledge gaps, we outline future directions aimed at elucidating their contribution to neuronal dysfunction and disease progression. This work underscores mitochondrial ribosomal proteins as underexplored determinants of neurodegenerative pathology and suggests that their systematic investigation may reveal novel mechanistic insights and therapeutic opportunities.
    Keywords:  Alzheimer's and Parkinson's disease; GEP3; MRPL44; NAM9; mitochondrial disease; mitochondrial genome; nuclear genome; yeast and C. elegans model organisms
    DOI:  https://doi.org/10.3389/fneur.2026.1882474
  7. Brief Bioinform. 2026 Jul 03. pii: bbag426. [Epub ahead of print]27(4):
    Exploring cell-type associations of rare disease phenotypes using non-diseased cell atlases.
    Jorge Novoa, Florencio Pazos, Monica Chagoyen.
      Rare diseases individually affect few patients but collectively impose a substantial global health burden. Many have a genetic origin, yet the cellular contexts in which disease genes exert their effects often remain unclear. Direct molecular investigation of disease-relevant tissues is often infeasible owing to small patient populations and frequent congenital or pediatric onset, limiting access to patient-derived samples. Here we investigate whether existing healthy human single-cell atlases can help identify candidate cellular contexts associated with rare disease phenotypes. Specifically, we test the hypothesis that cells expressing more genes linked to a phenotype than expected from their overall transcriptional activity may represent contexts particularly susceptible to disruption. Applied to more than 1300 phenotypes across multiple tissues, the analysis shows partial concordance with literature-derived phenotype-cell type relationships, with predictive performance reaching AUC ≈ 0.71 depending on the dataset. These findings suggest that transcriptional patterns captured in healthy single-cell atlases may contain informative signals about disease-relevant cellular contexts when the relevant cell populations are represented. At the same time, the results highlight the limitations of current reference resources and the need for continued efforts to improve single-cell atlases, phenotype-tissue mappings, and benchmarking datasets linking rare disease phenotypes to cellular contexts.
    Keywords:  human cell atlases; rare diseases; scRNA-seq
    DOI:  https://doi.org/10.1093/bib/bbag426
  8. Crit Rev Oncol Hematol. 2026 Aug 06. pii: S1040-8428(26)00417-8. [Epub ahead of print] 105530
    Mitochondrial transfer in the tumor microenvironment: mechanisms, immunometabolic consequences, and therapeutic implications.
    Sijia Feng, Yanan Hu, Shuqing Li, Yuqiao Chang, Zhenwei Li, Yanting Liu, Kai Xu.
      Mitochondrial transfer has emerged as a previously underappreciated layer of intercellular communication within the tumor microenvironment. Accumulating evidence demonstrates its contribution to the metabolic and functional plasticity of both tumor and immune cells. Rather than representing a rare stochastic event, mitochondrial exchange occurs across multiple cell types-including cancer cells, stromal cells, and infiltrating immune cells-via distinct structures such as tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and transient cell fusion events. In tumor cells, acquisition of exogenous mitochondria is commonly associated with enhanced oxidative phosphorylation (OXPHOS), improved metabolic adaptation, and increased tolerance to therapeutic stress. Conversely, immune cells that undergo mitochondrial depletion or receive dysfunctional mitochondria frequently display impaired bioenergetic capacity and diminished effector function, thereby contributing to immune dysfunction in the TME. Recent advances in intravital imaging, single-cell technologies, and lineage tracing have provided compelling evidence that mitochondrial transfer is a dynamic, context-dependent and often directional process. Beyond metabolic effects, mitochondrial components, particularly mitochondrial DNA (mtDNA), can engage innate immune pathways including TLR9, NLRP3, and cGAS-STING, thus modulating inflammatory signaling and antitumor immunity. Overall, mitochondrial transfer functions as a bidirectional regulator of immunometabolic states in cancer, with potential either to support tumor progression or to modulate immune responses, depending on cellular context. Understanding the molecular determinants governing this process may offer opportunities to selectively target pathological mitochondrial exchange or to exploit it for therapeutic benefit in cancer immunotherapy. This comprehensive review examines the molecular mechanisms, immunological consequences, and therapeutic implications of mitochondrial transfer in cancer.
    Keywords:  extracellular vesicles; metabolism; mitochondrial transfer; tumor immune microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105530
  9. Front Microbiol. 2026 ;17 1874222
    The Microbiome-Mitochondria Axis in aging: a self-reinforcing vicious cycle linking metabolic dysregulation, mitochondrial quality control failure, and inflammaging.
    Enshuo Liu, Jianbo Jia, Qi Liu, Chunyan Li, Shanhui Li, Tao Cai.
      Aging is a progressive degenerative process of cellular and systemic homeostasis in organisms, with mitochondrial dysfunction and altered intercellular communication as core hallmarks of this process. During aging, the gut microbiome and mitochondria exhibit a highly synchronized degenerative trajectory: this is characterized by decreased microbial diversity, reduced abundance of beneficial short-chain fatty acid (SCFA)-producing bacteria, and expansion of pro-inflammatory pathobionts in the gut, alongside impaired oxidative phosphorylation efficiency, excessive reactive oxygen species (ROS) production, and compromised quality control in mitochondria. Built on the evolutionary cornerstone of endosymbiotic theory, this review establishes a theoretical framework for the Microbiome-Mitochondria Axis (MMA) and proposes that the ancient molecular homology between mitochondria and modern gut bacteria has preserved a sensitive cross-species signal crosstalk mechanism. This review systematically dissects the bidirectional communication mechanisms of the MMA. First, microbial metabolites-including SCFAs, tryptophan-derived indole metabolites, and secondary bile acids-regulate mitochondrial energy metabolism, oxidative stress responses, and dynamic homeostasis via key signaling pathways such as AMPK-PGC-1α, AhR-Nrf2, and FXR/TGR5. Conversely, dysfunctional mitochondria actively reshape the gut microenvironment and propagate sterile inflammation through multiple pathways: mitochondrial ROS (mtROS)-mediated intestinal barrier disruption, metabolic reprogramming of immune cells toward a pro-inflammatory phenotype, and activation of the cGAS-STING innate immune pathway triggered by mitochondrial DNA (mtDNA) release. Here, we propose a unified theoretical framework centered on the MMA as a self-reinforcing pathological loop. In this model, gut dysbiosis drives depletion of beneficial microbial metabolites, which triggers mitochondrial quality control failure, mtDNA leakage, and inflammaging; in turn, inflammaging exacerbates gut dysbiosis by remodeling the intestinal microenvironment, thus forming a closed, self-amplifying vicious cycle. The MMA links multiple hallmarks of aging, including epigenetic alterations, immunosenescence, and stem cell exhaustion, providing a unifying pathological basis for age-related disorders such as neurodegenerative diseases, cardiovascular diseases, sarcopenia, and osteoarthritis. It also offers a systematic entry point for anti-aging interventions targeting the bidirectional metabolic-immune crosstalk between the microbiome and mitochondria.
    Keywords:  Microbiome-Mitochondria Axis; aging; inflammaging; metabolic dysregulation; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3389/fmicb.2026.1874222
  10. Aust J Gen Pract. 2026 Aug;55(8): 570-572
    Clarifying the complex: New guidance for rare disease care.
    Krista Recsei, Elizabeth Lissiman, Hiba Gundru, Natalie Roberts, Lauren McKnight, Adam Jaffe, Elizabeth Emma Palmer, Andrew Knight.
       BACKGROUND: Rare diseases, defined as conditions with a prevalence of less than one in 2000, are a public health priority, as they are collectively common and associated with poor outcomes. General practitioners (GPs) are central to improving outcomes for people living with rare disease by providing holistic, lifelong and family-centred care. However, the complexity, number of rare diseases and system-wide limitations create challenges for GPs and patients alike.
    OBJECTIVE: This article outlines the challenges faced by people living with rare disease and highlights supportive resources for GPs to provide, facilitate and coordinate care.
    DISCUSSION: The new National Recommendations for Rare Disease Health Care (the Recommendations), co-designed with people living with rare disease, provide practical guidance on supporting patients on their journeys. Using a case study, we show how GPs can use the Recommendations.
    DOI:  https://doi.org/10.31128/AJGP-07-25-7737
  11. Transl Oncol. 2026 Aug 07. pii: S1936-5233(26)00250-0. [Epub ahead of print]72 102913
    Intercellular mitochondrial exchange shapes tumor evolution, microenvironment adaptation, and therapeutic vulnerabilities.
    Zhiyong Wu, Jianhao Bai, Aiqin Chang, Tianyu Wang, Yuan Liu, Hong Yu.
      Mitochondrial transfer has emerged as a previously underappreciated mode of intercellular communication with major implications for tumor biology. Beyond their cell-autonomous roles in bioenergetics and signalling, mitochondria can be exchanged between cells as intact organelles or as mitochondrial cargo, thereby reshaping the metabolic state, stress tolerance and therapy responsiveness of recipient cells. In tumors, mitochondrial transfer can buffer oxidative stress, compensate for mtDNA damage and restore oxidative phosphorylation, enabling metabolic plasticity and contributing to immune dysfunction within the tumor microenvironment. This review synthesized current evidence for the structural routes and regulatory logic of mitochondrial exchange in cancer, spanning actin-based tunneling nanotubes, extracellular vesicle-mediated export and uptake, and other contact-dependent mechanisms. We highlight actionable "gatekeepers" that constrain transfer efficiency, including conduit biogenesis programs, MIRO1/2-TRAK-motor coupling that licenses mitochondrial trafficking, and EV biogenesis/uptake modules, as well as microenvironmental triggers such as hypoxia and redox stress. We also evaluate emerging methodological standards required to distinguish bona fide organelle transfer from dye leakage or indirect cargo exchange, and discuss how orthogonal validation (genetic reporters, mtDNA barcoding and functional rescue assays) can improve rigor and comparability across studies. By integrating current findings, this article aims to provide a theoretical foundation and strategic guidance for targeting tumor metabolic regulation and improving precision oncology approaches.
    Keywords:  Immune evasion; Mitochondrial transfer; Therapeutic strategies; Tumor metabolic reprogramming; Tumor microenvironment; Tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.tranon.2026.102913
  12. J Mol Neurosci. 2026 Aug 05. pii: 124. [Epub ahead of print]76(3):
    Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
    Lishu Guo.
      Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.
    Keywords:  Aging; Mitochondria; Mitochondrial permeability transition; Neurodegeneration; The permeability transition pore
    DOI:  https://doi.org/10.1007/s12031-026-02583-0
  13. J Med Internet Res. 2026 Aug 06. 28 e89963
    Stepwise Diagnostic Evaluation of Chinese Large Language Models: Comparative Study of Common and Rare Diseases.
    Jiayi Wang, Jiao Yang, Rui Guo.
       Background: Large language models (LLMs) are increasingly applied in clinical decision support, yet their diagnostic performance in Chinese-language settings and under realistic clinical workflows remains unclear. In particular, how LLMs perform across diseases with different prevalence and under stepwise diagnostic processes has not been well characterized.
    Objective: This study aimed to evaluate the diagnostic capabilities of LLMs for common diseases and rare diseases using clinical vignettes within a hypothetico-deductive framework and to identify their potential and limitations for clinical diagnosis.
    Methods: We evaluated 4 Chinese LLMs (Doubao 1.5, DeepSeek-V3, Kimi K1.5, and Leftdoctor GPT 3.5) using 56 clinical cases (28 chronic obstructive pulmonary disease [COPD], and 28 relapsing polychondritis [RP]) sourced from the China Clinical Case Results Database (March 31-April 14, 2025). Patient information was provided incrementally, starting with the initial medical history, followed by physical examination, and laboratory results. Evaluation metrics included top-3 accuracy (RTop3D), top-1 accuracy (RTopD), final diagnostic accuracy (RFA), and mean reciprocal rank (MRR). Statistical analysis was performed using generalized estimating equations (GEE), Friedman tests, and Wilcoxon signed-rank tests with Bonferroni correction. In addition, a qualitative analysis was conducted to characterize recurrent patterns of diagnostic errors.
    Results: LLMs demonstrated significantly higher diagnostic accuracy for COPD compared to RP across all metrics (P<.001). Diagnostic accuracy improved after additional clinical information was provided, with the improvement mainly observed in RP cases. In RP, diagnostic accuracy increased from 32.14% to 71.43% for DeepSeek and from 35.71% to 78.57% for Doubao, whereas COPD accuracy remained consistently high across all diagnostic stages (82.14%-92.86%). For COPD, ranking performance was high and comparable among all models (MRR range: 0.82-0.89; P=.71). In RP, diagnostic performance differed significantly among models (MRR range: 0.10-0.39; P<.001). Qualitative analysis showed that COPD errors were mainly related to a failure to recognize specific features, whereas RP errors involved more diverse patterns, particularly the neglect of negative evidence and the failure to recognize specific features.
    Conclusions: Chinese LLMs demonstrated relatively strong diagnostic performance for common diseases such as COPD, but lower and less stable performance for rare diseases such as RP. Additional clinical information improved diagnostic accuracy primarily in RP cases, although differences between models remained evident under diagnostically complex conditions. Error patterns in RP cases suggest that current LLMs remain limited in their ability to integrate complex clinical information and exclusionary findings. Careful evaluation and appropriate clinical oversight remain important for their application in clinical practice.
    Keywords:  artificial intelligence; clinical decision-making; decision support systems; diagnostic accuracy; large language models
    DOI:  https://doi.org/10.2196/89963
  14. Gut Microbes. 2026 Dec 31. 18(1): 2694140
    Mechanistic pathways linking gut microbial metabolites, microbial structural products, and host-microbe co-metabolites to mitochondrial function.
    Richard E Frye, Daniel A Rossignol.
      Gut-derived microbial metabolites modulate host mitochondrial function. To our knowledge, no prior systematic review has synthesized evidence linking these metabolites to direct mitochondrial endpoints across all major metabolite classes. PubMed, Scopus, and Web of Science were systematically searched through March 2026 for studies examining direct mitochondrial endpoints in relation to ten classes of gut-derived metabolites. Gut-derived microbial metabolites exert diverse effects on mitochondrial function, ranging from bioenergetic enhancement to direct toxicity. After contextual evidence was excluded from the certainty assessment, four metabolite-mitochondrial outcome groupings had moderate certainty: butyrate, propionate, indoxyl sulfate, and lipopolysaccharide. Evidence for p-cresyl sulfate, H₂S, and urolithin A was rated low; evidence for the remaining metabolite classes was low or very low. Butyrate generally enhances mitochondrial biogenesis, ATP generation, and electron transport chain activity across multiple experimental models. Indoxyl sulfate generally impaired mitochondrial function, whereas p-cresyl sulfate produced concentration- and model-dependent effects. PGC-1α emerges as a central regulatory node, integrating microbial metabolic signals to control mitochondrial biogenesis and oxidative metabolism. Many microbial metabolites demonstrate concentration-dependent biphasic effects. These findings support a mechanistic microbiome-mitochondrial framework in which diverse gut-derived molecules converge on a limited set of mitochondrial control nodes: electron transport chain activity, reactive oxygen species handling, biogenesis, and mitophagy. The evidence base is predominantly preclinical; these insights should be considered hypothesis-generating.
    Keywords:  Gut microbiome; butyrate; electron transport chain; microbial metabolites; microbiome–mitochondria axis; mitochondrial function; short-chain fatty acids; systematic review
    DOI:  https://doi.org/10.1080/19490976.2026.2694140
  15. Ann Child Neurol Soc. 2024 Sep;2(3): 189-205
    Rett syndrome: The Natural History Study journey.
    Alan K Percy, Timothy A Benke, Eric D Marsh, Jeffrey L Neul.
      Understanding clinical features and disease progression of Rett syndrome (RTT) and establishing clinical trial readiness was enhanced by the RTT Natural History Study (NHS). The NHS benefited from two key developments: one, the Orphan Drug Act passed by Congress in 1983 defining criteria for rare disorders in the United States and creating opportunities for pharmaceutical companies to develop products for individuals with rare disorders, and two, the Rare Diseases Act of 2002, which established the National Institutes of Health Office of Rare Diseases and provided research funding. Funding for the RTT and related disorders NHS was obtained in 2003, creating a broad network of experienced clinical investigators across the United States and producing critical results not only for RTT but also for related disorders: CDKL5 deficiency disorder, FOXG1 disorder, and MECP2 duplication syndrome. Longitudinal information from over 1800 participants (more than 1600 diagnosed with RTT) led to multiple reports describing their clinical features and natural progression and identified putative biomarkers and clinical outcome measures. Establishing clinical trial readiness assisted in evaluating the first FDA-approved medication for RTT in 2023 and continues to provide opportunities to develop potentially life-altering therapies. The experiences of the RTT NHS journey provide informative guidance for studying other rare neurological disorders. These lessons include positive features of developing productive collaborations focused on improving lives of people and families with RTT and related disorders, as well as lessons learned through retrospective analysis for improving overall conduct of natural history studies in rare disorders.
    Keywords:  Rett syndrome; clinical trials; natural history studies; rare disorders; related disorders
    DOI:  https://doi.org/10.1002/cns3.20086
  16. Front Immunol. 2026 ;17 1838940
    Designing an integrated data model for prospective genotype-phenotype in inborn errors of immunity research.
    Maram Ahmed, Ahmed Aziz Bousfiha, Farida Almarzooqi.
       Background: Inborn errors of immunity are rare, genetically heterogeneous disorders requiring coordinated clinical, laboratory, and genetic evaluation over time. Data are often fragmented across records, laboratory systems, and genomic reports, limiting longitudinal analysis and coordinated care, particularly in the Middle East and North Africa, where structured rare disease data infrastructures remain limited.
    Objective: To develop a Research Electronic Data Capture-based data management framework for inborn errors of immunity and demonstrate its use in a prospective multi-site setting.
    Methods: A Research Electronic Data Capture-based framework was developed at the College of Medicine and Health Sciences, United Arab Emirates University. Modular instruments captured consent, demographics, biospecimen processing, laboratory workflows, and genetic findings within a longitudinal structure. Data dictionaries, validation rules, and conditional logic ensured data quality. The framework was deployed across participating sites for prospective data collection.
    Results: The framework enabled integrated longitudinal documentation of enrollment, biospecimens, and genetic testing. It was implemented across two clinical sites and used to enroll patients with suspected or confirmed inborn errors of immunity. The platform supported standardized cross-site data capture and monitoring of genetic findings, including automated flagging of variants of uncertain significance.
    Conclusion: This study demonstrates the development and early multi-site implementation of a Research Electronic Data Capture-based framework for inborn errors of immunity. By enabling standardized integration of clinical, laboratory, and genetic data, the platform supports data quality, cross-site collaboration, and tracking of evolving diagnoses. It provides a scalable foundation for rare disease research and may support improved clinical decision-making.
    Keywords:  REDCap; United Arab Emirates; data management; genotype; inborn errors of immunity; phenotype
    DOI:  https://doi.org/10.3389/fimmu.2026.1838940
  17. Mitochondrion. 2026 Aug 04. pii: S1567-7249(26)00089-9. [Epub ahead of print]91 102199
    Organ-specific mitochondrial heterogeneity: An under-recognized variable in preclinical drug toxicity screening.
    Nirupama Lal.
      Mitochondria exhibit substantial organ-specific heterogeneity arising from the distinct physiological, metabolic, and functional demands of individual organs. Differences in bioenergetics, oxidative stress handling, calcium homeostasis, and metabolic adaptability may influence mitochondrial responses to pharmacological agents and contribute to organ-selective drug toxicity. However, contemporary preclinical drug toxicity screening continues to rely predominantly on generalized experimental systems that may incompletely capture these organ-specific mitochondrial vulnerabilities. This Perspective proposes integrating organ-adapted mitochondrial physiology into preclinical drug safety evaluation through tissue-relevant cellular models, functional mitochondrial assays, and emerging microphysiological platforms to improve predictive toxicology and strengthen translational relevance.
    Keywords:  Drug safety screening; Mitochondrial heterogeneity; Mitochondrial toxicity; Organ-specific mitochondria; Predictive toxicology; Translational pharmacology
    DOI:  https://doi.org/10.1016/j.mito.2026.102199
  18. Cell Signal. 2026 Aug 02. pii: S0898-6568(26)00436-5. [Epub ahead of print]148 112778
    Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
    Wei Guan, Wenxu Li, Zijun Li, Lu Peng, Shidan Shao, Juanjuan Zhang.
      Leber's hereditary optic neuropathy (LHON) is a genetically inherited disease of the eye triggered by mtDNA mutations, leading to degeneration of RGCs. We previously reported that the mitochondrial tRNAThr (MT-TT) 15927G > A homoplasmic mutation disrupted the base pairing (28C-42G) conserved in the anticodon stem of tRNAThr, impairing t6A modification, aminoacylation, and steady-state tRNAThr levels, ultimately resulting in mitochondrial dysfunction. However, the absence of suitable animal and cell models for LHON has delayed efforts to elucidate disease pathophysiology, particularly tissue-specific effects. In this study, RGC-like cells were generated from iPSCs derived from a Chinese family member carrying the m.15927G > A mutation and from a control subject without this mutation. Mitochondrial dysfunction and autophagy/mitophagy defects were investigated at three differentiation stages: iPSCs, NPCs, and RGC-like cells. Both iPSCs and NPCs harboring this mutation exhibited abnormal mitochondrial dynamics, mitochondrial dysfunction, and defects in autophagy and mitophagy. RGC-like cells carrying the mutation showed significant abnormalities, including shorter neurites, imbalanced mitochondrial dynamics, elevated ROS production, reduced mitochondrial membrane potential, and impaired autophagy and mitophagy. These results indicate that the m.15927G > A mutation induces progressive mitochondrial dysfunction and developmental defects in RGCs, providing new insights into LHON pathogenesis and establishing a valuable model for future therapeutic development.
    Keywords:  Autophagy; Induced pluripotent stem cells (iPSCs); Leber's hereditary optic neuropathy (LHON); Neural progenitor cells (NPCs); Retinal ganglion cells (RGCs)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112778
  19. Mol Neurobiol. 2026 Aug 03. pii: 803. [Epub ahead of print]63(1):
    Neurons Die Not by One Hit, but by Signaling Convergence.
    Divyanshi Chauhan, Falguni Goel, Mithun Singh Rajput.
      There is an emerging understanding of neurodegenerative diseases as complex diseases with a combination of multiple interrelated signaling pathways as opposed to one causative factor. This review examines the idea that neurons do not die in a single event, but through convergence of signals, which outlines the different pathological events such as oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium imbalance, impaired proteostasis and neuroinflammation that interact to determine the fate of neurons. The processes are closely connected by molecular nodes like ROS, NF-κB, and MAPK signaling pathways, Nrf2/Keap1 antioxidant axis, and dysregulated autophagy and endoplasmic reticulum stress responses. The review also discusses the contribution of neuron glia interactions and the impact of microglial activation, astrocyte malfunction and cytokine networks in enhancing neuronal damage in a feedback mechanism. Mechanisms that have been mentioned as the oxidative stress inflammation cycle, mitochondrial damage, ROS feedback, and protein aggregation cellular stress loop are cited to be the major contributors to disease progression. Also, the review mentions new biomarkers, multi-omics methods, and sophisticated research instruments, such as artificial intelligence and organoid models, which can contribute to our knowledge of disease pathogenesis and help diagnose it earlier. On the whole, this review presents a complete paradigm on how to perceive neurodegeneration as a systems-level phenomenon. It combines molecular, cellular, and clinical perspectives and offers the rationale for the need to consider the therapeutic approach to neurodegenerative diseases in a holistic and multi-dimensional manner.
    Keywords:  Calcium imbalance; Excitotoxicity; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-026-06093-3
  20. Front Public Health. 2026 ;14 1864284
    Evolution and synergy of healthcare security policies for rare diseases in China: a quantitative content analysis.
    Jingying Gao, Chaojie Liu, Xinyang Wang, Haojia Cai, Yuqing Tang.
       Background: Managing rare diseases presents substantial challenges to achieving universal health coverage. Despite growing policy interest, limited research has explored the evolution and synergy of healthcare security policies targeting rare diseases. This study addresses this gap through a case study of China.
    Methods: An innovative analytical framework was developed, structured around three dimensions of policy synergy: horizontal, vertical, and temporal. A comprehensive dataset of national and provincial policy documents related to healthcare security for rare diseases was systematically collected. Analytical techniques included quantitative content analysis, word frequency analysis, and semantic network analysis.
    Results: A total of 314 policies enacted between 2001 and 2025 remained effective at the time of data collection, showing a general upward trend in both quantity and policy strength. However, the majority of policies were notices and announcements, which typically carry lower enforcement authority than ordinances and regulations. While a diverse array of policy instruments was employed, horizontal synergy across sectors remained limited. Vertically, national policies emphasized screening and support for children with rare diseases, whereas provincial policies focused more on outpatient service subsidies.
    Conclusion: Rare diseases have gained increasing attention within China's healthcare security policy landscape. Nonetheless, significant gaps in horizontal and vertical policy synergy persist. A systems-based approach is recommended to enhance policy integration and effectiveness.
    Keywords:  China; health policy; healthcare security; policy synergy; rare diseases
    DOI:  https://doi.org/10.3389/fpubh.2026.1864284
  21. Mol Med Rep. 2026 Oct;pii: 273. [Epub ahead of print]34(4):
    Mitochondrial quality control in acute liver injury and its therapeutic implications (Review).
    Ziqiang Chen, Yunhe Wang, Yijing Li, Gang Cong, Yunhang Chu, Yunhui Bai, Yishuo Zhang, Liya Zhou.
      Acute liver injury (ALI) is a clinically important syndrome with limited mechanism‑based therapies. Notably, mitochondrial dysfunction is increasingly recognized as a central driver of hepatocellular damage and repair failure. The present narrative review aims to summarize the current evidence on mitochondrial quality control (MQC) in ALI, with an emphasis on mitophagy, mitochondrial biogenesis, mitochondrial dynamics, etiology‑specific regulation and therapeutic implications. For the present review, relevant experimental and translational studies addressing MQC‑related mechanisms and interventions in major forms of ALI, including drug‑induced liver injury, ischemia‑reperfusion injury and viral ALI, were reviewed and integrated. The findings indicated that MQC operates as an interconnected network rather than as isolated pathways. Mitophagy, mitochondrial dynamics and mitochondrial biogenesis are temporally coordinated to remove damaged mitochondria, remodel mitochondrial networks and restore bioenergetic capacity. However, MQC responses differ across ALI etiologies, and inappropriate or excessive activation may become maladaptive. In conclusion, understanding MQC as a dynamic and context‑dependent repair system may provide a conceptual basis for precision interventions in ALI. Future studies should clarify spatiotemporal MQC regulation, establish reliable biomarkers and validate MQC‑targeted therapies in clinically relevant settings.
    Keywords:  acute liver injury; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2026.13984
  22. Eur J Med Genet. 2026 Aug 06. pii: S1769-7212(26)00030-3. [Epub ahead of print] 105096
    Developing consensus on rare disease care pathways and ERN integration across Europe: insights from stakeholder workshops and a Delphi study.
    JA JARDIN WP6 collaborators
       BACKGROUND: Rare disease care pathways are complex and require coordination among specialised and non-specialised services, including genetic diagnostics, multidisciplinary expertise, and cross-border collaboration. Despite increasing policy attention and the establishment of European Reference Networks, the development and implementation of cohesive rare disease care pathways remain inconsistent across Europe. A shared, consensus-based framework reflecting stakeholder priorities is needed.
    METHODS: This exploratory study combined structured stakeholder workshops and a Delphi consensus process. Nine workshops were conducted within the JARDIN project, engaging stakeholders from 16 European countries. Data were collected using standardised Miro boards and analysed thematically using MAXQDA, guided by the SEIPS 2.0 framework. Insights from this analysis informed the development of statements, which were evaluated through a Delphi survey. Consensus was predefined as a median score of at least 4, an interquartile range (IQR) ≤1, and ≥80% agreement (ratings 4-5).
    RESULTS: A total of 216 individuals participated in the workshops, of whom 164 contributed during live sessions. Workshop data generated 1,767 entries mapped across SEIPS domains. Seven thematic areas were identified: national strategy and governance; financing and sustainability; organisational structures and care coordination; access and equity; digital infrastructure and data systems; capacity building and education; and patient empowerment. Eighty-eight participants completed the Delphi survey, and consensus was achieved on all statements in the first round.
    CONCLUSION: The findings demonstrate strong cross-country agreement on system-level requirements for effective rare disease care pathways. These consensus statements provide a structured framework for developing national care pathways and integrating European Reference Networks activities into routine healthcare systems.
    Keywords:  European Reference Network (ERN); JARDIN; Rare disease; care pathway; healthcare
    DOI:  https://doi.org/10.1016/j.ejmg.2026.105096
  23. J Cardiovasc Transl Res. 2026 Aug 04. pii: 97. [Epub ahead of print]19(1):
    Beyond the Pump: Unravelling Immunometabolic Crosstalk and Organelle Dynamics in Sepsis-Induced Cardiomyopathy.
    Guangfu Liu, Liya Hao, Junfeng Zhang, Yidan Guo, Guangyue Lv, Jiuyuan Liu, Cheng Cheng, Han Yi, Jingjing Zhou, Zhenzhu Liu.
      Sepsis-induced cardiomyopathy (SICM) has traditionally been viewed as pump-centered contractile failure, but this paradigm fails to explain the clinical spectrum and recovery patterns. This review presents an integrative framework where immunometabolic crosstalk and organelle dysfunction drive disease, including metabolic routing defects, mitochondrial fission, ER stress, and epigenetic regulation via m6A modification and lactylation. Clinically, it proposes a four-phenotype taxonomy (hyperdynamic, hypodynamic, right ventricular-predominant, Takotsubo-like) and advocates for strain imaging and MRI over ejection fraction. Diagnostic innovation includes liquid biopsy for mitochondrial DNA, extracellular vesicles, and metabolomics. Therapeutically, metabolic resuscitation and phenotype-guided vasopressors offer disease modification. The authors call for adaptive trials, biobanking, and organelle-targeted interventions, positioning SICM as a model for precision immunometabolic medicine.
    Keywords:  Immunometabolism; Metabolic resuscitation; Mitochondrial dynamics; Organelle crosstalk; Sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.1007/s12265-026-10826-z
  24. Front Med (Lausanne). 2026 ;13 1896433
    Reconceiving orphan drug market exclusivity as a conditional public-law entitlement: a sustainable regulatory governance model with comparative lessons for China.
    Guiyu Quan, Yi Zhou, Yi Liu, Yinan Wu, Yong Yan.
       Background: Rare disease patients, who collectively number over 400 million worldwide, remain systematically underserved within existing universal health coverage frameworks. Orphan drug market exclusivity is a widely adopted regulatory incentive designed to stimulate pharmaceutical innovation for rare diseases. Recent regulatory reforms in China, the United States, and the European Union have introduced conditional mechanisms, signaling a shift from static proprietary protection toward a conditional regulatory governance model. Japan, while not undertaking legislative reform in 2026, offers a distinct reference point through its re-examination system. To date, no study has systematically integrated these latest legislative reforms into a comparative regulatory analysis or examined how the institutional design of orphan drug exclusivity can be calibrated to balance innovation incentives with equitable patient access.
    Methods: This study employs an integrated multi-method approach combining comparative legal analysis, doctrinal interpretation, evidence-based policy evaluation, and case analysis. A structured analytical framework is constructed around four key regulatory dimensions-eligibility criteria, exclusivity duration, scope of protection, and exception mechanisms. Using this framework, the study compares the orphan drug exclusivity regimes of the United States, the European Union, and Japan, and assesses the institutional risks embedded in China's newly enacted legislation.
    Results: This article proposes a novel theoretical model that reconceptualizes orphan drug market exclusivity as a conditional public-law entitlement whose legitimacy is premised on the continuing fulfillment of public health objectives. Applying this framework, the study identifies four core structural deficiencies in China's current regime and, drawing on mature comparative practices, develops targeted institutional design proposals for each regulatory dimension.
    Conclusions: Reconceiving orphan drug market exclusivity as a conditional public-law entitlement, rather than as an intellectual property right, offers a sustainable governance pathway for reconciling innovation incentives with the equity and financial protection goals of universal health coverage. Embedding conditional constraints into pharmaceutical exclusivity rules ensures that regulatory incentives serve long-term public health objectives and carries implications for addressing market failures and access challenges in other areas of global public health.
    Keywords:  access to medicines; conditional public-law entitlement; health equity; market exclusivity; orphan drugs; pharmaceutical regulation; public health policy; sustainable governance
    DOI:  https://doi.org/10.3389/fmed.2026.1896433
  25. J Peripher Nerv Syst. 2026 Sep;31(3): e70146
    Clinical Development of Therapies for Charcot-Marie-Tooth Disease: Recommendations for Trial Design, Endpoints, and Regulatory Pathways.
    ToPIC:CMT Steering Committee
      Charcot-Marie-Tooth disease (CMT) encompasses a heterogeneous group of inherited peripheral neuropathies. Despite being the most common genetic neurological condition, individual CMT subtypes are rare, presenting unique challenges for therapeutic development. The Together Patients Industry Clinicians versus CMT (ToPIC: CMT) Advocacy Group was formed with a diverse group of patient advocacy groups, clinician-scientists who treat patients with CMT, and pharmaceutical industry representatives to develop a common guidance on development of new treatments for CMT with clear expectations for meaningful patient outcomes and objective assessments of improvement. The ToPIC: CMT Group developed recommendations for clinical development of drugs and biological products for treating CMT, addressing trial design considerations for this rare progressive disease. Key challenges in CMT include small patient populations, variable disease progression, and the need for sensitive outcome measures. Recommendations emphasize flexible trial designs including adaptive designs, external controls, and single-participant designs when scientifically justified. Where possible, broad inclusion criteria based on clinical phenotype rather than genetic subtype alone are recommended. Disease-specific, validated outcome measures should assess function across ages and disease stages. Biomarkers reflecting peripheral nervous system health may serve as surrogate endpoints to support accelerated approval pathways. Patient and care partner perspectives are essential throughout development, particularly regarding treatment goals, risk tolerance, and meaningful endpoints. Successful therapeutic development for CMT and related neuropathies requires innovative approaches that balance rigorous scientific standards with the realities of rare disease research. Regulatory flexibility, informed by patient input and natural history data, can facilitate efficient development while maintaining assurance of safety and effectiveness.
    Keywords:  Charcot–Marie–tooth disease; clinical trials; drug development; inherited neuropathy; peripheral neuropathy; regulatory agency
    DOI:  https://doi.org/10.1111/jns.70146
  26. Hum Reprod. 2026 Aug 03. pii: deag118. [Epub ahead of print]
    Mitochondria-targeted therapeutic strategies in assisted reproduction: challenges and potential solutions.
    Raziye Melike Yildirim, Gizem Nur Sahin, Richard T Scott, Emre Seli.
      Mitochondria are central to oocyte competence and early embryonic development, with roles that extend beyond energy production to include regulation of redox homeostasis, apoptosis and cellular aging. Mitochondrial dysfunction is increasingly recognized as a key contributor to diminished ovarian reserve, impaired embryo development, and accelerated reproductive aging. Mitochondria-targeted therapeutic strategies, including pharmacological approaches such as Coenzyme Q10, mitoquinone, resveratrol, rapamycin, and NAD+ precursors, as well as mitochondrial replacement techniques such as maternal spindle and pronuclear transfer, have shown promise in preclinical models; however, clinical outcomes remain heterogeneous and often inconclusive. This translational gap likely reflects critical limitations, including variability in therapeutic targets, suboptimal timing of intervention relative to oocyte development, and insufficiently powered or standardized clinical studies. Greater emphasis on well-defined, physiologically justified therapeutic targets, along with the use of physiologically relevant experimental systems, may improve therapeutic precision and efficacy. Rigorous evaluation of safety, particularly for interventions with pleiotropic effects or heritable consequences, remains essential. A more targeted, developmentally informed and systematically validated approach is needed to advance mitochondria-based therapies toward meaningful improvements in reproductive outcomes.
    Keywords:  embryo aneuploidy; mitochondrial dysfunction; mitochondrial replacement therapy; oocyte quality; ovarian reserve
    DOI:  https://doi.org/10.1093/humrep/deag118
  27. Ther Adv Neurol Disord. 2026 ;19 17562864261474798
    Lamotrigine-induced Stevens-Johnson syndrome in the setting of mitochondrial encephalomyopathy: A case report.
    Ye Tian, Teng Chen, Jingwen Liu, Juan Wang, Lihong Zhang.
      A 67-year-old male with Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS) who developed life-threatening Stevens-Johnson Syndrome (SJS) more than one month after initiating lamotrigine (LTG) for epilepsy management. Despite prompt LTG discontinuation and aggressive immunomodulatory therapy, the patient succumbed to severe infection and multiple organ failure. LTG-induced SJS is associated with multiple risk factors. The immune-activating microenvironment resulting from mitochondrial dysfunction may potentiate the risk of LTG-induced SJS. Lamotrigine should be used cautiously for epilepsy in high-risk patients, particularly those with mitochondrial encephalomyopathy (ME), and comprehensive evaluation is required to minimize severe hypersensitivity reactions.
    Keywords:  Stevens-Johnson syndrome; adverse effect; case report; lamotrigine; mitochondrial encephalomyopathy
    DOI:  https://doi.org/10.1177/17562864261474798
  28. FEBS J. 2026 Aug 05.
    The (European) protein homeostasis network.
    Eric Chevet.
      Proteostasis, the cellular network that governs protein synthesis, folding, trafficking, and degradation, is essential for maintaining cellular and organismal homeostasis. This review series highlights the breadth and impact of European research in the field of proteostasis, spanning fundamental mechanisms, organelle-specific quality control pathways, and emerging therapeutic opportunities. Contributions from leading laboratories across Europe examine key components of the proteostasis network, including translational regulation, molecular chaperones, ubiquitin-dependent protein degradation, organelle communication, and adaptive stress responses. Particular emphasis is placed on proteostasis mechanisms operating within the endoplasmic reticulum and mitochondria as well as on their roles in aging, inflammation, neurodegeneration, and other human diseases. The series also showcases the collaborative efforts that have strengthened the European proteostasis community through major networking initiatives and training programs. Together, these articles provide a comprehensive overview of current advances in proteostasis research and underscore its growing importance as a framework for understanding cellular adaptation and developing innovative therapeutic strategies.
    Keywords:  cellular signaling network; protein degradation; protein folding; protein quality control; protein synthesis; proteostasis; stress response; ubiquitin
    DOI:  https://doi.org/10.1111/febs.70663
  29. Mol Biol Rep. 2026 Aug 04. pii: 1331. [Epub ahead of print]53(1):
    The microbiome-mitochondria axis: the context-dependent role of urolithin A in aging and cancer via mitophagy.
    Jiayuan Wu, Xinxin Ye, Wei Hua, Yuyang Yao, Lu Sun, Hongyu Ma, Congcong Yu, Yanling Cheng, Shengquan Mi.
      Urolithin A (UA) is a gut microbiota-derived metabolite formed from dietary ellagitannins and ellagic acid. It has drawn sustained interest because it can influence mitochondrial quality control, but the evidence does not support a simple anti-aging or anticancer label. In this review, UA is examined across microbial metabolism, urolithin metabotypes, pharmacokinetic exposure, mitophagy biology, aging-related phenotypes, and cancer. The emphasis is placed on what has been shown, what remains model-dependent, and where translational claims are still premature. Preclinical work links UA to PINK1/Parkin-, TFEB-, AMPK-, sirtuin-, and Nrf2-associated pathways, with reported improvements in mitochondrial turnover and inflammatory signaling. Human data are narrower: most trials have been short and have focused on safety, muscle performance, mitochondrial signatures, and circulating biomarkers. Evidence for cancer prevention or cancer therapy still comes mainly from cell and animal studies. Because mitophagy can limit early mitochondrial damage but may also help established tumors survive hypoxia, nutrient restriction, dormancy, and therapy-induced stress, UA is better regarded as a microbiome-dependent mitochondrial modulator whose effects depend on biological setting. The next step is to define direct molecular targets, test native and conjugated UA at human-relevant exposure ranges, account for UM-A, UM-B, and UM-0 metabotypes, and evaluate cancer-specific endpoints before making therapeutic claims.
    Keywords:  Aging; Cancer; Gut microbiota; Mitophagy; Urolithin A; Urolithin metabotype
    DOI:  https://doi.org/10.1007/s11033-026-12542-y
  30. J Neurosci Res. 2026 Aug;104(8): e70148
    Astrocytes in Genetic Epilepsies: Supporting Actor or Key Player?
    Jenny Lange, Erica Zhao, Ellie O'Connell, Olivia Gillham, Amy McTague.
      Epilepsy is one of the most common neurological disorders worldwide, affecting around 1% of the population. The epilepsies represent a diverse group of conditions, ranging from acquired forms resulting from neurological insults to common multifactorial epilepsies and rare, often monogenic epilepsies caused by highly penetrant genetic variants. The genetic epilepsies demonstrate frequent comorbidity with a range of neurodevelopmental and psychiatric disorders, and epileptic seizures are also a common feature of neurodevelopmental disorders such as Fragile X syndrome and Rett syndrome. Astrocytes, the most numerous glial cells in the central nervous system, have emerged as crucial players in the pathophysiology of acquired epilepsies. Whilst the contribution of astrocytes to acquired epilepsy has been widely reviewed, astrocyte dysfunction in rare genetic epilepsies or neurodevelopmental disorders has been neglected, despite the fact that the genes implicated are expressed in astrocytes, albeit to a lesser extent than in neurons. Additionally, affected individuals with rare genetic epilepsies are more likely to exhibit drug-resistant seizures, highlighting the need to identify novel therapeutic targets. In this paper, we review the existing literature on astrocyte dysfunction in genetic epilepsy syndromes and neurodevelopmental disorders with seizures. We have identified several key studies that highlight alterations in crucial astrocyte functions including calcium signaling and ion homeostasis. Our review highlights the need for further research to establish the contribution of astrocyte dysfunction to neuronal health and seizure activity in rare genetic epilepsies.
    Keywords:  astrocytes; epilepsy; neurodevelopment
    DOI:  https://doi.org/10.1002/jnr.70148
  31. Exp Gerontol. 2026 Aug 02. pii: S0531-5565(26)00239-1. [Epub ahead of print]223 113260
    Brain aging clocks: From methodological advances to cellular mechanisms.
    Kyoungho Suk.
      Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution. This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes. Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging. SIGNIFICANCE STATEMENT: As populations age globally, predicting who will develop dementia or cognitive decline before symptoms appear has become a critical medical challenge. Brain aging clocks - tools that measure whether a person's brain appears biologically older or younger than their chronological age - offer a promising solution. This review explains how these tools have advanced from simple brain scans to sophisticated methods that detect aging at the level of individual cell types, and how "zombie cells" called senescent cells drive accelerated brain aging. We also show that brain aging may be slowed through lifestyle changes and emerging drugs, though robust human efficacy trials are ongoing. These insights open new paths toward earlier diagnosis and personalized treatments for Alzheimer's disease and other brain disorders.
    Keywords:  Biological age; Brain age gap; Brain aging; Cellular senescence; Epigenetic clock; Mitochondrial dysfunction; Neurodegeneration; Plasma biomarkers; Senotherapeutics; Vascular aging
    DOI:  https://doi.org/10.1016/j.exger.2026.113260
  32. Expert Opin Drug Discov. 2026 Aug 07. 1-22
    Foundation models for low-data drug discovery: mining heterogeneous public and proprietary data in neglected indications.
    Michail Papadourakis, Evangelia Efraimia Amaxopoulou, Minos-Timotheos Matsoukas.
       INTRODUCTION: This review examines how Foundation Models can address critical limitations of data scarcity in drug discovery, particularly for neglected diseases where traditional approaches are ineffective. It highlights the need for new methodologies that integrate heterogeneous data sources to enable more equitable and efficient therapeutic development.
    AREAS COVERED: This review synthesizes recent advances in Foundation Models and related machine learning approaches for low-data drug discovery, with a focus on applications in neglected diseases. The authors searched PubMed, Scopus, and Web of Science for available literature using terms related to foundation models, machine learning, deep learning, AI with neglected diseases, drug discovery, low-data settings, transfer learning, and related methodological and disease-specific terms. Reference lists of included reviews were additionally screened for relevant primary literature.
    EXPERT OPINION: Foundation Models are poised to play a central role in drug discovery. Nevertheless, their effectiveness for low-data and neglected diseases will depend on strong collaboration, responsible and ethical use, and continued technical innovation.
    Keywords:  AI; Foundation models; ML; data; drug discovery; neglected indications
    DOI:  https://doi.org/10.1080/17460441.2026.2712551
  33. Hum Mol Genet. 2026 Jul 28. pii: ddag072. [Epub ahead of print]35(16):
    Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.
    Emma Ehn, Håkan Thonberg, Inger Nennesmo, Anna Lindstrand, Malin Kvarnung, Caroline Graff.
      Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.
    Keywords:  Neurogenetics; neurodegeneration; rare variants; whole genome sequencing
    DOI:  https://doi.org/10.1093/hmg/ddag072
  34. Mol Neurobiol. 2026 Aug 01. pii: 800. [Epub ahead of print]63(1):
    Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
    Mengqi Chu, Miaomiao Tan, Xulin Gan, Shumao Cui, Liyun Shi.
      Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.
    Keywords:  Microglia; Mitochondria; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-026-06091-5
  35. J Biol Phys. 2026 Aug 03. pii: 28. [Epub ahead of print]52(1):
    Microswimming as a mechanism for mitochondrial wiggling.
    José S González-García.
      In many plant cells, there are two types of mitochondrial motion: directed and wiggling. While the former is mediated by F-actin and microtubules, the latter is not. The fact that mitochondria migrate via wiggling suggests the existence of other mechanisms of motion aside from those related to the cytoskeleton and protein motors. In this work, it is assumed that wiggling mitochondria are active Brownian particles, self-propelled bodies whose motion at low Reynolds number is affected by noise. The proposed mechanism of motion is microswimming, where a wiggling mitochondrion is driven by a cycle of shape changes resembling a peristaltic wave travelling along its body. The peristaltic wave is modelled on a two-sphere swimmer under the far-field approximation, yielding expressions for the kinetic and dynamic variables involved, as well as for the factors determining its interaction with chloroplasts. The calculations show that the microswimmer can reach reported speeds with small size deformations and explain the observed high percentage of wiggling mitochondria captured by chloroplasts. Using the hydrodynamic results enables the application of a theoretical probabilistic model, including active and passive noise, which fits well with experimental results on speed distribution and trajectories of wiggling mitochondria. Taken together, the results explain the main mitochondrial wiggling characteristics observed in experiments, thus suggesting the feasibility of microswimming as a mechanism for mitochondrial wiggling.
    Keywords:  Active Brownian particle; Far-field approximation; Microswimming; Mitochondrial wiggling; Two-sphere swimmer
    DOI:  https://doi.org/10.1007/s10867-026-09722-z
  36. Drug Discov Today. 2026 Aug 04. pii: S1359-6446(26)00159-5. [Epub ahead of print] 104754
    Can agentic AI dent Eroom's Law? Large reasoning models across the drug discovery and development pipeline.
    Sheraz Khan, John G Samuelsson, Xuemei Cai, Kannan Natarajan, Subha Madhavan.
      Productivity in pharmaceutical R&D continues to fall despite deeper biological insight and steady gains in clinical development operations - a phenomenon termed Eroom's Law. Agentic AI workflows powered by reasoning-trained large language models (LLMs), increasingly described as large reasoning models (LRMs), could potentially dent this trend. Unlike earlier task-specific models, these systems couple multi-step reasoning with the ability to plan, invoke external tools and retrieve authoritative information, enabling them to decompose and execute complex scientific and operational tasks. This review discusses agentic AI applications across the drug development continuum, from target discovery to post-market surveillance, and highlights three near-term use cases: algorithmic drug repurposing, informed consent support and automated drafting of regulatory documents. For each, we outline plausible architectures, the current level of supporting evidence and the principal failure modes that constrain deployment. Realizing these gains, however, requires prospective validation, rigorous human oversight and governance frameworks that align algorithmic outputs with clinical, ethical, legal and regulatory standards. When implemented responsibly, agentic AI could transform human-AI collaboration in biopharma, improving R&D efficiency and accelerating delivery of safer, more-effective therapies.
    Keywords:  Agentic AI; Eroom’s Law; drug development; drug discovery; human-in-the-loop; large language models; large reasoning models; pharmaceutical R&D productivity; regulatory affairs; retrieval-augmented generation
    DOI:  https://doi.org/10.1016/j.drudis.2026.104754
  37. Int J Popul Data Sci. 2026 ;11(5): 3568
    Accelerating AI-Driven Neuroimaging Research in Dementia.
    Lewis Hotchkiss, Chloe Tulip, Emma Squires, Simon Thompson.
      Artificial intelligence (AI) is rapidly advancing neuroimaging research for earlier and more accurate detection of dementia, yet the complexity, size, and heterogeneity of neuroimaging data create substantial barriers to scalable analysis within secure environments. Neuroimaging datasets require specialised processing, harmonisation across cohorts, and significant computational capacity - challenges that exceed those associated with typical structured health data. To address these issues, the Dementias Platform UK (DPUK) has developed a comprehensive neuroimaging infrastructure within its Trusted Research Environment (TRE), enabling secure, efficient, and standardised access to large-scale imaging resources for AI-driven research. We implemented automated pipelines to convert raw scans into research-ready datasets, adopting the Brain Imaging Data Structure (BIDS) standard across more than 20 cohort and clinical datasets. Harmonised imaging-derived features were produced to support cross-study comparability, and a curated clinical imaging collection focused on dementia was created to facilitate targeted AI model development. All datasets and workflows are available through the DPUK Data Portal, which provides researchers with high-performance compute, scalable storage, and established neuroimaging and AI tools within a secure environment. The resulting harmonised imaging resource offers a rich platform for investigating neurodegenerative disease trajectories and developing generalisable AI models. In collaboration with Dementias Platform Australia, we are extending this work internationally by federating TREs and aligning imaging collections using shared harmonisation methods, enhancing data diversity while preserving governance and privacy standards. By integrating processing pipelines, standardisation tools, and advanced infrastructure, DPUK has enabled scalable, responsible, and high-quality AI research using population-scale neuroimaging data.
    DOI:  https://doi.org/10.23889/ijpds.v11i5.3568
  38. Hepatol Commun. 2026 Sep 01. pii: e0998. [Epub ahead of print]10(9):
    Challenges in the care of rare vascular liver diseases: Insights from patients, health care providers, and patient organizations.
    Mercedes Guilabert, Agnes Dumas, Eva Gil-Hernández, Lynda Sifer-Rivière, Jane Sattoe, Guenda Bernegger, Maria Caiata Zufferey, María Purificación, Giada Danesi, Virginia Hernandez-Gea, Sarwa Darwish Murad, Pierre-Emmanuel Rautou, Laure Elkrief, Benedetta Terziroli Beretta-Piccoli, Andrea De Gottardi, Annalisa Berzigotti, Aurelie Plessier, José Joaquín Mira.
       BACKGROUND: Patients with rare vascular liver diseases (VLDs), including non-cirrhotic portal vein thrombosis and Budd-Chiari syndrome, may develop severe complications from an early age. Yet, little is known about their healthcare experience and unmet needs. This study aimed to identify key challenges in the care of these patients across 4 European countries.
    METHODS: Semi-structured interviews were conducted with patients, members of patient advocacy organizations (PAOs), and health care providers (HCPs) from France, Spain, Switzerland, and the Netherlands. A standardized interview guide explored challenges and unmet needs in healthcare. Using thematic framework analysis, themes were first identified nationally, then synthesized internationally.
    RESULTS: Thirty-seven individuals participated: 13 patients, 7 PAO representatives, and 17 HCPs. Across countries, VLDs were seen as difficult to diagnose, communicate, and manage, given the uncertainty about their etiology, progression, and treatment. Four core challenges were identified: (1) diagnostic wandering, sometimes due to insufficiently targeted imaging requests and limited radiologic experience; (2) challenges in communicating the diagnosis given the complexity and severity of the disease; (3) scientific uncertainty regarding the etiology, progression, and treatment of VLDs, leading to difficulties for HCPs in risk interpretation and for patients in understanding and managing their condition; (4) challenges in care coordination, particularly for patients with associated diseases or comorbidities. In addition, supportive care, particularly in addressing mental health issues and fatigue, was considered insufficient, and management of reproductive and sexual health was considered to require tailored communication strategies.
    CONCLUSIONS: This study highlights perceived cross-country challenges in the care of patients with rare VLDs, underscoring the need for targeted interventions in communication and care coordination to improve their healthcare experience and outcomes.
    Keywords:  Health Service Research; Patient-Centered Care; Physician-Patient Relations; Qualitative Research; Rare Disease
    DOI:  https://doi.org/10.1097/HC9.0000000000000998
  39. Brain. 2026 Aug 02. pii: awag269. [Epub ahead of print]
    Multilevel impairment of mitochondrial respiration in inclusion body myositis.
    Ibrahim Shammas, Hazem Iaali, Jens O Watzlawik, Noemi Vidal Folch, Surendra Dasari, Graeme Preston, Thi Kim Oanh Nguyen, Wolfdieter Springer, Tamas Kozicz, Linda Hasadsri, Eugenia Trushina, Ian R Lanza, Elie Naddaf.
      Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.
    Keywords:  aging; mitochondrial DNA abnormalities; mitophagy; myopathy; oxidative phosphorylation; oxidative stress
    DOI:  https://doi.org/10.1093/brain/awag269
  40. Front Aging Neurosci. 2026 ;18 1865186
    Caenorhabditis elegans in neuroscience: from neural communication to neurodegenerative disease modeling.
    Ziheng Pan, Yunlong Shen, Dejian Peng, Li Tang, Tianlu Ran, Yaohui Liu, Xinyi Zeng, Hui Liu.
      Consistent with humans and other metazoans, the nematode Caenorhabditis elegans (C. elegans) undergoes progressive structural and functional decline during aging. Possessing highly conserved genetic pathways that share extensive homology with human genes, and characterized by a streamlined, fully mapped connectome, C. elegans has emerged as a robust model for dissecting the mechanisms underlying neuronal aging and degeneration. In this review, we summarize the intrinsic advantages of C. elegans as a model organism, highlighting its readily quantifiable behavioral phenotypes, short lifespan, and genetic tractability. We elaborate on its foundational neural communication architecture and its unique utility in constructing molecular models of neurodegenerative diseases. Additionally, we explore the integration of this model system with high-throughput pharmacological screening, environmental toxicology evaluations, and advanced genomic sequencing technologies. Ultimately, this synthesis aims to provide a comprehensive framework for investigating neurodegenerative mechanisms and facilitating clinical translation under specific stress conditions, particularly hypoxia.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; model organism; neurodegenerative disease; synaptic transmission
    DOI:  https://doi.org/10.3389/fnagi.2026.1865186
  41. Mol Biol Rep. 2026 Aug 03. pii: 1324. [Epub ahead of print]53(1):
    Calreticulin as a stress-responsive integrator of ER proteostasis, calcium homeostasis, and immune clearance.
    Arsene Mutombo Menga, Xin Hong, Rui Shi.
      Calreticulin (CALR) is a multifunctional endoplasmic reticulum (ER) protein that couples lectin-like chaperone activity in the calnexin/calreticulin cycle with high-capacity Ca²⁺-binding, thereby linking ER proteostasis to luminal calcium homeostasis. Although classically viewed as an ER-resident chaperone, CALR is increasingly recognized as a stress-responsive regulator whose functions extend beyond the ER lumen. Under stress, CALR can relocalize to the cell surface or extracellular space, where it functions as an immune-recognition and pro-clearance signal for damaged or dying cells. Across aging and chronic degenerative conditions, persistent ER stress, altered calcium handling, and defective clearance of stressed or senescent cells may reshape CALR expression, localization, and stress-responsive functions. However, CALR has not been widely conceptualized as an integrative regulator linking ER proteostatic stress, calcium dysregulation, senescence-associated remodeling, and immune surveillance. In this review, we examine CALR as a stress-responsive integrator of ER proteostasis, calcium homeostasis, senescence-associated stress adaptation, and immune-mediated clearance, and discuss how this framework may inform mechanistic studies and therapeutic strategies in chronic degenerative diseases.
    Keywords:  Calcium homeostasis; Calreticulin; Immune clearance; Proteostasis; Senescence
    DOI:  https://doi.org/10.1007/s11033-026-12416-3
  42. Nagoya J Med Sci. 2026 May;88(2): 297-311
    Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.
    Liwen Wang, Yuenong Jiao, Tianqi Nie, Linlan Jiang, Shuyi Gao, Jinyu Wang.
      Age-related hearing loss (ARHL) is closely linked to mitochondrial dysfunction in cochlear hair cells; however, its molecular regulation remains unclear. Sestrin2 (SESN2), a stress-inducible protein crucial for regulating energy metabolism, has not been comprehensively studied in the context of ARHL. To investigate SESN2's role, cochlea-specific SESN2 overexpression and knockout mouse models were established via adeno-associated virus 9 (AAV9) delivery through posterior semicircular canal injection. These models, combined with an H2O2-induced accelerated-aging paradigm and H2O2-treated House Ear Institute-organ of Corti 1 (HEI-OC1) cellular oxidative injury system, were systematically evaluated using auditory brainstem response (ABR), immunofluorescence (IF), mitochondrial membrane potential assays, western blotting, and other methods. Analysis of ARHL mouse cochleae revealed downregulation of SESN2 in hair cells, accompanied by mitochondrial membrane disruption and increased apoptosis. In aged mice, SESN2 overexpression significantly improved low-frequency hearing thresholds (p < 0.01). Mechanistically, SESN2 reduced oxidative stress, restored mitochondrial function, and suppressed excessive PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy, thereby maintaining mitochondrial quality control. This study is the first to show that SESN2 protects against ARHL through a tripartite cascade: antioxidant defense, mitochondrial functional restoration, and dynamic mitophagy regulation. These findings highlight SESN2's pivotal role in auditory preservation and identify it as a promising new therapeutic target for age-related hearing deterioration.
    Keywords:  SESN2; Sestrin2; age-related hearing loss; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.18999/nagjms.88.2.297
  43. Brain Res. 2026 Aug 05. pii: S0006-8993(26)00349-5. [Epub ahead of print] 150487
    Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
    Shanshan Shi, Ruyue Liu, Chang Liu, Yuyao Chen, Yujun Pan, Chunyan Wang.
       BACKGROUND: Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD). While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is limited. We engineered mitochondrial-enriched sEVs (Exo-Mito) to evaluate their effects on microglia-neuron interactions in a PD-relevant model.
    METHODS: BMSC-Exo-Mito were characterized via TEM, NTA, and immunoblotting. Their therapeutic efficacy was assessed using an MPP + -induced BV2/SH-SY5Y transwell co-culture model. Assessments included ROS levels, mitochondrial membrane potential, ATP quantification, mitophagy flux, and signaling pathway analysis.
    RESULTS: Exo-Mito significantly restored mitochondrial homeostasis by reducing ROS, preserving membrane potential, and increasing ATP production. Mechanistically, Exo-Mito enhanced PINK1/Parkin-dependent mitophagy and PGC-1alpha/TFAM-mediated biogenesis. In BV2 microglia, Exo-Mito suppressed the NF-kappaB/NLRP3 axis, reduced proinflammatory cytokines, and promoted M2 polarization. In SH-SY5Y cells with dopaminergic phenotype, Exo-Mito was associated with reactivated PI3K/Akt/mTOR signaling, preserved tyrosine hydroxylase expression, and inhibited apoptosis. Functionally, Exo-Mito improved SH-SY5Y cell and restored microglial migratory capacity, showing superior efficacy to unmodified BMSC-Exo.
    CONCLUSION: Mitochondria-enriched BMSC sEVs protect SH-SY5Y cells by coordinating mitochondrial quality control and modulating neuroinflammation. These findings support Exo-Mito as a promising cell-free therapeutic strategy for Parkinson's disease.
    Keywords:  Mesenchymal stem cells; Mitochondria; Mitophagy; Neuroinflammation; PI3K/Akt/mTOR; Parkinson’s disease; Small extracellular vesicles
    DOI:  https://doi.org/10.1016/j.brainres.2026.150487
  44. Epileptic Disord. 2026 Aug 04.
    KBG syndrome: A scoping review of electroclinical features of patients with epilepsy.
    Stefania Kalampokini, Evripidis Pityrigkas, Zoi Kallia, Georgia Pepe, Antonis Frontistis, Dimitrios Profer, Vasilios Kimiskidis.
       BACKGROUND AND OBJECTIVES: KBG syndrome is a rare autosomal developmental disorder caused by pathogenic variants of the ANKRD11 gene. This scoping review aimed to explore all current literature data regarding clinical and electroencephalographic features of patients with KBG syndrome and epilepsy.
    MATERIALS AND METHODS: We conducted a literature review of previously published cases of patients with KBG syndrome and epilepsy in PubMed, Scopus, and Web of Science databases in English, focusing on seizure semiology and electroencephalographic features.
    RESULTS: Fifty-four studies were included in the review, including 233 patients with KBG syndrome and epilepsy. Most children with KBG syndrome and epilepsy (89.7%) had developmental delay and intellectual disability. The most common neurological symptoms were hypotonia (30.7%), sleep disturbances (20%), ataxia (18.7%), migraine (8.3%), and stereotypies (6.7%) (N = 75, available data on neurological symptoms). The median age of developing seizures was 4 years (range 1 month-51 years). Patients with KBG syndrome had most commonly generalized seizures (73.9%), although focal seizures occurred in 37.9% of cases (N = 140, available data on seizure type). Generalized tonic-clonic seizures were the most common seizure type (38.2%), followed by absences (26.6%), and focal seizures with or without preserved consciousness (21.9% and 19.1%, respectively). Interictal EEG showed focal and, less frequently, generalized discharges (24.6% vs. 15%) in the 118 patients with available EEG data. Almost 70% of patients were seizure-free after a mean follow-up of 9.9 years, while drug-resistant epilepsy was reported in 22.6% of cases. Patients with focal impaired consciousness seizures had significantly lower odds of achieving seizure freedom.
    CONCLUSION: Epileptic seizures in patients with KBG syndrome are usually generalized and have an onset between infancy and mid-teens. Common epileptological features in KBG syndrome comprise the good response to antiseizure medication and, in most cases, the remitting nature of epilepsy. Drug-resistant epilepsy can be observed in up to one-third of cases.
    Keywords:  KBG syndrome; electroclinical features; epilepsy; seizures
    DOI:  https://doi.org/10.1002/epd2.70365
  45. Front Public Health. 2026 ;14 1887767
    Building data science capacity in the public health workforce: a Public Health Data Science Life Cycle framework.
    Emily M Burke, Jordan A Fox, Sarah Gusman, Kaitlin Tager, Rebecca Wurtz, Gulzar H Shah, Maureen Y Lichtveld.
      The digital transformation of public health systems has increased the need for a workforce capable of using data science to inform population health decision-making. However, public health workforce development efforts have not fully integrated data science competencies into training and professional development pathways. This paper presents a competency mapping framework, and a proposed national training agenda designed to operationalize data science skills for the public health workforce. Drawing on and synthesizing existing public health competency frameworks, accreditation standards, and governmental public health workforce task analyses, competencies were mapped to an eight-stage Public Health Data Science Life Cycle. Competency gaps were then identified, and additional competencies were developed to address emerging needs in public health data science practice. The analysis found that existing competencies are concentrated in the middle stages of the Public Health Data Science Life Cycle - particularly data collection and management, data analysis and modeling, and data interpretation and implications - with fewer competencies addressing earlier stages, such as problem framing, and later stages, including communication and life cycle preservation. Key gaps were identified in areas including project feasibility and problem definition, data governance and interoperability, bias and ethical data use, data interpretation and visualization, and the communication and translation of findings to inform policy and community action. Building on these findings, this paper proposes a practical framework to guide the integration of public health data science competencies into workforce training and continuing professional learning. By aligning competencies with the full life cycle of public health data science practice, this approach supports a more comprehensive and applied model for workforce development, with the goal of strengthening data-informed decision-making and improving population health outcomes.
    Keywords:  core competencies; data modernization; data science framework; public health data science; workforce development and training
    DOI:  https://doi.org/10.3389/fpubh.2026.1887767
  46. Int J Popul Data Sci. 2026 ;11(5): 3468
    Data Governance Transformation: Now is the time to revisit Data Governance Policy.
    Jacob Pasner.
      This paper presents MDI's Data Governance Transformation (DGT) project, an already-in-use data governance policy & infrastructure framework developed to support robust implementation of Privacy Enhancing Technologies (PETs), govern rapid AI development, and confront precedent shattering data use in the United States. As government agencies increasingly rely on complex and distributed data ecosystems, traditional data management approaches have proven insufficient to ensure data quality, accessibility, privacy, and interoperability. This framework establishes a cross-functional data governance structure that includes clearly defined roles, a RACI (Responsible, Accountable, Consulted, Informed) matrix, a standardized change control process, and an architecture rooted in medallion-style data layering. It also includes practical guidance on the following: conducting a data inventory, aligning with cloud and privacy requirements, and coordinating with contractors to ensure data portability and reproducibility. By embedding PETs and clear accountability mechanisms, this framework not only supports compliance with regulatory mandates but also enables data-driven decision-making and responsible use of AI. The framework serves as a replicable model for other government and non-government entities seeking to implement or refresh their data governance strategies to meet the demands of modern public service delivery.
    DOI:  https://doi.org/10.23889/ijpds.v11i5.3468
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