bims-polgdi Biomed News
on POLG disease
Issue of 2026–09–20
57 papers selected by
Luca Bolliger, lxBio
  1. The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.
  2. Caring for Rare Genetic Disease: A Vision for the Future.
  3. Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
  4. Living with a rare disease: Why lived experience must shape research.
  5. Biological Foundation Models for Complex Disease Research and Clinical Translation.
  6. Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
  7. Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
  8. First for RNA therapy: man with rare motor-neuron disease improves after treatment.
  9. Mitochondrial Fitness as a Functional Immune Checkpoint in Cancer: Metabolic Plasticity, Tumor Evolution, and Immunotherapy.
  10. Beyond copy number: circulating cell-free mitochondrial DNA Fragmentomics and structural states in liquid biopsy.
  11. Organ-Specific Mitochondrial DNA Copy Number Responses in Neonatal Mice Following in Utero Irradiation.
  12. Identifying methodological guidance used for systematic reviews, clinical practice guidelines, and health technology assessment for rare diseases: a scoping review protocol.
  13. Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
  14. Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility.
  15. MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease.
  16. Aging in Spaceflight, Oxidative Stress, and Microbiome Dysbiosis: A Comprehensive Review.
  17. Mitochondrial Distress Signals at the Heart-Liver Interface: Molecular Links Between MASLD and Heart Failure.
  18. Bridging the translational gap in drug repurposing for rare diseases: clinical success versus regulatory conversion.
  19. Mitophagy-pyroptosis-macrophage polarization crosstalk in cardiovascular diseases: mechanistic insights and therapeutic potential.
  20. Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
  21. Mitochondrial transfer: a novel paradigm for wound healing.
  22. MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
  23. Patient pathways for rare liver diseases: a European template developed by ERN RARE-LIVER.
  24. Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
  25. Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
  26. TargetQC: A targeted quality control framework for clinical genomic testing.
  27. Inhibition of mitochondrial dynamics in Dictyostelium discoideum through the overexpression of FszA and FszB proteins.
  28. Maternal hyperhomocysteinemia promotes adverse pregnancy outcomes via mtDNA-cGAS-STING signaling-mediated trophoblast mitophagy.
  29. Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
  30. Somatic Mitochondrial-Nuclear DNA Transfer in Lymphoproliferative Disorders.
  31. "NanoDel": Identification of large-scale mitochondrial DNA deletions using long-read sequencing.
  32. Nitric oxide signaling and mitophagy in Parkinson's disease: implications for aerobic exercise-related neuroprotection.
  33. Guidelines or Other Guidance Documents for Rare Diseases in the Netherlands: When and Where to Invest (Effort, Time and Money)?
  34. Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
  35. Emerging roles of the ciliary-mitochondrial axis in cellular homeostasis and neuroprotection.
  36. Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks.
  37. Mitochondrial Control of Myelination, Bioenergetics, Oxidative Stress, and the Pathogenesis of Optic Neuropathies.
  38. Immune dysregulatory disorders: perspective from solving a diagnostic odyssey.
  39. Normal neuroimaging in an infant with SUCLA2-related mitochondrial DNA depletion syndrome type 5: a case report of likely pathogenic variant.
  40. The European Health Data Space and the Secondary Use of Sensitive Health Data.
  41. Extracellular vesicles in targeted drug delivery: from biological functions to surface engineering.
  42. Synaptic mitochondrial dysfunction and Alzheimer's disease: from molecular mechanisms to therapeutic strategies.
  43. Loss of Ca2+ Signaling Fidelity During Aging: Mitochondrial Dysfunction, Senescence, and Cognitive-Motor Decline.
  44. Bacterial Extracellular Vesicles as Regulators of the Gut Microbiome-Circadian Axis in Inflammatory and Metabolic Diseases.
  45. Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.
  46. Peritoneal Dialysis for End-Stage Kidney Disease due to Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS): A Case Report.
  47. Characterization of mesenchymal stromal cell-mediated mitochondrial transfer to healthy and diseased intervertebral disc cells.
  48. Diabetic kidney disease: emerging mechanistic and nutritional perspectives from the Mediterranean diet-mitochondria axis. A narrative review.
  49. Contribution of copy number variants to schizophrenia in East Asian populations.
  50. Lipid regulation of mitochondrial function in metabolic Diseases: Lipotoxic mediators and therapeutic targeting.
  51. IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation.
  52. Advancing evidence generation in pediatric rheumatology beyond traditional randomized clinical trials: the potential of innovative designs.
  53. Standardising Access to Sensitive Data with Machine-Actionable Access Conditions.
  54. Advances in the Application of Adenine Base Editor (ABE) in Biology and Medicine: Prospects and Challenges.
  55. Sperm subpopulations differing in mitochondrial abundance show divergent nuclear allele frequencies.
  56. Genomic Screening for Infants and Reproductive Adults.
  57. Mitochondrial defects in the cAMP-PKA-DRP1 pathway in a Crppa deletion model of dystroglycanopathy.
  1. Mamm Genome. 2026 Sep 18. pii: 108. [Epub ahead of print]37(1):
    The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.
    Danielle Brister, Mariana Zarate-Mendez, Denisa Hathazi, Rita Horvath.
      Mitochondria are essential organelles responsible for cellular energy production and the regulation of key metabolic and signalling pathways. Their function depends on the coordinated expression of both mitochondrial and nuclear genomes, and mitochondrial dysfunction leads to a diverse group of mitochondrial diseases. The nervous system is particularly vulnerable to mitochondrial dysfunction due to the high energetic demands and complex morphology of neurons. Neurons rely heavily on mitochondrial ATP production to support processes such as synaptic transmission, axonal transport, and calcium homeostasis, which are tightly regulated by mitochondrial dynamics, intracellular trafficking, and quality control mechanisms. In mitochondrial diseases, impairment of these processes contributes to a range of neurological manifestations, including epilepsy, stroke-like episodes, Leigh syndrome, ataxia, and peripheral neuropathy. Despite the ubiquitous presence of mitochondria, neuronal vulnerability varies between distinct neuronal populations, reflecting differences in neuronal morphology and metabolic demands. This review summarises key mechanisms underlying neuronal susceptibility in mitochondrial disease and highlights how defects in mitochondrial bioenergetics, dynamics, and transport contribute to characteristic neurological phenotypes. Understanding these mechanisms may provide insights into tissue-specific vulnerability and identify potential therapeutic targets to treat mitochondrial diseases and other neurodegenerative disorders associated with mitochondrial mechanisms.
    DOI:  https://doi.org/10.1007/s00335-026-10278-5
  2. J Genet Couns. 2026 Oct;35(5): e70284
    Caring for Rare Genetic Disease: A Vision for the Future.
    Ruth Horn, Sarah L Wynn, Sofia Douzgou Houge.
      The United Nations, 2021 resolution to promote and protect the human rights of the estimated 300 million People Living with a Rare Disease and their families, set a milestone worldwide. At the same time, the successful diagnostic results of large genomic initiatives are reshaping rare disease healthcare in many countries. However, increasing diagnostic capability does not necessarily translate into improved care. Patients, families, and healthcare professionals navigate challenges in variant interpretation and prognosis, uneven access to specialist expertise and follow-up, limited natural history information and therapeutic options, and the wider familial and reproductive implications of genomic findings. Healthcare systems also face challenges related to workforce and service capacity, data governance, equity, research sustainability, and the integration of genomic technologies into longitudinal care. Drawing on published evidence, patient-organization experience and illustrative clinical scenarios, we argue that the value of genomic medicine for rare disease should be assessed beyond diagnostic yield alone and across individual, clinical and societal levels. Our vision for the future includes accessible education for families and professionals, multidisciplinary and longitudinal rare disease services embedded within publicly funded healthcare, sustainable research and data-sharing frameworks, partnership with patient advocacy organizations, and meaningful representation of people living with rare disease in governance, research, and innovation.
    Keywords:  advocacy; diagnosis; education; engagement; genomic medicine; healthcare; people living with a rare disease
    DOI:  https://doi.org/10.1002/jgc4.70284
  3. Cells. 2026 Aug 27. pii: 1548. [Epub ahead of print]15(17):
    Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
    Lingling Cheng, Gaojie Song.
      Aging mesenchymal stem/stromal cells (MSCs) lose regenerative capacity as redox imbalance, mitochondrial damage, defective organelle quality control and chronic inflammation converge. Yet these processes are commonly considered in isolation, obscuring whether damaged mitochondrial cargo reaches lysosomes and is ultimately degraded. Here, we define mitochondria-lysosome quality flux (MLQF) as an author-proposed, evidence-graded framework that tracks mitochondrial damage from recognition and sorting through lysosomal delivery to terminal lysosomal degradation in aging MSCs. The framework explicitly separates delivery to an acidic compartment from completed degradation and distinguishes direct MSC evidence from cross-model mechanisms and candidate pathways. MSC studies most strongly support macroautophagy-dependent mitophagy, particularly when assessed using dynamic flux reporters. By contrast, mitochondria-derived vesicles and microautophagy-like or piecemeal routes remain incompletely validated in MSCs. Studies in non-MSC systems further show that mitochondria-lysosome contact sites can support lysosomal acidification, although their contribution to natural MSC aging remains unresolved. By locating rate-limiting defects across this continuum, MLQF provides a testable basis for linking incomplete mitochondrial clearance to inflammatory signaling, lineage drift and regenerative decline, and for selecting bottleneck-matched interventions.
    Keywords:  cellular senescence; mesenchymal stem/stromal cells; mitochondrial quality control; mitochondria–lysosome quality flux; mitophagy
    DOI:  https://doi.org/10.3390/cells15171548
  4. PLoS Med. 2026 Sep;23(9): e1005253
    Living with a rare disease: Why lived experience must shape research.
    Gemma Whyatt, Jodi Whitehouse.
      Rare diseases are often defined by numbers and clinical perspectives, a narrative that needs re-writing. Drawing on decades of patient advocacy, two women living with the rare condition Congenital Melanocytic Naevus argue that lived experience must shape research from the outset, and discuss how genuine patient-researcher partnership transforms science, care and identity.
    DOI:  https://doi.org/10.1371/journal.pmed.1005253
  5. Biology (Basel). 2026 Sep 03. pii: 1527. [Epub ahead of print]15(17):
    Biological Foundation Models for Complex Disease Research and Clinical Translation.
    Tiana Noll-Walker, Yong Chen.
      Complex diseases, including cancer, rare genetic disorders, neurodevelopmental and psychiatric conditions, and neurodegenerative diseases, arise from interactions among genetic variation, gene regulation, and cellular states that are difficult to capture using a single data type or biological scale. Biological foundation models address this challenge by treating nucleotides and genes as tokens and learning representations that can be transferred to downstream biomedical and clinical tasks. In this review, we examine two major model classes, genomic sequence foundation models and cell foundation models, and compare their tokenization strategies, model architectures, pretraining objectives, and adaptation methods. We summarize their emerging applications in regulatory variant interpretation, disease-associated cell-state analysis, drug-response prediction, and therapeutic target discovery across complex diseases. We distinguish applications supported by experimental or retrospective validation from those that remain primarily computational or conceptual. We further discuss key challenges to clinical translation, including multimodal data integration, model interpretability, benchmarking, patient-specific prediction, and privacy protection. We highlight future opportunities to integrate biological foundation models with emerging frameworks of medical digital twins, agentic AI, and federated learning. By linking model design to translational goals, this review provides a practical framework for evaluating biological foundation models and their readiness for complex disease research and clinical use.
    Keywords:  biological foundation model; complex disease; large language model; precision medicine; single-cell omics
    DOI:  https://doi.org/10.3390/biology15171527
  6. Aging Cell. 2026 Sep;25(9): e70718
    Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
    Renin Chang, Andy P Tsai, Boyang Wang, Kuan-Hao Tsui, Cheng-Yoong Pang, Chia-Jung Li.
      The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue-specific molecular clock of aging. We trace foundational single-cell and multi-tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single-cell and population-scale studies that have transformed the field: deep multi-tissue surveys revealing tissue-specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ-specific disease, and a two-step mechanism in which cryptic replication-error mutations become detectable through age-related clonal mosaicism. We discuss technologies such as single-cell mtDNA genotyping, duplex and long-read sequencing, and droplet digital PCR that now read the clock at single-molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA-driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood-based biomarker of biological age.
    Keywords:  aging; clonal expansion; heteroplasmy; mitochondrial DNA; molecular clock; respiratory chain deficiency; somatic mutation
    DOI:  https://doi.org/10.1111/acel.70718
  7. Nat Commun. 2026 Aug 15. pii: 9829. [Epub ahead of print]17(1):
    Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
    Hyunmin Cho, Ruhi Sayana, Abhishek Koladiya, Pasqualina Colella, Sangkyun Cho, James W S Jahng, Juan Jose Vasquez, Jessica Arozqueta Basurto, Joseph C Wu, Natalia Gomez-Ospina.
      Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41467-026-76775-y
  8. Nature. 2026 Sep 18.
    First for RNA therapy: man with rare motor-neuron disease improves after treatment.
    Rachel Fieldhouse.
      
    Keywords:  Brain; Diseases; Gene therapy; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-02945-z
  9. Cancers (Basel). 2026 Sep 01. pii: 2818. [Epub ahead of print]18(17):
    Mitochondrial Fitness as a Functional Immune Checkpoint in Cancer: Metabolic Plasticity, Tumor Evolution, and Immunotherapy.
    Fortunato Morabito, Enrica Antonia Martino, Antonella Bruzzese, Nicola Amodio, Ernesto Vigna, Massimo Gentile.
      Mitochondria are increasingly recognized as dynamic regulators of cancer-cell adaptation, immune function, and therapeutic response. Beyond their canonical role in energy production, mitochondrial metabolism, dynamics, quality control, and stress signaling influence tumor-cell survival and the capacity of immune effector cells to sustain antitumor activity within the tumor microenvironment. In this narrative review, we examine mitochondrial fitness as a multidimensional functional property encompassing bioenergetic capacity, metabolic flexibility, redox homeostasis, mitochondrial quality control, and adaptation to cellular and therapeutic stress. We propose the mitochondrial functional immune checkpoint as a conceptual framework linking mitochondrial fitness in malignant and immune cells to tumor-immune interactions and immunotherapy response. We discuss how mitochondrial metabolic plasticity, mitochondrial stress and mtDNA signaling, reactive oxygen species, mitochondrial dynamics, and intercellular mitochondrial transfer contribute to immune escape and treatment resistance. We further examine the relevance of mitochondrial fitness to immune checkpoint blockade, CAR-T-cell therapy, and T-cell-redirecting bispecific antibodies, with particular attention to hematological malignancies, including acute myeloid leukemia and multiple myeloma, while incorporating selected evidence from solid tumors to highlight shared mitochondrial mechanisms and their broader oncologic relevance. Finally, we discuss emerging strategies for mitochondrial targeting and functional mitochondrial profiling and their potential integration with established molecular and measurable residual disease assessments. Current evidence supports mitochondrial biology as a complementary dimension of precision oncology, although important challenges remain regarding context dependence, biomarker standardization, therapeutic selectivity, and preservation of immune-cell fitness. Prospective studies are needed to determine whether functional mitochondrial profiling can improve patient stratification and guide rational therapeutic combinations that selectively exploit tumor mitochondrial vulnerabilities while preserving effective antitumor immunity.
    Keywords:  CAR-T cells; T-cell exhaustion; bispecific antibodies; cancer metabolism; immune escape; immunotherapy; mitochondria; oxidative phosphorylation; precision oncology; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18172818
  10. Clin Chim Acta. 2026 Sep 14. pii: S0009-8981(26)00525-5. [Epub ahead of print]594 121343
    Beyond copy number: circulating cell-free mitochondrial DNA Fragmentomics and structural states in liquid biopsy.
    Muhammad Tahir Naseem, Wajid Zaman, Aziz Ullah.
      Circulating cell-free mitochondrial DNA (cf-mtDNA) is commonly treated as a concentration-based biomarker, yet the measured signal is a composite of biologically distinct molecular states that are differentially affected by blood collection, platelet activation, centrifugation, storage, extraction, amplification, and sequencing. This analytical heterogeneity has become more consequential as cf-mtDNA research moves from copy-number assays toward fragmentomics, topology, heteroplasmy, oxidative lesions, and carrier-resolved measurements. Recent multi-cohort studies indicate that fragment size, 5'-end composition, motif diversity, and regional breakage patterns can support cancer detection and tissue-of-origin inference, while clinical chemistry studies demonstrate that routine preanalytical choices can markedly alter the mitochondrial fraction recovered from plasma. This review develops a laboratory-medicine framework in which cf-mtDNA is considered a multidimensional analyte rather than a single abundance variable. We integrate mitochondrial release biology with the extracellular carrier states of mtDNA; explain how TFAM, membrane pores, mitophagy, extracellular vesicles, platelets, and nucleases shape the observed fragmentome; evaluate preanalytical and analytical sources of bias; and assess translational evidence across oncology, critical illness, cardio-renal disease, metabolic inflammation, transplantation, and neuroinflammatory disorders. Particular emphasis is placed on distinguishing true biological variation from procedure-induced redistribution of cf-mtDNA between soluble, vesicular, platelet-associated, and cell-free mitochondrial compartments. We propose minimum analytical descriptors, quality-control priorities, and validation steps required before cf-mtDNA fragmentomic signatures can become transportable clinical tests. The central implication is that the next phase of cf-mtDNA diagnostics will depend less on measuring more DNA than on measuring the correct molecular fraction with traceable preanalytics, orthogonal characterization, and clinically locked computational models.
    Keywords:  Cell-free mitochondrial DNA; Extracellular vesicles; Fragmentomics; Laboratory medicine; Liquid biopsy; Preanalytics
    DOI:  https://doi.org/10.1016/j.cca.2026.121343
  11. Int J Mol Sci. 2026 Aug 27. pii: 7671. [Epub ahead of print]27(17):
    Organ-Specific Mitochondrial DNA Copy Number Responses in Neonatal Mice Following in Utero Irradiation.
    Haruka Kubo, Ryosuke Seino, Hisanori Fukunaga.
      Early-life ionizing radiation exposure may induce molecular responses without changes in birth outcomes. We examined whether in utero exposure to 0.2 Gy X-rays affects mitochondrial DNA copy number (mtDNAcn) and an index estimating the proportion of mitochondrial DNA (mtDNA) molecules amplifiable across a defined long region. Pregnant mice received sham irradiation or exposure on embryonic day 8 (E8) or 15 (E15). Offspring brain, heart, and liver were examined at birth, with litter means used as experimental units. Litter size and neonatal body weight showed no group differences. In organ-wise comparisons, brain mtDNAcn was higher after E8 and E15 exposure, heart mtDNAcn was higher after E15 exposure, and liver mtDNAcn showed no statistically detectable difference. Mixed-effects analysis supported an organ-dependent pattern of mtDNAcn responses, although direct E8-versus-E15 comparisons were not significant within any organ. The estimated proportion of long-fragment-amplifiable mtDNA was lower in the brain after E15 exposure in the organ-wise analysis, but mixed-effects analysis did not support organ- or gestational-stage-dependent patterns in this measure. Thus, in utero X-ray exposure produced organ-dependent mtDNAcn responses at birth but no demonstrable gestational-stage-specific response within individual organs.
    Keywords:  PCR; X-ray; developmental origins of health and disease; in utero irradiation; mitochondrial DNA
    DOI:  https://doi.org/10.3390/ijms27177671
  12. JBI Evid Synth. 2026 Sep 14.
    Identifying methodological guidance used for systematic reviews, clinical practice guidelines, and health technology assessment for rare diseases: a scoping review protocol.
    Abigail M Day-Sharman, Danielle Pollock, Timothy H Barker, Johanna H van der Lee, Tracy Merlin, Mirthe J Klein Haneveld, Cindy Stern, Brendan V Schultz, Federico Germini, Konstantinos Margetis, Iméze J Hieltjes, Zachary Munn.
       OBJECTIVE: This scoping review will identify methodological guidance relevant to systematic reviews (SRs), clinical practice guidelines (CPGs), and health technology assessments (HTAs) for rare diseases, and examine methodological challenges associated with their development.
    INTRODUCTION: Rare diseases affect approximately 400 million people worldwide. However, individual rarity limits health care provider knowledge and awareness and, subsequently, management of rare diseases is hindered by diagnostic delays, limited treatment options, and high treatment costs. Heterogenous populations and sparse, low-quality evidence also impede research quality and render traditional evidence evaluation methods ill-suited to rare diseases. Consequently, existing methodological frameworks guiding evidence-based development of SRs, CPGs, and HTAs may not appropriately consider contextual nuances of rare diseases.
    ELIGIBILITY CRITERIA: This scoping review will consider both peer-reviewed and gray literature relevant to methodological guidance for SRs, CPGs, and HTAs. Eligible sources will focus on rare diseases collectively, or specific conditions that meet the criteria of a rare disease, and address at least 1 aspect of methodology used to develop SRs, CPGs, or HTAs relevant to rare disease contexts.
    METHODS: The 3-step search strategy began with an exploratory PubMed search to refine terms, which will be followed by comprehensive searches in MEDLINE, Embase, Scopus, and the Cochrane CENTRAL Library. Gray literature will be searched via Google Scholar, Orphanet, the World Health Organization Institutional Repository for Information Sharing, the International Network of Agencies for Health Technology Assessment, and the National Institute for Health and Care Excellence. Identified sources will be independently screened, selected, and extracted by multiple reviewers. Data will be analyzed using descriptive statistics and qualitative content analysis, then presented in summary tables and summarized descriptively.
    REVIEW REGISTRATION: OSF https://osf.io/mrfev.
    Keywords:  clinical practice guidelines; health technology assessments; methodological guidance; rare diseases; systematic reviews
    DOI:  https://doi.org/10.11124/JBIES-25-00506
  13. Mater Today Bio. 2026 Oct;40 103636
    Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
    Xianquan An, Li Zhang, Xin Zhang, Meidan Fang, Cong Wang, Yu Han, Zheng Wang, Jinfeng Wang, Shuting Zuo.
      Neuropathic pain remains a major clinical challenge due to limited efficacy and tolerability of current treatments. Mitochondrial dysfunction in dorsal root ganglion (DRG) cells is recognized as a key pathogenic mechanism, but effective strategies to restore mitochondrial homeostasis are lacking. Here, we first identified profound deficits in mitochondrial quantity and quality in DRG neurons and satellite glial cells (SGCs) from a chemotherapy-induced peripheral neuropathy (CIPN) model. To address this, we developed an extracellular vesicle-based nanoplatform (EVs@Mi/UR) loaded with a mitophagy inducer, which integrates exogenous mitochondrial transplantation with mitophagy induction. EVs@Mi/UR not only increased mitochondrial mass in DRG neurons and SGCs through efficient mitochondrial transplantation, but also improved mitochondrial quality by eliminating damaged organelles, thereby enhancing mitochondrial respiration and metabolic function. In both CIPN and spared nerve injury (SNI) mouse models, EVs@Mi/UR significantly alleviated mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity with superior efficacy. Notably, even in SNI models that did not exhibit baseline mitochondrial deficits, EVs@Mi/UR still produced analgesic effects by improving mitochondrial quality. This work establishes mitochondrial remodeling as a promising strategy for neuropathic pain and provides a translatable EV-based nanoplatform for dual-modality mitochondrial intervention.
    Keywords:  Dorsal root ganglion; Extracellular vesicles; Mitochondrial transplantation; Mitophagy; Neuropathic pain
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103636
  14. bioRxiv. 2026 Sep 02. pii: 2026.09.02.748825. [Epub ahead of print]
    Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility.
    Rabina Saud, Kimberly Foster-Lemieur, Brett Duguay, Russell Swerdlow, Maria Kalamvoki.
      Herpes simplex virus 1 (HSV-1) infects approximately 67% of the population worldwide. It establishes lifelong reservoirs in sensory neurons and has been linked to several diseases including neuronal dysfunction. Disruption of mitochondrial homeostasis is a hallmark of HSV-1 infection, however a molecular understanding of these changes and their significance is not yet well defined. HSV-1 infection causes a UL12.5-dependent inhibition of mitochondrial biogenesis through the loss of mitochondrial DNA and mitochondrial transcription factors, PGC-1α (peroxisome proliferator-activated receptor-gamma co-activator) and TFAM (mitochondrial transcription factor). Conversely, UL12.5-independent mechanisms inhibit mitochondrial fusion by activating the OMA1 metallopeptidase that cleaves the inner mitochondrial membrane fusion protein OPA1 (optic atrophy protein 1) and by down-modulating the outer mitochondrial membrane fusion protein MFN2 (mitofusin 2). This inhibition of fusion results in a smaller mitochondrial network that clusters to perinuclear regions, likely supplying energy for viral replication and envelopment. The inner mitochondrial membrane protein TIM23 is also down-modulated during infection in a UL12.5-independent mechanism. Failure of the virus to promote these changes negatively impacts the infection. Despite these changes, mitochondria are protected from mitophagy due to the viral-induced degradation of several mitophagy adaptor proteins, whereby damaged mitochondrial components, including mitochondrial DNA, are extruded via extracellular vesicles. These mitochondrial changes still support functions necessary for HSV-1 infection. Basal cell respiration is preserved, while spare respiratory capacity and extracellular acidification rates increase, indicating glycolytic activity. Mitochondrial membrane potential is also preserved. Overall, our studies provide mechanistic insight into how HSV-1 impacts mitochondria, which could contribute to viral pathogenesis.
    Importance: Mitochondria are often referred to as the "powerhouse" of the cell because they are the main energy producers. Disruption of mitochondrial homeostasis is associated with multiple diseases and occurs after infection with pathogens such as HSV-1. By investigating the mechanism(s) by which HSV-1 disrupts mitochondrial homeostasis, we can better understand how HSV-1 causes pathogenesis. HSV-1 infection impacts mitochondrial homeostasis through disruption of four key processes, including: 1) inhibition of mitochondrial biogenesis and the generation of new mitochondria; 2) inhibition of mitochondrial fusion, which rescues reversibly damaged mitochondria; 3) sustaining mitochondrial fission, which removes damaged content; and 4) preventing mitophagy, which clears damaged mitochondria. UL12.5-dependent and UL12.5- independent events during HSV-1 infection disrupt mitochondrial homeostasis, redirecting mitochondrial resources towards progeny virus production. These changes cause irreversible damage to host cells, ultimately driving pathogenesis.
    DOI:  https://doi.org/10.64898/2026.09.02.748825
  15. Cell Death Dis. 2026 Sep 15. pii: 801. [Epub ahead of print]17(1):
    MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease.
    Alexander Becker, Thomas O Eichmann, Viacheslav Vasiliev, Kira An Mey, Patrick Petzsch, Andrea Rossi, Felix Distelmaier, Ruchika Anand.
      Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. Here, we report an affected individual carrying a pathogenic MIC13 variant (c.260-2 A > G) associated with early-onset mitochondrial hepato-encephalopathy. Such mitochondrial hepatopathies are rare, multisystemic disorders with major liver involvement, difficult to diagnose, lack effective treatment, and are poorly understood, in part due to the absence of faithful disease-relevant cellular models. To investigate hepatocyte-specific consequences of the MIC13 variant, we generated iPSCs carrying this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a key component of the MICOS complex required for cristae formation, was disrupted in these cells, and the resultant iHeps exhibited the same cristae defects observed in clinical samples. Integrated multi-omics and biochemical analyses revealed extensive metabolic rewiring, including disrupted amino acid turnover, accumulation of tricarboxylic acid (TCA) and urea cycle intermediates. Additionally, profound alterations in methionine cycle and transsulfuration pathways, along with enhanced bile acid synthesis, collectively affect methylation potential, redox homeostasis, and detoxification. Lipid metabolism was also impaired, with incomplete β-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodeling, increased intracellular collagen accumulation and enhanced cell migration indicated an early fibrotic phenotype, linking metabolic rewiring to ECM homeostasis. Overall, this clinically relevant model uncovers how cristae defects drive metabolic imbalance and hepatocyte dysfunction, ultimately leading to early fibrotic changes in mitochondrial liver disease. These findings provide a strong mechanistic foundation for understanding mitochondrial liver disease and developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09283-y
  16. Int J Mol Sci. 2026 Aug 26. pii: 7644. [Epub ahead of print]27(17):
    Aging in Spaceflight, Oxidative Stress, and Microbiome Dysbiosis: A Comprehensive Review.
    Charles C Naney, Joseph L Graves, Scott H Harrison.
      The evolutionary theory of aging demonstrates that the force of natural selection declines with age in multicellular organisms. Two population genetic mechanisms are consistent with the evolutionary theory: mutation accumulation and antagonistic pleiotropy. These in turn account for the physiological, cellular, and molecular mechanisms associated with aging. Spaceflight provides an opportunity to examine how organisms physiologically acclimate to environmental conditions. Mitochondria and the gut microbiome are central regulators of host metabolism, redox homeostasis, immune function, and physiological resilience, and both are impacted by host adaptations and acclimations. Mitochondrial dysfunction and oxidative stress have consequently emerged as important candidate mechanisms linking biological aging and spaceflight-associated physiological change. This review examines evidence surrounding mitochondrial dysfunction, oxidative stress, and gut microbiome dysbiosis across humans, mice, and fruit flies under spaceflight and corresponding terrestrial control conditions. This review reports further on the progression of theory and recent evidence from spaceflight missions for how biomarker genes most associated with mutation accumulation and antagonistic pleiotropy appear to have a core role in natural aging and extreme physiological acclimation.
    Keywords:  aging; microbiota; oxidative stress; spaceflight
    DOI:  https://doi.org/10.3390/ijms27177644
  17. Int J Mol Sci. 2026 Aug 28. pii: 7734. [Epub ahead of print]27(17):
    Mitochondrial Distress Signals at the Heart-Liver Interface: Molecular Links Between MASLD and Heart Failure.
    Xing Yang, Kun Cheng, Chen Chen, Yuxin Zhang, Dao Wen Wang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD-HF overlap.
    Keywords:  cardio-hepatic crosstalk; heart failure; metabolic dysfunction-associated steatotic liver disease; mitochondrial distress signaling; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms27177734
  18. Drug Discov Today. 2026 Sep 18. pii: S1359-6446(26)00212-6. [Epub ahead of print] 104807
    Bridging the translational gap in drug repurposing for rare diseases: clinical success versus regulatory conversion.
    Wael Khazen, Arnaud Valent, Samantha Parker, Solange Corriol-Rohou, Teresinha Evangelista, Xavier Nissan, Alexandre Mejat.
      Repurposing of drugs to treat rare diseases (RDs) is vital, but the translational gap between clinical evidence and regulatory approval remains unquantified. Analysis of 47 clinical trials showed that 66 % of completed studies met their primary or key secondary endpoints. Nevertheless, only 39 % achieved marketing authorization (MA) by at least one major regulatory agency (32 % by the European Medicines Agency [EMA], 32 % by the US Food and Drug Administration [FDA], and 24 % by both agencies). A marked 'Sponsor gap' exists: academics led 64 % of trials, yet industry drove 75 % (EMA) and 67 % (FDA) of regulatory successes. When looking at Marketing Authorization Holders (MAHs), industry sponsors held 100 % of EMA authorizations in this cohort. To bridge this translational divide, we propose a framework combining AI-driven screening and N-of-1 trials to optimize academic-industrial handoffs and harmonize regulatory pathways, accelerating approval for underserved patient populations.
    DOI:  https://doi.org/10.1016/j.drudis.2026.104807
  19. Front Cardiovasc Med. 2026 ;13 1886093
    Mitophagy-pyroptosis-macrophage polarization crosstalk in cardiovascular diseases: mechanistic insights and therapeutic potential.
    Jieying Yuan, Tingru Ji, Ruquan Chen, Yuesong Yuan, Lin Ji.
      Cardiovascular disease (CVD) is one of the leading causes of global morbidity and mortality. Its development and progression are closely associated with mitochondrial dysfunction, sterile inflammation, and immunometabolic dysregulation. Mitophagy, a key mechanism of mitochondrial quality control, maintains mitochondrial homeostasis by selectively removing damaged mitochondria. However, either insufficient or excessive mitophagy may disrupt cellular metabolism, promote ROS production and mitochondrial DNA (mtDNA) release, and activate inflammatory signaling pathways, thereby aggravating cardiovascular injury. Increasing evidence indicates that mitophagy is closely linked to pyroptosis and macrophage polarization. Impaired mitophagy can enhance inflammasome activation and gasdermin-mediated pyroptosis. In turn, inflammatory mediators released during pyroptosis may further impair mitochondrial quality control, forming a self-amplifying inflammatory loop. Meanwhile, mitophagy regulates macrophage metabolic reprogramming and phenotypic switching, thereby influencing the balance between pro-inflammatory M1-like responses and reparative M2-like functions. This review summarizes the molecular mechanisms underlying the crosstalk among mitophagy, pyroptosis, and macrophage polarization in CVD, with particular emphasis on myocardial infarction (MI) and myocardial ischemia-reperfusion injury. Current evidence suggests that restoring appropriate mitophagic flux, inhibiting aberrant pyroptosis, and reshaping macrophage phenotypes may help alleviate inflammatory injury and adverse cardiac remodeling. This review aims to provide a mechanistic framework for immunometabolic regulation in CVD and to support the development of precision therapeutic strategies targeting mitochondrial quality control and inflammatory cell responses.
    Keywords:  cardiovascular disease; immunometabolic regulation; macrophage polarization; mitochondrial quality control; mitophagy; pyroptosis
    DOI:  https://doi.org/10.3389/fcvm.2026.1886093
  20. Front Cardiovasc Med. 2026 ;13 1925684
    Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
    Shujun Ding, Yuna Hu, Qin Zhang, Xinyi Liu, Xuan Zhao, Yajing Zhao, Wen Zhang.
      Cardiac function depends on tightly regulated energy metabolism, with mitochondria serving as key sites of cellular energy production. Mitophagy, a selective form of autophagy that maintains mitochondrial quality, has received growing attention for its role in cardiomyocyte metabolism. Under specific physiological and pathological conditions, the myocardium increases its use of ketone bodies as energy substrates, and ketone body metabolism is closely linked to mitochondrial function. However, the relationship between mitophagy and ketone body metabolism is incompletely understood, particularly in cardiovascular disease. This review summarizes their roles and regulatory mechanisms in the myocardium and evaluates evidence for a potential bidirectional relationship. Mitophagy may preserve the mitochondrial capacity required for ketone body oxidation, whereas ketone body metabolism and β-hydroxybutyrate-mediated signaling may regulate mitophagy and mitochondrial stress resilience. By integrating these interactions across cardiovascular disease phenotypes, this review highlights their potential therapeutic relevance and identifies priorities for mechanism-based intervention and clinical translation.
    Keywords:  ketone body; metabolic flexibility; mitochondria; mitophagy; myocardial metabolism
    DOI:  https://doi.org/10.3389/fcvm.2026.1925684
  21. Burns Trauma. 2026 ;14 tkag043
    Mitochondrial transfer: a novel paradigm for wound healing.
    Yin He, Hong-Chao Huang, Lei Li, Si-Ya Wang, Guang-Yi Wang, Shi-Chu Xiao, Yong-Jun Zheng.
      Mitochondria not only serve as cellular powerhouses and metabolic regulatory hubs but also play crucial roles in calcium homeostasis, apoptosis regulation, and signal transduction. During wound repair, mitochondria modulate inflammatory and immune responses; drive angiogenesis; and supply energy for the proliferation, differentiation, and migration of repair cells such as fibroblasts and epithelial cells. When mitochondrial dysfunction exceeds the self-regulatory capacity, cellular energy deficits, metabolic disturbances, dysregulated signaling, and oxidative stress damage occur. These abnormalities collectively impair cellular repair mechanisms, ultimately contributing to chronic nonhealing wounds. Historically, mitochondria were thought to be acquired via vertical inheritance through cell division or mitochondrial biogenesis. However, the discovery of intercellular mitochondrial transfer provides novel insights into mitochondrial acquisition and presents new avenues for rescuing mitochondrial dysfunction. This article comprehensively reviews the dialectical relationship between mitochondrial dysfunction and impaired wound healing by integrating mechanisms of mitochondrial transfer, including modes, triggers, and regulatory pathways. It further highlights the therapeutic potential of mitochondrial transfer in wound repair. Additionally, this article provides forward-looking perspectives on clinical applications and future developments in mitochondrial transfer for wound healing, aiming to establish a theoretical foundation for mitochondrial transplantation therapies.
    Keywords:  Mitochondria; Mitochondrial transfer; Mitochondrial transplantation; Wound healing
    DOI:  https://doi.org/10.1093/burnst/tkag043
  22. J Neuropathol Exp Neurol. 2026 Sep 16. pii: nlag102. [Epub ahead of print]
    MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.
    Allison R Hanaford, Elizaveta A Olkhova, Ryan Liao, Ashley Ching, Alvin Huang, Erin Shien Hsieh, Kino Watanabe, Yihan Chen, Megan Wichman, Noelle Hwang, Katerina James, Michael Mulholland, Vivian Truong, Holly Coulson, Kerry Gibbins, Owen Cairns, Anastasia Dimitriou, Ernst-Bernhard Kayser, Brittany M Johnson, Sarkar Surojit, Vandana Kalia, Simon C Johnson.
      Primary genetic mitochondrial diseases (GMDs) are clinically and genetically diverse diseases. Leigh syndrome (LS), the most common pediatric presentation of GMD is a severe progressive multi-system disorder with diverse manifestations. No effective treatments currently exist. Recent data from the Ndufs4(-/-) LS mouse model show that peripheral macrophages contribute to brain lesions, that disease is driven by innate immune populations and that depletion of innate immune cells prevents disease. However, the mechanisms underlying the immune activation in LS remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and DNA are detected by toll-like receptors (TLRs) at the endosome and may mediate innate immune activation in LS. To assess TLR signaling in an LS mouse model, we generated TLR signaling-deficient Ndufs4(-/-)/MyD88(-/-) animals. Prophylactic antibiotic treatment with enrofloxacin enabled production of MyD88(-/-) animals from Ndufs4(+/-)/MyD88(+/-) breeder pairs. Loss of MyD88 in Ndufs4(-/-) animals increased survival and delayed the onset but disease courses were not altered. We conclude that Myd88-mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of MyD88(-/-) animals modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in mitochondrial diseases warrants further investigation.
    Keywords:  Leigh syndrome; electron transport chain complex I; innate immune system; mitochondrial disease
    DOI:  https://doi.org/10.1093/jnen/nlag102
  23. Orphanet J Rare Dis. 2026 Sep 05. pii: 316. [Epub ahead of print]21(1):
    Patient pathways for rare liver diseases: a European template developed by ERN RARE-LIVER.
    Sarah Raevens, Renée Duijzer, Andreea Fodor, Matt Bolz Johnson, Nagham Issa, Sophie Pénisson, Samir Patel, Alice Bertolini, Carmen A J Teemer, Clemence Ramier, Laure Elkrief, Marco Senzolo, Virginia Hernandez-Gea, Ansgar W Lohse, Bogdan Procopet, Joost P H Drenth, Aurélie Plessier.
       BACKGROUND: Rare liver diseases are associated with diagnostic delay, fragmented care, inconsistent management, and limited patient support. Patient pathways may help address these challenges by translating clinical guidance and patient priorities into practical, coordinated care processes.
    MAIN BODY: This manuscript presents a European template for developing patient-centred pathways for rare liver diseases within ERN RARE-LIVER. The template was developed through multidisciplinary collaboration involving hepatologists, specialist nurses, patient representatives, patient organisations, and EURORDIS, and was informed by clinical guidance, patient-journey principles, and iterative expert and patient review. The proposed framework follows four phases of the patient journey: pre-diagnosis, diagnosis, management, and long-term follow-up. It includes disease-specific sections, educational resources, frequently asked questions, and "10 key questions" to support shared decision-making. Pathways for non-cirrhotic portal vein thrombosis, polycystic liver disease, and portosinusoidal vascular disorder illustrate the practical application of the template.
    CONCLUSION: This European template provides a practical, adaptable framework aimed at supporting harmonised, multidisciplinary, and patient-centred care for rare liver diseases across European healthcare settings. Future work should evaluate implementation, usability, and impact on care coordination and patient experience.
    Keywords:  Multidisciplinary care; Patient empowerment; Patient pathway; Rare liver disease
    DOI:  https://doi.org/10.1186/s13023-026-04556-3
  24. Nucleic Acids Res. 2026 Sep 07. pii: gkag876. [Epub ahead of print]54(17):
    Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
    Lisa Hubers, Alexander Myhr Skjetne, Luisa Luna, Yohan Lefol, Solveig Osnes Lund, Ane Marit Wågbø, Xavier Renaudin, Annikka Polster, Zoe J da Silva, Anders Knoph Berg-Eriksen, Francisco Jose Naranjo-Galindo, Anna Campalans, Torkild Visnes, Hilde Loge Nilsen, Nicola Pietro Montaldo.
      Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1-/- cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1-/- cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.
    DOI:  https://doi.org/10.1093/nar/gkag876
  25. Mol Med Rep. 2026 Nov;pii: 309. [Epub ahead of print]34(5):
    Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
    Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Xu Zhang, Yanguang Cao, Binbin Tang, Xiaolin Shi, Kang Liu.
      Mitochondria‑associated endoplasmic reticulum membranes (MAMs) are specialized endoplasmic reticulum (ER) membrane domains at ER‑mitochondrial contact sites that coordinate Ca²+ transfer, lipid exchange, mitochondrial quality control and cellular stress responses. In osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy, altered ER‑mitochondrial communication has been linked to recurrent disturbances in Ca²+ homeostasis, mitochondrial function, ER stress, inflammatory signaling and cell fate. However, evidence for MAM involvement varies markedly in directness and biological context. This narrative review compares these evidence patterns and their therapeutic implications across degenerative musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM‑associated regulators and functional pathways, whereas sarcopenia‑specific mechanisms remain largely informed by aging muscle and related experimental models. The direction and consequences of contact remodeling also vary with cell type, metabolic state and disease stage, arguing against a uniform gain‑ or loss‑of‑contact model. Interventions targeting contact‑site regulators or MAM‑related Ca²+ and mitochondrial pathways have shown preclinical benefit, but MAM‑specific target engagement and human validation remain limited. Progress will require paired structural and functional assessment together with validation in clinically characterized human tissues and patient‑derived systems.
    Keywords:  ER‑mitochondrial contacts; endoplasmic reticulum stress; ferroptosis; mitochondrial dysfunction; mitochondria‑associated endoplasmic reticulum membranes; musculoskeletal degeneration; organelle communication
    DOI:  https://doi.org/10.3892/mmr.2026.14020
  26. iScience. 2026 Sep 18. 29(9): 117393
    TargetQC: A targeted quality control framework for clinical genomic testing.
    Fangfang Lan, Yaqiong Wang, Yulan Lu, Bingbing Wu, Xiao Wang, Chuan Li, Bo Liu, Xinran Dong.
      Reliable genetic testing depends on accurate assessment of sequencing quality in clinically relevant genomic regions that directly influence variant interpretation. We developed TargetQC, a flexible quality control framework that supports user-defined gene sets, coverage thresholds, and variant sets for evaluating sequencing performance across exome sequencing (ES) and genome sequencing (GS) platforms. TargetQC assesses exon and gene coverage, identifies regions meeting predefined coverage thresholds, evaluates variant detection accuracy, and measures sequencing quality at pathogenic variant sites. We applied TargetQC to the reference sample NA12878 and 665 clinical samples across five ES platforms and one GS platform. ES-VendorB and ES-VendorE achieved the most complete coverage of OMIM coding regions in NA12878, whereas ES-VendorD and ES-VendorE showed the highest coverage compliance in clinical samples. ES-VendorB and GS demonstrated the highest variant detection accuracy. TargetQC provides a practical framework for benchmarking sequencing performance and informing platform selection in clinical genomics.
    Keywords:  exome sequencing; genetic diagnosis; genome sequencing; quality control; rare diseases
    DOI:  https://doi.org/10.1016/j.isci.2026.117393
  27. Front Cell Dev Biol. 2026 ;14 1903771
    Inhibition of mitochondrial dynamics in Dictyostelium discoideum through the overexpression of FszA and FszB proteins.
    Ashley Ryan, Kari Naylor.
      Mitochondria play a central role in cells through energy production, calcium regulation, and cell death regulation. Dysfunction of mitochondria can impair energy production causing cellular damage which could be detrimental to an organism. Mitochondrial dynamics such as fission, fusion, and motility determine the organelle's structure and can indicate the overall health of the cell. Dictyostelium discoideum, a well-established model for mitochondrial dynamics, contains two GTPase proteins that are predicted to mediate mitochondrial dynamics, FszA and FszB. In this study, we overexpressed GFP tagged FszA and FszB proteins to gain insight into their role in the mitochondrial dynamics of D. discoideum. Through live imaging, we quantified mitochondrial fission and fusion events, localization of the proteins with respect to fission and fusion events, and mitochondrial velocity. Results show that the overexpression of FszA-GFP, FszB-GFP, and GFP-FszB significantly decreased mitochondrial fission and fusion, and overexpressed GFP-FszA significantly decreased mitochondrial fusion compared to the control AX4 strain. Images of GFP-FszA and FszA-GFP strains showed little co-localization with the mitochondria during fission and fusion events, but GFP-FszB and FszB-GFP were localized to the mitochondria during fission events. Overexpression of FszB-GFP and GFP-FszB also significantly decreased mitochondrial velocity. The results of this study give insight into the underlying mechanism behind mitochondrial dynamics and could advance future studies in D. discoideum neurodegeneration models.
    Keywords:  Dictyostelium discoideum; FszA; FszB; FtsZ proteins; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2026.1903771
  28. Redox Biol. 2026 Sep 12. pii: S2213-2317(26)00396-4. [Epub ahead of print]97 104397
    Maternal hyperhomocysteinemia promotes adverse pregnancy outcomes via mtDNA-cGAS-STING signaling-mediated trophoblast mitophagy.
    Chaoqun Liu, Zhuoqiao Gao, Jianyin Chen, Yunyan Yang, Qiaolin Xiao, Shaohui Deng, Yumei Zhang, Wenen Su, Tao Liu.
       OBJECTIVES: Hyperhomocysteinemia (HHcy) is a recognized risk factor for adverse pregnancy outcomes. However, the underlying mechanisms precipitating placental dysfunction, particularly the potential involvement of mitochondrial DNA (mtDNA), remain largely elusive. This study aims to investigate the association between maternal HHcy and adverse pregnancy outcomes mediated by reduced placental mtDNA copy number (mtDNAcn), and to elucidate the underlying molecular mechanisms driving HHcy-induced placental dysfunction.
    METHODS: We prospectively investigated the associations between maternal HHcy, placental mtDNA copy number (mtDNAcn), and adverse pregnancy outcomes using data from the PEOH (Prenatal Environments and Offspring Health) birth cohort. To elucidate the underlying mechanisms, human placental tissues, maternal HHcy rat placentae, and HTR-8/SVneo trophoblast cells were utilized to assess HHcy-induced mitochondrial damage, PINK1/Parkin-mediated mitophagy, and downstream inflammatory signaling.
    RESULTS: Epidemiological analysis revealed that maternal HHcy was significantly associated with increased risks of preterm birth and low birth weight, with reduced placental mtDNAcn serving as a critical mediator. Mechanistically, HHcy exposure induced severe mitochondrial dysfunction and excessive PINK1/Parkin-dependent mitophagy across human placentae, maternal HHcy rat placentae, and HTR-8/SVneo cells. This unrestrained mitophagic flux precipitated the leakage of mtDNA into the cytosol, which directly engaged and activated the cGAS-STING pathway, leading to placental sterile inflammation and subsequent placental dysfunction via upregulating COX-2 and pro-inflammatory cytokines.
    CONCLUSION: Maternal HHcy exposure contributes to adverse pregnancy outcomes by reducing placental mtDNAcn and triggering a cascade of PINK1/Parkin-mediated mitophagic disruption, cytosolic mtDNA release, and subsequent cGAS-STING-driven sterile inflammation and placental dysfunction, underscoring the need for clinical Hcy monitoring and early intervention.
    Keywords:  Adverse pregnancy outcomes; Homocysteine; Mitochondrial DNA copy number; Mitochondrial damage
    DOI:  https://doi.org/10.1016/j.redox.2026.104397
  29. Autophagy. 2026 Sep 16.
    Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
    Jiamin Yi, Xin Yong, Da Jia.
      Mitochondrial ubiquitination is a central component of mitochondrial quality control. The PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway established how loss of mitochondrial membrane potential can trigger a phospho-ubiquitin feed-forward cascade on the outer mitochondrial membrane (OMM). It remains less clear how mitochondrial ubiquitination is achieved when PRKN is absent or inactivated. In our recent work, we identify a recruitment platform organized by AMBRA1 (autophagy and beclin 1 regulator 1), in which RMC1 (regulator of MON1-CCZ1) positions HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) at mitochondria. This spatial arrangement promotes HUWE1-dependent ubiquitination and turnover of OMM proteins, including MFN2 (mitofusin 2), VDAC1 (voltage-dependent anion channel 1), and VDAC2 (voltage-dependent anion channel 2). Our findings raise the question of how cells select among distinct mitochondrial ubiquitination pathways and whether these pathways function independently, sequentially, or cooperatively.
    Keywords:  AMBRA1; HUWE1; PINK1-PRKN; RMC1; mitochondrial quality control; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2026.2735210
  30. EJHaem. 2026 Oct;7(5): e70387
    Somatic Mitochondrial-Nuclear DNA Transfer in Lymphoproliferative Disorders.
    James Peter Stewart, Nikos Darzentas, Miguel Alcoceba, Maria Eugenia Sarasquete, Anthony V Moorman, Mark Catherwood, Binaya Regmi, Christiane Pott, Anton W Langerak, David Gonzalez.
       Introduction: Somatic mitochondrial-nuclear DNA transfer (SMNT) is a process by which mitochondrial DNA (mtDNA), of varying sizes, integrate into the nuclear genome and has been previously reported in solid tumours.
    Methods: EuroClonality-NGS DNA Capture sequencing data from 755 lymphoid malignancies and 59 lymphoid cell lines were analysed for SMNT-associated structural variants.
    Results: Five malignancies (0.66%) harboured SMNTs, predominantly involving IGH genes, with one PTEN gene disruption identified. Breakpoint features supported non-homologous end joining-mediated integration.
    Conclusion: SMNTs are rare but recurrent events in lymphoid malignancies and may represent stable clonal markers for minimal residual disease monitoring.
    Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
    DOI:  https://doi.org/10.1002/jha2.70387
  31. Bioinformatics. 2026 Sep 15. pii: btag684. [Epub ahead of print]
    "NanoDel": Identification of large-scale mitochondrial DNA deletions using long-read sequencing.
    C Fearn, J Poulton, C Fratter, C Oliva, C Griguer, R A Baldock, S C Robson, R E McGeehan.
       MOTIVATION: Traditional methods for detecting large-scale mitochondrial DNA (mtDNA) deletions (LSMDs) in cells present challenges, i.e. requiring a priori information, high DNA inputs, and are not always sensitive and/or quantitative. Mitigation can be achieved through high-throughput DNA sequencing using e.g. Illumina and Oxford Nanopore Technologies (ONT), in combination with LSMD breakpoint identification and quantification using bioinformatics. Splice-aware RNA alignment tools increase the sensitivity for detecting LSMD breakpoints compared with DNA aligners. Long-read sequencing (LRS) also offers potential advantages over short-read sequencing (SRS), e.g. greater read lengths and capturing variants on single reads. Here we aimed to capture the benefits of both a splice-aware alignment tool and LRS.
    RESULTS: We developed "NanoDel", a LRS pipeline, to sensitively and accurately detect cellular LSMDs. Using artificial datasets, "NanoDel" was more sensitive and accurate than other pipelines. In samples diagnosed with mitochondrial disease, it identified both known and previously uncharacterised (including mixtures) of LSMDs, without a priori information. Analysis of selected LSMDs revealed proximity to repeat, putative G-quadruplex motifs, and the "contact zone". Together with occurrence in a range of healthy and pathological tissues, indicates potential for a shared vulnerability landscape in mtDNA, shaped by sequence motifs and structural constraints. This proof-of-concept study shows that "NanoDel" combined with one-amplicon LR-PCR offers a robust strategy for detecting LSMDs across a variety of cell/tissue samples. Applying "NanoDel" to a larger and broader range of samples would confirm this, yielding new mechanistic insights into LSMD formation, and further our understanding of mtDNA instability in the future.
    AVAILABILITY AND IMPLEMENTATION: "NanoDel" is available at https://github.com/uopbioinformatics/NanoDel (DOI: 10.5281/zenodo.20119070) and raw read data are available through the NCBI Sequence Read Archive (SRA) under BioProject accession code PRJNA1369153 (https://www.ncbi.nlm.nih.gov/bioproject/1369153).
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag684
  32. Med Gas Res. 2027 Jan 01. 17(1): 129-138
    Nitric oxide signaling and mitophagy in Parkinson's disease: implications for aerobic exercise-related neuroprotection.
    Yang Zhou, Yongliang Wu.
      Parkinson's disease is strongly associated with mitochondrial dysfunction and impaired mitochondrial quality control, including defective mitophagy. Aerobic exercise is increasingly recognized as a safe and accessible intervention that can improve motor and non-motor outcomes in Parkinson's disease and may also engage mechanisms relevant to disease modification. In this review, we propose a context-dependent framework in which aerobic exercise reshapes nitric oxide signaling toward a more adaptive profile, characterized by relatively moderate, transient, and spatially restricted nitric oxide bioactivity, and we discuss how this shift may influence mitochondrial biogenesis, mitophagy initiation, and autophagic flux regulation. Rather than treating nitric oxide as uniformly protective or deleterious, we argue that its biological effects in Parkinson's disease depend on source, concentration, duration, subcellular localization, cellular target, and surrounding redox milieu. However, direct evidence that exercise-derived nitric oxide activates these pathways in Parkinson's disease-relevant neural tissue is still limited. We further highlight major translational gaps, including cell-type and brain-region heterogeneity, incomplete definition of exercise dose-response relationships, and the lack of validated in vivo biomarkers of neuronal mitophagy and nitric oxide dynamics in patients with Parkinson's disease. Overall, aerobic exercise is a plausible modulator of mitophagy-related pathways in Parkinson's disease, and nitric oxide is a credible contributor to this effect; however, the current evidence supports a multi-node, context-dependent model rather than a simple linear mechanism.
    Keywords:  PINK1/Parkin pathway; Parkinson’s disease; S-nitrosylation; aerobic exercise; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neuroprotection; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.4103/mgr.MEDGASRES-D-26-00008
  33. Clin Public Health Guidel. 2026 Jul;3(3): e70070
    Guidelines or Other Guidance Documents for Rare Diseases in the Netherlands: When and Where to Invest (Effort, Time and Money)?
    Iméze J Hieltjes, Charlotte M W Gaasterland, Marieke Hermsen, Anne Marie van Wermeskerken, Ilse van Herk, Johanna H van der Lee.
       Introduction: Developing Clinical Practice Guidelines (CPGs) is resource-intensive, making it essential to prioritise those CPG projects that are most needed. One of the rules pertains to prevalence, which excludes virtually all guideline development for rare diseases. Still, guidance is needed for their management. We discuss considerations pertaining to the decision to develop a CPG or another type of guidance document for a rare disease.
    Methods: Using a consensus-based approach, an expert group developed a decision support flowchart to decide about the development of a clinical practice guideline or an alternative type of guidance document for rare diseases. An expert group of three guideline methodologists, a paediatrician, and two quality of care policy officers drafted an initial flowchart. The flowchart was reviewed and refined through three rounds of steering committee discussions in different settings, after which final adaptations were made.
    Results: The flowchart serves as a support tool to consider whether a CPG is the most suitable type of guidance document for addressing clinical challenges in a particular rare disease. Several alternatives may be more appropriate than developing a CPG, such as a local protocol, a care pathway, a didactic paper, or adolopment or adaptation of an international CPG illustrated by three conditions.
    Discussion: The proposed flowchart provides a framework to consider all relevant aspects around the choice for development of a guidance document or CPG. Although it results from the Dutch national situation and the rare disease field, it may also be applied in other countries and for more prevalent diseases. We encourage external validation and, if necessary, refinement of the flowchart. It supports strategic decision-making, ensuring that the efforts and resources needed for the development of CPGs or other guidance documents are focused on areas where they will have the greatest impact on medical specialist care.
    DOI:  https://doi.org/10.1002/gin2.70070
  34. J Bioenerg Biomembr. 2026 Sep 14. pii: 52. [Epub ahead of print]58(1):
    Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
    Gino A Kurian.
      Cardiovascular disease is strongly influenced by mitochondrial dysfunction, yet how mitochondrial stress is communicated beyond the affected cell to coordinate systemic responses remains incompletely understood. Mitokines are stress-responsive signaling factors that link mitochondrial perturbation to cellular and interorgan adaptation. These include nuclear-encoded proteins such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), as well as mitochondrial-derived peptides including Humanin and MOTS-c. This review critically examines mitokine regulation and signaling in the context of cardiovascular stress, with emphasis on mitochondrial unfolded protein response and integrated stress response pathways, receptor and downstream signaling mechanisms, and the functional divergence among major mitokines. Transient mitokine responses during physiological or metabolic challenge may support metabolic flexibility, cytoprotection, and stress adaptation, whereas persistent elevations of FGF21 and GDF15 in cardiovascular and cardiometabolic disease frequently accompany unresolved mitochondrial stress and adverse clinical phenotypes. Importantly, such associations do not establish that sustained mitokine signaling is itself maladaptive, and major mechanistic uncertainties remain, particularly for mitochondrial-derived peptides. We integrate these observations within a proposed "mitokine code" framework in which mitokine identity, relative patterns, temporal dynamics, and disease context may collectively provide information about mitochondrial stress and systemic adaptation. We further evaluate the potential and current limitations of mitokines as cardiovascular biomarkers and therapeutic targets. This framework positions mitokine signaling at the interface between mitochondrial dysfunction, systemic stress adaptation, and cardiovascular disease while identifying mechanistic and translational questions requiring prospective validation.
    Keywords:  Cardiovascular disease; Integrated stress response; Mitochondrial stress signaling; Mitochondrial unfolded protein response; Mitochondrial-derived peptides; Mitokines
    DOI:  https://doi.org/10.1007/s10863-026-10136-8
  35. Mol Neurodegener Adv. 2025 Dec;1(1): 5
    Emerging roles of the ciliary-mitochondrial axis in cellular homeostasis and neuroprotection.
    Emiko Miller, Peter Bambakidis, Phoebe Templin, Bindu D Paul, Andrew A Pieper.
      Primary cilia and mitochondria, long studied as separate cellular players, are now recognized as a tightly coupled signaling and metabolic hub whose interplay powerfully shapes cell fate. The bidirectional ciliary-mitochondrial axis integrates extracellular sensing, calcium dynamics, bioenergetics, and organelle quality control to drive adaptive responses to stress and sustain neuronal resilience. Recent studies reveal compelling associations that merit further investigation, such as the impact of primary cilium-initiated signaling cascades on mitochondrial dynamics and mitophagy, and the effects on cilia of shifting mitochondrial metabolic states. Dysfunction at any node in this axis has potential to trigger neurodegeneration. Framing primary cilia and mitochondria as a coordinated physiologic axis enables reconsideration of neurodegeneration and reveals novel, tractable entry points for therapeutic restoration of brain homeostasis. This review traces the field's evolution, synthesizes key molecular mechanisms, and highlights exciting translational opportunities to harness the ciliary-mitochondrial axis for neuroprotection.
    Keywords:  Alzheimer’s disease; Ciliopathy; Mitochondria; Neurodegeneration; Primary cilia
    DOI:  https://doi.org/10.1186/s44477-025-00005-w
  36. J Physiol Sci. 2026 Sep 14. pii: S1880-6546(26)00048-X. [Epub ahead of print]76(3): 100102
    Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks.
    Motohiro Nishida.
      Cardiovascular homeostasis is increasingly understood not as the output of isolated pathways, but as an emergent and history-dependent property of interactions across biological scales. Cutting-edge technologies have revealed coupling between transcription and metabolism, signaling within molecular microdomains, organelle networks, communication between cardiomyocytes and non-myocytes, neurovascular regulation, and interorgan interactions. This special issue brings together five perspectives that examine how such interactions preserve physiological function and, under stress, redirect the cardiovascular system toward adaptation or disease. As a representative multiscale example, this Editorial highlights hierarchical mitochondrial quality control. Biogenesis, fusion-fission dynamics, proteostasis, mitochondria-derived vesicles, organelle contacts, and mitophagy form a graded defense network that matches the response to the burden and location of damage. The same network connects mitochondrial dysfunction to innate immunity and tissue remodeling. Defining directionality, spatial context, temporal order, and flux within these interactions will be essential for converting descriptive interaction maps into causal physiology and selective therapies.
    Keywords:  Cardiovascular homeostasis; Cellular circuits; Functional interaction; Heart failure; Microdomains; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100102
  37. Int J Mol Sci. 2026 Aug 27. pii: 7678. [Epub ahead of print]27(17):
    Mitochondrial Control of Myelination, Bioenergetics, Oxidative Stress, and the Pathogenesis of Optic Neuropathies.
    Haya Sahibzada, Rizwan Malik, Khaled K Abu-Amero.
      Myelination, mitochondrial bioenergetics, and oxidative stress are usually discussed as separate problems in optic nerve disease. This review draws them together and reads the published evidence through a single variable, the balance between the energy a retinal ganglion cell (RGC) axon spends and the energy its mitochondria can supply. We review the role of myelin in conduction and axonal support, the mitochondrial cost of building and maintaining it, the vulnerability of oligodendrocytes and myelin to oxidative injury, and the nuclear control of mitochondrial output. We summarize the inherited optic atrophies linked to OPA1, OPA3, AFG3L2, SPG7, and TMEM126A, and set these primary mitochondrial disorders against the immune-mediated demyelinating optic neuropathies. Published studies already support several parts of this picture, including the energetic cost of demyelination, the mitochondrial dependence of RGC axons, and oxidative injury in inflammatory lesions. Drawing on that evidence, we propose, as a testable hypothesis rather than a settled mechanism, that optic nerve degeneration is favored when axonal ATP demand outruns mitochondrial supply, most sharply where the axon crosses from its unmyelinated to its myelinated segment near the lamina cribrosa. We use this framework to separate initiating lesions from disease modifiers and downstream consequences, and to set out therapeutic predictions open to experimental and clinical tests.
    Keywords:  OPA1; bioenergetics; demyelination; mitochondria; myelination; optic neuropathy; oxidative stress; retinal ganglion cell
    DOI:  https://doi.org/10.3390/ijms27177678
  38. Curr Opin Pediatr. 2026 Sep 09.
    Immune dysregulatory disorders: perspective from solving a diagnostic odyssey.
    Lauren Crowther, Lori Broderick.
       PURPOSE OF REVIEW: Inborn errors of immunity (IEIs), once considered rare disorders characterized primarily by recurrent infections, are now recognized as a rapidly expanding group of diseases encompassing autoimmunity, autoinflammation, allergy, malignancy, and immune dysregulation. Advances in next-generation sequencing, functional immunology, and systems biology have revealed overlap between traditionally distinct disease categories and highlighted the complexity of genotype-phenotype relationships.
    RECENT FINDINGS: While this evolution has led to the discovery of hundreds of previously unrecognized disorders, it has also challenged conventional diagnostic paradigms and demonstrated how patients may have care spread across multiple specialties, without a clear medical home. These discoveries have also highlighted ongoing challenges translating scientific findings to the clinic including difficulties in accessing genomic testing, interpretation of variants of uncertain significance, impacts of incomplete penetrance and somatic mosaicism, and limited availability of specialized functional assays. Emerging computational approaches, including artificial intelligence, offer opportunities to accelerate diagnosis but cannot replace comprehensive clinical evaluation or longitudinal physician-patient relationships.
    SUMMARY: This perspective examines how the diagnostic odyssey for immune dysregulatory disorders has evolved, side-by-side with the changing framework for diagnosing rare immune diseases. We propose an integrated approach combining clinical phenotyping, genomics, functional validation, and multidisciplinary expertise to unite ongoing discovery between clinicians and scientists, diagnostics, and patient outcomes.
    Keywords:  diagnostic odyssey; immune dysregulation; inborn errors of immunity; next-generation sequencing
    DOI:  https://doi.org/10.1097/MOP.0000000000001616
  39. Oxf Med Case Reports. 2026 Sep;2026(9): omag172
    Normal neuroimaging in an infant with SUCLA2-related mitochondrial DNA depletion syndrome type 5: a case report of likely pathogenic variant.
    Mohammad Obada Alsadi, Youssef Heikal, Farah Al-Hasani, Dana Al Khasawneh, Aia Nasab, Heba Hrizat, Fatema Almoustafa, Barah Hussain.
      Mitochondrial DNA depletion syndrome type 5 (MTDPS5), caused by SUCLA2 mutations, is a rare autosomal recessive disorder manifesting as early-onset encephalomyopathy. Clinical diagnosis is challenging due to phenotypic overlap and potentially unremarkable early investigations. We report a male infant of consanguineous parents who presented with progressive hypotonia, global developmental delay, and involuntary nocturnal movements at 3 months. Despite an unremarkable newborn metabolic screen and normal initial brain MRI, the patient demonstrated a significant failure to achieve age-appropriate gross motor milestones, including independent sitting and crawling, by 12 months. Whole-exome sequencing (WES) definitively identified a homozygous likely pathogenic SUCLA2 variant (p.Met329Val). Following the initiation of a mitochondrial cocktail, the patient showed substantial clinical improvement. This case emphasizes that MTDPS5 should be considered in infants with unexplained encephalomyopathy, even when initial findings are normal, underscoring the necessity of early WES to guide clinical management.
    Keywords:  Encephalomyopathy; SUCLA2; WES; mitochondrial
    DOI:  https://doi.org/10.1093/omcr/omag172
  40. Stud Health Technol Inform. 2026 Sep 17. 340 257-267
    The European Health Data Space and the Secondary Use of Sensitive Health Data.
    Sameeksha Sriram, Sin-Yin Huei, Marie Haucke, Ulrich Sax.
       INTRODUCTION: The European Health Data Space (EHDS) is one of the European Union's most ambitious data-governance projects. It aims to create a common framework through which electronic health data can be accessed and reused across Member States for care, research, innovation, policy, and public-interest purposes. Its practical viability depends not only on digital infrastructure, but also on legal, ethical, and organisational harmonisation, particularly for genetic and genomic data.
    METHODS: This paper examines the EHDS with emphasis on the secondary use of health data. It reviews the EHDS institutional architecture, discusses Finland's Findata as a national model for structured access, and analyses challenges for data holders and data donors, including interoperability, governance burdens, privacy protection, residual re-identification risk, and genomic-data sensitivity.
    RESULTS: A cross-border cancer-genomics case study shows that the EHDS can streamline data discovery and the routing of access requests, but does not by itself eliminate legal fragmentation, heterogeneous ethics review, and consent-related barriers.
    DISCUSSION: Effective implementation will require harmonisation beyond infrastructure, including clearer consent standards, more consistent ethics procedures, interoperable metadata, and proportionate safeguards for genomic data.
    Keywords:  EHDS; Findata; genomic data; interoperability; record linkage; secondary use of health data; secure processing environments
    DOI:  https://doi.org/10.3233/SHTI261011
  41. Mol Biomed. 2026 Sep 16. pii: 171. [Epub ahead of print]7(1):
    Extracellular vesicles in targeted drug delivery: from biological functions to surface engineering.
    Giulia Duca, Vincenza Tinnirello, Nima Rabienezhad Ganji, Riccardo Alessandro, Stefania Raimondo.
      Achieving precise and efficient targeting represents a major challenge in drug delivery to overcome the limitations of conventional therapies. Surface functionalization of extracellular vesicles (EVs)-nanosized membranous particles released by all cell types- has emerged as a promising strategy to enhance targeted drug delivery. EVs are naturally involved in intercellular communication by transferring bioactive molecules from donor to recipient cells, and their biologically active interface confers inherent targeting properties and a favorable safety profile, making them attractive vehicles compared to synthetic nanoparticles. However, the naїve use of EVs is often limited by nonspecific biodistribution and off-target accumulation, reducing their therapeutic efficacy. To overcome these limitations, increasing efforts have focused on engineering EVs through cargo loading and surface functionalization strategies, enabling enhanced targeting and improved delivery of therapeutic molecules. In this review, we first describe the biological features of EVs, including their biogenesis, heterogeneity, and molecular composition, which underlie their potential as drug delivery systems. We then discuss the main determinants of EV-mediated drug delivery and present current engineering strategies, including cargo loading and surface functionalization approaches, highlighting their advantages and limitations. Finally, we summarize the application of engineered EVs in the treatment of several pathological conditions, including cardiovascular, neurological, autoimmune, and cancer diseases, and discuss the major challenges in clinical translation and future perspectives for EV-based targeted therapies.
    Keywords:  Extracellular vesicles; Loading approaches; Nanoparticles; Pathological conditions; Surface functionalization; Targeted drug delivery
    DOI:  https://doi.org/10.1186/s43556-026-00578-2
  42. Front Pharmacol. 2026 ;17 1849218
    Synaptic mitochondrial dysfunction and Alzheimer's disease: from molecular mechanisms to therapeutic strategies.
    Yuxin Wang, Weidong Wu, Lishuang Yan, Bo Zhang, Quan Li, Yanyan Zhou.
      The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies-disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission/fusion, and defective autophagy-converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood-brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.
    Keywords:  AD; Alzheimer’s disease; ROS; oxidative stress; synaptic mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fphar.2026.1849218
  43. Mech Ageing Dev. 2026 Sep 14. pii: S0047-6374(26)00094-1. [Epub ahead of print] 112242
    Loss of Ca2+ Signaling Fidelity During Aging: Mitochondrial Dysfunction, Senescence, and Cognitive-Motor Decline.
    Sergio Linsambarth, Alejandra Lopez-Moroni, Cesar Casanova, Simon Alarcon, Loreto Araos, Andrea Puebla-Huerta, Fabian Jaña, Alenka Lovy, Carlos Villalobos, J Cesar Cárdenas.
      Aging is characterized by a progressive decline in cellular homeostasis that ultimately compromises tissue integrity, regenerative capacity, and organismal function. Among the molecular processes increasingly recognized as central regulators of aging, intracellular Ca2+ signaling has emerged as a major determinant of metabolic adaptation, stress responses, inflammation, and cell fate. Ca2+ controls essential biological functions in virtually every tissue. Importantly, the remarkable versatility of Ca2+ signaling depends on the precise spatial and temporal coordination of channels, pumps, exchangers, buffering proteins, and organelle contact sites that together generate highly organized intracellular Ca2+ microdomains. During aging, the quality of this signaling progressively deteriorates. Altered activity of plasma membrane channels, defective endoplasmic reticulum (ER) Ca2+ handling, impaired mitochondrial buffering, oxidative stress, and chronic inflammation collectively destabilize intracellular Ca2+ homeostasis. These alterations converge on mitochondrial dysfunction, one of the central hallmarks of aging, leading to bioenergetic decline, excessive reactive oxygen species production, cellular senescence, and impaired tissue adaptation. In the nervous system, disrupted Ca2+ signaling contributes to synaptic dysfunction, neuroinflammation, and neuronal vulnerability associated with cognitive decline and neurodegenerative disease. In skeletal muscle, defective Ca2+ handling impairs excitation-contraction coupling, mitochondrial metabolism, and regenerative capacity, thereby promoting sarcopenia and motor decline. In this review, we discuss how aging remodels the cellular Ca2+ signaling toolkit across neuronal and muscular systems, with particular emphasis on mitochondrial dysfunction, senescence and inter-organelle communication. Finally, we examine therapeutic strategies aimed at restoring Ca2+ signaling fidelity as potential interventions to preserve tissue function and extend healthspan.
    Keywords:  Channels; MERCs; mitochondria; neurodegeneration; sarcopenia
    DOI:  https://doi.org/10.1016/j.mad.2026.112242
  44. J Microbiol Biotechnol. 2026 Aug 26. 36 e2607032
    Bacterial Extracellular Vesicles as Regulators of the Gut Microbiome-Circadian Axis in Inflammatory and Metabolic Diseases.
    Hyejin Choi, Sangnam Oh, Younghoon Kim.
      Bacteria-derived extracellular vesicles (BEVs) have emerged as key mediators of intercellular and interkingdom communication. These nanoscales, lipid bilayer-enclosed particles are secreted by both Gram-positive and Gram-negative bacteria and carry diverse bioactive cargoes, including proteins, lipids, nucleic acids, and metabolites. Through the delivery of these molecules, BEVs regulate host physiology by modulating immune responses, epithelial barrier integrity, and gut microbial community composition. Accumulating evidence indicates that BEVs derived from probiotics or commensal bacteria promote gut homeostasis, whereas vesicles released by pathogenic bacteria exacerbate dysbiosis, inflammation, and disease progression. The gut microbiome plays a central role in maintaining immune and metabolic homeostasis, and its disruption contributes to the development of inflammatory and metabolic diseases, including inflammatory bowel disease, atopic dermatitis, and metabolic dysfunction-associated steatohepatitis. In parallel, circadian rhythms orchestrate host metabolism, immunity, and microbial interactions, and emerging evidence highlights a bidirectional relationship between the gut microbiome and the circadian clock. Disruption of this microbiome-circadian axis further exacerbates inflammation and metabolic dysfunction. This review integrates current knowledge of the structural and functional characteristics of BEVs, their roles in regulating the gut microbiome, and their emerging involvement in circadian biology. We further discuss how BEVs may mediate communication within the gut microbiome-circadian axis and contribute to the pathogenesis or resolution of inflammatory and metabolic diseases. Understanding the BEV-gut microbiome-circadian axis provides new mechanistic insights into host-microbe communication and highlights BEVs as promising postbiotic candidates for restoring immune-metabolic homeostasis and developing next-generation microbiome-targeted therapeutics.
    Keywords:  Bacteria-derived extracellular vesicle (BEVs); Circadian rhythm; Gut microbiome; Inflammatory diseases; Metabolic diseases
    DOI:  https://doi.org/10.4014/jmb.2607.07032
  45. Aging Cell. 2026 Sep;25(9): e70716
    Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.
    Rui Yamada, Hirotaka Nagai, Chisato Numa, Yunhui Zhu, Midori Nagai, Kohei Ota, Yusuke Kawashima, Nobuhiko Ohno, Tomoyuki Furuyashiki.
      Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.
    Keywords:  cognitive aging; mice; mitochondria; oxidative stress; prefrontal cortex; synapse
    DOI:  https://doi.org/10.1111/acel.70716
  46. Nephrology (Carlton). 2026 Sep;31(9): e70283
    Peritoneal Dialysis for End-Stage Kidney Disease due to Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS): A Case Report.
    Zi Chan, Ka Lok Chan, Chi Kwan Lam, Wai Ping Law, Wai Lun Will Pak, Yick Hei Wong, Sunny Sze Ho Wong.
      We report a 23-year-old male with kidney failure secondary to childhood Focal Segmental Glomerulosclerosis who presented with sepsis, severe lactic acidosis, and encephalopathy. Following stabilization of the acute condition with Continuous Veno-Venous Hemofiltration, a diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) was confirmed by muscle biopsy and the identification of the m.3243A>G mutation. This case highlights the diagnostic difficulties of this rare disease and the challenges in selecting a long-term renal replacement therapy. Specifically, the use of lactate-buffered peritoneal dialysis fluids in these patients remains controversial. In our case, the patient demonstrated poor tolerance to intermittent haemodialysis due to MELAS-associated cardiomyopathy. However, despite theoretical concerns regarding lactate load, steady-state serum lactate remained stable on Continuous Ambulatory Peritoneal Dialysis (CAPD), and the patient achieved good functional recovery. We conclude that while acute decompensation requires aggressive management, CAPD is a feasible long-term dialysis modality for patients with kidney failure secondary to MELAS.
    Keywords:  MELAS; focal segmental glomerulosclerosis; kidney failure; lactic acidosis; peritoneal dialysis
    DOI:  https://doi.org/10.1111/nep.70283
  47. PLoS One. 2026 ;21(9): e0357296
    Characterization of mesenchymal stromal cell-mediated mitochondrial transfer to healthy and diseased intervertebral disc cells.
    Ashley Cardenas, Noah Willett, Anthony Robayo, Jessica Berger, Blake Boadi, Chibuikem A Ikwuegbuenyi, Ibrahim Hussain, Roger Härtl, Lawrence J Bonassar.
      Intradiscal injection of mesenchymal stromal cells has gained widespread interest for the treatment of intervertebral disc degeneration. Mesenchymal stromal cells have been shown to impart a therapeutic benefit on treated tissues through a variety of mechanisms including mitochondrial transfer. Mitochondrial transfer from mesenchymal stromal cells to diseased cells has been demonstrated, in numerous model systems, to increase the survival and function of recipient cells. To date there are few studies that have investigated mitochondrial transfer from mesenchymal stromal cells to intervertebral disc cells. The goal of this study is to characterize mitochondrial transfer from mesenchymal stromal cells to bovine and human intervertebral disc cells using confocal microscopy. Following a 24-hour coculture period, bovine mesenchymal stromal cells were shown to transfer mitochondria to bovine annulus fibrosus cells under both healthy and inflammatory conditions. In addition, human mesenchymal stromal cells were shown to transfer mitochondria to diseased, patient-derived intervertebral disc cells. Mitochondrial transfer quantity was found to increase under inflammatory stress conditions and with patient age, though functional consequences of this transfer remain to be determined. This study is the first to show mesenchymal stromal cells transfer mitochondria to bovine annulus fibrosus cells and patient derived intervertebral disc cells. We provide evidence that mitochondrial transfer is a relevant mechanism by which mesenchymal stromal cells communicate with intervertebral disc cells.
    DOI:  https://doi.org/10.1371/journal.pone.0357296
  48. J Nutr Health Aging. 2026 Sep 15. pii: S1279-7707(26)00220-4. [Epub ahead of print]30(11): 100987
    Diabetic kidney disease: emerging mechanistic and nutritional perspectives from the Mediterranean diet-mitochondria axis. A narrative review.
    Giovanna Mercurio, Antonia Giacco, Nicla Scopigno, Michela Vigliotti, Giuseppe Petito, Maria Moreno, Federica Cioffi, Elena Silvestri.
       OBJECTIVES: To examine mitochondrial dysfunction as a key driver of diabetic kidney disease (DKD) and to evaluate the Mediterranean diet (MD) as a potential nutritional modulator of renal mitochondrial health.
    METHODS: Clinical, epidemiological, and preclinical studies addressing mitochondrial alterations in podocytes and proximal tubular cells were critically reviewed, with particular attention to MD adherence and MD-derived bioactive compounds.
    RESULTS: Evidence indicates that early, cell-specific mitochondrial dysfunction contributes to DKD progression through impaired bioenergetics, oxidative stress, altered mitochondrial dynamics, defective mitophagy, and reduced biogenesis. Clinical and epidemiological studies consistently associate higher MD adherence with preserved renal function and lower DKD risk, while experimental studies suggest that MD-derived bioactives modulate mitochondrial quality control pathways in renal cells.
    CONCLUSION: The MD-mitochondria axis represents a biologically plausible framework linking nutrition and mitochondrial homeostasis in DKD. Mediterranean diet adherence may therefore contribute to renal resilience and complement current strategies aimed at preventing DKD progression.
    Keywords:  Cell type–specific mitochondrial dysfunction; Dietary polyphenols; Mitochondrial quality control; Nutritional nephroprotection
    DOI:  https://doi.org/10.1016/j.jnha.2026.100987
  49. Nat Genet. 2026 Sep 11.
    Contribution of copy number variants to schizophrenia in East Asian populations.
    Stanley Global Asia Initiatives
      Studies on schizophrenia-associated rare copy number variants (CNVs) have predominantly focused on people of European (EUR) ancestry. Here we present a rare CNV study of schizophrenia in East Asian (EAS) populations, comprising 20,903 cases and 23,258 controls. We observed a significantly elevated genome-wide rare CNV burden in EAS cases compared with controls. Cross-population comparisons showed largely consistent rare CNV effects on schizophrenia risk. In the EAS sample, we identified nine genome-wide-significant schizophrenia-associated rare CNV loci. Meta-analysis with EUR data yielded 14 significant loci, including 8 that reached genome-wide significance for the first time. Genes within these 14 loci were significantly less tolerant to loss-of-function variants than genes in other CNV loci. The new rare CNVs associated with schizophrenia in EAS populations showed higher carrier frequencies in EAS than in EUR populations (0.38% versus 0.0017%). Overall, this study underscores the importance of increasing population diversity to fully capture the genetic underpinnings of schizophrenia.
    DOI:  https://doi.org/10.1038/s41588-026-02732-6
  50. Biochem Pharmacol. 2026 Sep 15. pii: S0006-2952(26)00817-8. [Epub ahead of print]254(Pt 2): 118475
    Lipid regulation of mitochondrial function in metabolic Diseases: Lipotoxic mediators and therapeutic targeting.
    Hao Cui, Hongxing Li, Weihua Wang, Junhua Li, Meng Cai, Yixin Wang, Yi Zhang, Shuo Li.
      Lipid dysregulation is a key driver of chronic metabolic and degenerative diseases. However, lipid abnormalities and mitochondrial dysfunction are often examined separately, with limited attention given to their mechanistic links. As the central hub of energy metabolism, mitochondria continuously adapt their structure, substrate utilization, and quality control in response to the surrounding lipid environment and lipid-derived regulatory signals. This review examines mitochondrial function from the perspective of lipid regulation, focusing on how membrane lipid remodeling, lipid droplet-mitochondria coupling, substrate flux, bioactive lipid signaling, and mitochondrial turnover collectively determine mitochondrial function during lipid stress. In obesity, metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, cardiovascular disease, and neurodegenerative disorders, disruption of lipid-dependent mitochondrial regulation manifests in tissue-specific patterns but consistently involves excessive lipid supply, aberrant membrane remodeling, and impaired mitochondrial quality control. These alterations do not arise from a single pathway but reflect the combined disruption of multiple lipid-related processes. This lipid-centered perspective identifies lipid imbalance as a central determinant of mitochondrial fate in disease and supports the critical evaluation of both the therapeutic potential and pharmacological limitations of targeting the lipid-mitochondria axis, with particular attention to target engagement, structural tractability, and translational feasibility.
    Keywords:  Lipid metabolism; Lipid–mitochondria interactions; Lipotoxic mediators; Metabolic disease; Mitochondrial function; Therapeutic targeting
    DOI:  https://doi.org/10.1016/j.bcp.2026.118475
  51. J Adv Res. 2026 Sep 13. pii: S2090-1232(26)00750-2. [Epub ahead of print]
    IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation.
    Shuai-Shuai Xie, Yu-Hang Dong, Long Xu, Ze-Hui Dong, Ying-Ying Gao, Wei Li, Wen-Xian Ma, Ya-Xin Ru, Tian Zhao, Rui Hou, Lei-Xiang Zhang, Qin Yang, Juan Jin, Jia-Gen Wen, Xiao-Ming Meng.
       INTRODUCTION: Sepsis is a life-threatening systemic inflammatory syndrome frequently complicated by multiple organ dysfunction, yet the molecular mechanisms driving organ failure during sepsis remain poorly understood. Insulin-like growth factor-binding protein 7 (IGFBP7) has been implicated in various organ diseases; however, its role in sepsis-induced multiple organ dysfunction remains unclear.
    OBJECTIVES: This study aimed to determine whether IGFBP7 contributes to the pathogenesis of sepsis-induced multiple organ dysfunction and to elucidate the underlying mechanisms.
    METHODS: Circulating IGFBP7 levels were measured in patients and mice with sepsis. Global and organ-specific Igfbp7 knockout mice were used to evaluate the role of IGFBP7 in cecal ligation and puncture (CLP)-induced sepsis. Liquid chromatography-tandem mass spectrometry was used to investigate the downstream mechanisms.
    RESULTS: Serum IGFBP7 levels were markedly elevated in patients with sepsis and positively correlated with indices of organ dysfunction. IGFBP7 expression was also increased in the circulation and multiple organs of septic mice. Global or organ-specific deletion of Igfbp7 significantly alleviated CLP-induced multiple organ injury and inflammatory responses. Mechanistically, IGFBP7 interacted with 2-oxoglutarate dehydrogenase (OGDH) and was associated with reduced OGDH-sirtuin 5 association, increased overall OGDH succinylation, enhanced OGDH activity, and excessive succinate accumulation. Succinate accumulation disrupted mitochondrial homeostasis, promoted oxidative stress, and amplified proinflammatory responses. Importantly, anti-IGFBP7 treatment restored mitochondrial integrity, improved organ function, and reduced systemic inflammation.
    CONCLUSION: These findings identify IGFBP7 as a critical metabolic regulator in sepsis and highlight an IGFBP7-OGDH-succinate axis that contributes to mitochondrial dysfunction and inflammatory injury. Targeting IGFBP7 may represent a potential therapeutic strategy for sepsis-induced multiple organ dysfunction.
    Keywords:  IGFBP7; Inflammation; Mitochondria; OGDH; Sepsis; Succinate
    DOI:  https://doi.org/10.1016/j.jare.2026.09.013
  52. Curr Opin Immunol. 2026 Sep 18. pii: S0952-7915(26)00118-4. [Epub ahead of print]103 102841
    Advancing evidence generation in pediatric rheumatology beyond traditional randomized clinical trials: the potential of innovative designs.
    Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Associated Group of Milan and Lombardy Area (PRAGMA)
      Over recent years, innovative trial methodologies have been increasingly developed to address important limitations of conventional randomized controlled trials, which may require large sample sizes, entail prolonged development timelines, and offer limited flexibility to incorporate emerging evidence as a study progresses. Master protocols, including basket, umbrella, and platform trials, are innovative trial designs enabling the evaluation of multiple interventions, populations, or research questions within a unifying protocol. By allowing different hypotheses to be tested within a common infrastructure, these trials offer a flexible and efficient framework for therapeutic development in rare and heterogeneous conditions sharing underlying immunopathogenic mechanisms, such as pediatric rheumatic diseases. Adaptive features can be incorporated into these designs, enabling emerging therapeutic targets, biomarkers, and treatment strategies to be integrated into ongoing studies. Although these approaches have been successfully applied to evaluate treatments for immune-mediated inflammatory diseases, with examples including biologic and CAR T-cell therapies, their use in pediatric studies has been limited so far. In this review, we discuss selected complex trial designs with particular relevance for pediatric rheumatology, focusing on Master Protocol and Sequential, Multiple Assignment Randomized Trials (SMART); we illustrate their potential application to pediatric rheumatic diseases and summarize recent methodological and regulatory guidance on key aspects required for their successful implementation.
    DOI:  https://doi.org/10.1016/j.coi.2026.102841
  53. Int J Popul Data Sci. 2026 ;11(1): 3454
    Standardising Access to Sensitive Data with Machine-Actionable Access Conditions.
    Lucas van der Meer, Ahmad Hesam, Jetze Touber, Ricarda Braukmann, Deborah Thorpe, Emilie Kraaikamp, Tom Emery.
       Introduction: While many countries have invested heavily in secure technical infrastructures such as Trusted Research Environments (TREs), the rules that determine who may access which data, under what conditions, and for which purposes are still expressed primarily as natural language legal and administrative documents, with little or no accompanying machine-readable representation. This limits automation, interoperability, and scalability, particularly for research that spans multiple data holders.
    Objectives: This paper examines these challenges through the Dutch social science data landscape and presents a framework for standardising access governance using machine-actionable access conditions, with the aim of bridging the gap between secure technical environments and scalable access governance.
    Methods: Building on the Open Digital Rights Language (ODRL), we propose a library of reusable access condition templates and a Data Access Broker service. The framework was developed through iterative consultation with data holders in the Dutch SSH domain and draws on ongoing developments within the European Open Science Cloud (EOSC) and related data sharing initiatives.
    Results: We demonstrate that machine-actionable access conditions can operationalise legal and organisational oversight in a transparent, auditable, and interoperable way without replacing it. The proposed framework addresses key challenges identified in the Dutch context - including fragmentation, administrative burden, and inconsistent decision-making - and is applicable across European data infrastructures.
    Conclusions: The approach does not replace legal or organisational oversight, but operationalises it in a transparent, auditable, and interoperable way. While grounded in the Dutch context and the ODISSEI infrastructure, the challenges addressed are common across Europe. The paper presents a concrete implementation pathway supporting ongoing developments within EOSC and related data sharing initiatives.
    Keywords:  Trusted Research Environment; data access broker; machine-actionable access conditions; open digital rights language
    DOI:  https://doi.org/10.23889/ijpds.v11i1.3454
  54. Curr Gene Ther. 2026 Sep 10.
    Advances in the Application of Adenine Base Editor (ABE) in Biology and Medicine: Prospects and Challenges.
    Ziyang Yue, Haonan Li, Yi Hu, Decheng Wang, Xuan Xia.
      Adenine base editors (ABEs), which achieve A·T to G·C conversions in the genome precisely, symbolize a groundbreaking development in genetic engineering across animal, plant, and microbial systems. This review systematically summed up the research progress and current challenges of ABE in medical and biological applications: it outlined the historical context and pivotal milestones of its technological development; it emphasized major therapeutic advances for genetic diseases including spinal muscular atrophy, mitochondrial genetic disorders, and hyperlipidemia; it provided a comprehensive overview of its prospective uses for enhancing genetic traits in agricultural crops, including grains and fruits; this review conducted a multidimensional assessment of ABE performance through systematic comparison with other base editing technologies, comprehensively evaluating both editing efficiency and inherent limitations. It specifically addresses biosecurity risks such as off-target effects and genomic instability. Finally, safety concerns were proposed as the central challenge hindering its clinical translation, although ABE holds immense promise for precision medicine and agricultural breeding. Unlike previous reviews that mainly summarized early ABE development and general applications, this review particularly emphasizes recently engineered ABE systems, translational bottlenecks, delivery strategies, comparative clinical feasibility, and unresolved biosafety challenges that currently limit broader therapeutic and agricultural applications.
    Keywords:  Adenine base editors; crop improvement; gene editing; genetic disease; off-target effect; sgRNA
    DOI:  https://doi.org/10.2174/0115665232488406260825103338
  55. PLoS One. 2026 ;21(9): e0358219
    Sperm subpopulations differing in mitochondrial abundance show divergent nuclear allele frequencies.
    Tyler Weide, James Koltes, Juan Steibel, Karl Kerns.
      Mammalian ejaculates contain heterogeneous sperm subpopulations that differ in subcellular architecture and developmental history, despite appearing morphologically uniform. The extent to which this cellular heterogeneity reflects underlying nuclear genomic structure within a sire remains largely unexplored. Mitochondrial architecture in sperm is established during spermatogenesis, with final assembly and organization occurring during spermiogenesis under nuclear genomic control, positioning variation in mitochondrial abundance and organization as a potential phenomic indicator of within-sire allelic segregation. Here, we tested whether sperm subpopulations defined by differing mitochondrial abundance exhibit systematic differences in nuclear allele representation. Boar sperm were resolved into low and high mitochondrial subpopulations using fluorescence-activated cell sorting based on MitoTracker™ Green fluorescence while excluding debris, doublets, and non-viable cells. Epifluorescence microscopy confirmed that high MitoTracker™ Green fluorescence sperm possessed longer mitochondrial sheaths, validating a structural distinction between subpopulations. Whole-genome sequencing of paired mitochondrial subpopulations from three boars was performed, and allelic ratio distortion was evaluated relative to heterozygous baseline populations. Analyses across heterozygous loci genome-wide identified candidate allele frequency shifts between mitochondrial-defined subpopulations, suggesting non-random segregation of alleles within ejaculates. Using a minimum sequencing depth of 30 reads in both sorted fractions, 182 candidate SNPs were identified with evidence of allele-frequency differences between mitochondrial fluorescence-defined subpopulations. These findings suggest that sperm mitochondrial abundance can potentially serve as an indirect, high-throughput marker of nuclear genomic heterogeneity within sires. This proof-of-concept framework establishes a foundation for future studies integrating sperm phenotyping, genome-wide allele-frequency analysis and functional validation to better characterize gamete-level heterogeneity.
    DOI:  https://doi.org/10.1371/journal.pone.0358219
  56. Annu Rev Med. 2026 Sep 17.
    Genomic Screening for Infants and Reproductive Adults.
    Stephen F Kingsmore, Martin Delatycki.
      Recent progress in genomic sequencing, bioinformatics, cloud computation, and artificial intelligence is advancing a more mature understanding of the architecture of childhood genetic diseases. This knowledge and these technologies are enabling expanded genomic screening of infant and reproductive adult populations. With many new disease-modifying and curative therapies in development and approval processes, there exists unparalleled opportunity to identify, treat, and decrease the population burden of genetic disease and transform medical genetics. Broad implementation of genomic population screening, however, requires investments for overcoming remaining evidence gaps and operational challenges, and for delivery in a sustainable manner that is acceptable to parents, prospective parents, and physicians.
    DOI:  https://doi.org/10.1146/annurev-med-042425-014721
  57. Dis Model Mech. 2026 Sep 01. pii: dmm052890. [Epub ahead of print]19(9):
    Mitochondrial defects in the cAMP-PKA-DRP1 pathway in a Crppa deletion model of dystroglycanopathy.
    Jihang Luo, Yidan Liu, Danyu Song, Shiqi Yang, Xiaona Fu, Lin Ge, Cuijie Wei, Liya Cui, Yanwei He, Jin Xu, Qiang Shen, Yuxuan Guo, Motoi Kanagawa, Tatsushi Toda, Jingmin Wang, Hong Zhang, Hui Xiong.
      Dystroglycanopathies (DGPs) are autosomal recessive muscular dystrophies caused by abnormal α-dystroglycan glycosylation. CRPPA is one causative gene, with deletion of exons 6-9 identified as a founder variant in Chinese patients. Our previous study revealed mitochondrial abnormalities in patient muscle biopsies, although the underlying mechanism(s) remained unclear. A Crppa knockout mouse (dyC/dyC) was generated based on the founder variant, displaying muscle weakness, cerebellar hypoplasia, retinal abnormalities and neonatal lethality within 24 h. Electron microscopy showed mitochondrial structural defects in skeletal muscle, consistent with patient findings. RNA sequencing revealed dysregulation of the cAMP-PKA pathway, accompanied by decreased ATP and reduced phosphorylation of PKA and DRP1 (Ser637). To verify the link between CRPPA deficiency and mitochondrial dysfunction, Crppa knockdown C2C12 cells and CRPPA-related DGP patient-derived fibroblasts were examined. Both models exhibited reduced DRP1 Ser637 phosphorylation and ATP levels. Treatment with cAMP-PKA activators restored DRP1 phosphorylation and ATP production in a time-dependent manner. Recovery of mitochondrial membrane potential was confirmed by JC-1 staining. These findings suggest that CRPPA deficiency is associated with mitochondrial dysfunction involving the cAMP-PKA-DRP1 axis, suggesting a candidate pathway warranting further investigation for DGPs.
    Keywords:   CRPPA ; Dystroglycanopathies; Mitochondrial; Mouse model; cAMP-PKA-DRP1
    DOI:  https://doi.org/10.1242/dmm.052890
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