bims-polgdi Biomed News
on POLG disease
Issue of 2026–05–17
forty-four papers selected by
Luca Bolliger, lxBio
  1. 170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
  2. Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
  3. Mitochondrial transfer technologies with molecular insights into clinical applications.
  4. Mitochondria and Qi: Merging Eastern and Western Medicine.
  5. Mitochondrial morphology in human fibroblasts and induced pluripotent stem cells in Leigh syndrome: A comparative analysis.
  6. In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.
  7. Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".
  8. Modulation of mitochondrial DNA copy number: therapeutic potential of phytochemicals and plant extracts-a comprehensive review.
  9. Skin Aging and Mitochondrial Dysfunction: Structural Changes, Mechanistic Insights, and Therapeutic Perspectives.
  10. Sex differences in mitochondrial function in aging mouse skeletal muscle.
  11. Neurodegenerative Diseases in Children: A Comprehensive Review.
  12. Patient experience informing outcomes and research in rare disease: Citrin deficiency as a case study.
  13. Mammalian mtDNA gene expression: Concepts learned from in vivo models.
  14. Mitofusin-Decorated Extracellular Vesicles Enable Targeted Nucleic Acid Delivery to Mitochondria.
  15. How Studying Rare Disease Leads to Mechanistic Insights and Therapeutic Development: Lessons from Nonmammalian Models.
  16. MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
  17. Rare diseases in children-Knowledge, experiences and challenges faced by pediatricians in Tanzania.
  18. Rare disease genomics in an era of human pangenomics and telomere-to-telomere genome references.
  19. PI(3)P regulates mitochondrial dynamics through EXC-5-dependent actin remodeling.
  20. Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.
  21. Modeling human neurodegenerative disorders in Drosophila: strategies and translational opportunities.
  22. Mitochondria as an Integrative Hub of Cellular Homeostasis and Stress Response.
  23. Time to accelerate rare disease research: AI-powered in silico trials, digital twin-driven RCTs and decision-grade real-world evidence.
  24. Flexible Data Integration for Genomics-Driven Decision Support in Rare Genetic Epilepsy.
  25. Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.
  26. The cooccurrence of psychosis and emergent cognitive impairment/decline in rare genetic disorders: A scoping review.
  27. Uridine-responsive epileptic encephalopathy: Precision treatment across the age spectrum - a case series.
  28. Moving beyond good intentions: a qualitative study exploring healthcare professionals' perspectives on delivering equitable prenatal testing in the English NHS.
  29. Gene therapy for liver diseases: methods, challenges and opportunities.
  30. Zinc dyshomeostasis, mitochondrial dysfunction, and their pathological cycle in ischemic stroke pathophysiology: Mechanisms and potential therapeutic targets.
  31. Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
  32. AMPK: a master regulator of mitochondrial quality and quantity.
  33. Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio).
  34. Platelet Mitochondrial Function, Physical Performance, and Body Composition in Older People Living with HIV: A Preliminary Study.
  35. Population-scale genomic medicine with the Hong Kong Genome Project.
  36. Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.
  37. Predicting recurrence risk of leigh syndrome using prenatal mtDNA heteroplasmy assessment.
  38. Convergent effects of neurodevelopmental disorder-associated variants at mitochondria.
  39. Genetic counseling assistant-led education supports efficiency in rare disease care.
  40. Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
  41. Extracellular Vesicles Delivered a Functional ARG1 Enzyme and Restored Its Activity in a Mouse Model of ARG1-D Resulting in Improved Lifespan.
  42. Decoding RNA regulation: Challenges and opportunities for RNA-based therapies in Europe.
  43. Characterization of mitochondrial dysfunction induced by BAX trigger site activator 1 in the ARPE-19 retinal pigment epithelial cell model.
  44. Centering the marginalized: AI-driven strategies for advancing health equity in rare disease care.
  1. J Clin Pharmacol. 2026 May;66(5): e70209
    170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
    Volkmar Weissig.
      One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.
    Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.1002/jcph.70209
  2. Bioessays. 2026 May;48(5): e70146
    Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
    Yi Sheng, Zachary Markovich, Sung Min Han, Rui Xiao.
      Mitochondria are vital not only for energy production but also for regulating signaling pathways that influence aging. While mitochondrial dysfunction contributes to age-related decline, emerging evidence shows that mild, regulated mitochondrial stress can paradoxically promote longevity. This review highlights recent advances in mitochondrial biology and aging across species. We explore the dual role of reactive oxygen species (ROS) as both damaging agents and signaling molecules that activate adaptive stress responses. Key pathways such as the mitochondrial unfolded protein response (UPRMT) and integrated stress response (ISR) are discussed, including their tissue-specific as well as non-cell-autonomous effects on aging. Additionally, we examine the impact of mitochondrial protein import/export, dynamics (fission, fusion, mitophagy, biogenesis), and quality control in aging. Finally, we address challenges in understanding context-dependent mitochondrial responses and mitonuclear communication. Together, these insights position mitochondria as central regulators of aging and highlight their potential as therapeutic targets to enhance health span and longevity.
    Keywords:  aging; integrated stress response; mitochondria ROS; mitochondrial dynamics; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1002/bies.70146
  3. Stem Cells. 2026 May 07. pii: sxag026. [Epub ahead of print]
    Mitochondrial transfer technologies with molecular insights into clinical applications.
    Vahan Martirosian, Berney Peng, Michael A Teitell.
      Mitochondria are essential cell signaling, survival, and bioenergetic organelles that uniquely harbor a maternally inherited, multicopy genome called mitochondrial DNA (mtDNA). The occurrence or accumulation of mtDNA mutations underlies a spectrum of inherited and acquired mitochondrial syndromes and diseases and is increasingly recognized as a source of metabolic plasticity, clonal fitness, and therapy tolerance in cancer. Recent studies have revealed mitochondrial transfer as a potential mode of intercellular communication that could compensate for mtDNA mutation-associated mitochondrial dysfunction. Transfer of mitochondria can restore homeostasis in stressed recipient cells by rebuilding respiratory capacity, rebalancing redox state, and reshaping cell fate. Reported mechanisms of transfer include tunneling nanotubes, extracellular vesicles, cell fusion, and others, such as macropinocytosis. Here, we review and evaluate emerging technologies developed for mitochondrial transfer studies and define the impact of transfer on cell physiology and pathology. We discuss translational opportunities for mitochondrial transfer-based interventions, as well as how mitochondrial exchange may represent a new framework for understanding tumor heterogeneity, adaptation, and aggressiveness.
    Keywords:  Mitochondria; Mitochondrial transfer; mtDNA; techniques; transplantation
    DOI:  https://doi.org/10.1093/stmcls/sxag026
  4. Pharmacol Res. 2026 May 11. pii: S1043-6618(26)00158-1. [Epub ahead of print] 108243
    Mitochondria and Qi: Merging Eastern and Western Medicine.
    Wanqing Xie, Deborah G Murdock, Douglas C Wallace.
      Since the discovery of mitochondrial DNA (mtDNA) diseases almost 40 years ago, large numbers of diseases have been linked to mutations in both mtDNA and nuclear DNA (nDNA) genes that perturb the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS). Mitochondrial dysfunction is being implicated not only in rare primary mitochondrial diseases but also a wide range of common diseases, yet the availability of effective mitochondrial therapies remains limited. One potential source of mitochondrial therapeutic approaches is Traditional Chinese Medicine (TCM). TCM emphasizes the health-preservation philosophy and practical experience centered around the concept of "Qi", or vital force, and has generated Qi-oriented therapies over the past several thousand years. We propose that various properties and functions attributed to Qi may be explained by modulation of mitochondrial bioenergetics, the interplay between OXPHOS and fatty acid oxidation versus glycolysis and the pentose phosphate pathway (PPP), and the mitochondrial regulation of the immune system through mitochondrial reactive oxygen species (mROS). Hence, TCM therapeutics may provide approaches for treating the increasing spectrum of mitochondria associated diseases.
    Keywords:  Mitochondria; Qi; TCM; energy; mtDNA; therapy
    DOI:  https://doi.org/10.1016/j.phrs.2026.108243
  5. Physiol Rep. 2026 May;14(9): e70911
    Mitochondrial morphology in human fibroblasts and induced pluripotent stem cells in Leigh syndrome: A comparative analysis.
    Fibi Meshrkey, Ajibola B Bakare, Raj R Rao, Shilpa Iyer.
      Mitochondria are dynamic organelles that regulate several vital cellular functions in both health and disease. Accurately quantifying different mitochondrial shapes using simple, affordable techniques remains challenging. We have previously developed a Mitochondrial Cellular Phenotype (MitoCellPhe) tool to quantify 24 different mitochondrial shapes, enabling sensitive analysis and quantification of mitochondrial phenotype in health, under stress, and in diseased conditions. This approach permits us to study the morphological changes, if any, associated with perturbations in the mitochondrial genome and function that contribute to mitochondrial diseases like Leigh Syndrome (LS), a fatal pediatric neurodegenerative and muscular disorder represented with different clinical phenotypes in infancy. Using images generated from normal and diseased fibroblasts and human induced pluripotent stem cells (hiPSCs) (undifferentiated), we have identified and characterized differences in morphologies between a healthy and diseased state in both undifferentiated hiPSCs and differentiated fibroblasts. These results will help us better understand the pathophysiology of devastating mitochondrial diseases like LS, especially in its early developmental stages.
    Keywords:  mitochondria; morphology; networks; stem cells; structure
    DOI:  https://doi.org/10.14814/phy2.70911
  6. EMBO Rep. 2026 May 14.
    In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.
    Lisa Dengler, Francesco Padovani, Bianca Lemke, Rebecca Brugger, Alissa Benedikt, Benedikt Westermann, Boris Maček, Kurt M Schmoller, Jennifer C Ewald.
      Mitochondrial biogenesis and inheritance must be tightly coordinated with cell division to maintain mitochondrial function and cell survival. The dynamics of the mitochondrial network, including fusion and fission, are essential for mitochondrial inheritance and quality control. In budding yeast, simultaneous inhibition of both processes compromises mitochondrial DNA (mtDNA) integrity, increasing the frequency of petite cells. Loss of fusion alone completely eliminates mtDNA. Although this has been known for decades, why mtDNA is lost remained unclear. Here, we examine the effects of impaired mitochondrial fusion by depleting the mitofusin Fzo1. By analyzing over thirty thousand single cells across their cell cycles, we show that Fzo1-depletion induces rapid mitochondrial fragmentation and loss of membrane potential, followed by progressive declines in mtDNA content and growth rate. During division, Fzo1-depleted daughters inherit disproportionately large mitochondrial amounts, leaving mothers with too little. This imbalance, combined with an inability to upregulate compensatory mtDNA synthesis, drives rapid mtDNA loss. Our results reveal how fusion defects cause mtDNA loss and mitochondrial dysfunction, which might have implications for diseases linked to impaired fusion.
    DOI:  https://doi.org/10.1038/s44319-026-00794-5
  7. J Neurol Sci. 2026 Apr 15. pii: S0022-510X(26)00202-9. [Epub ahead of print]487 125920
    Comment on "profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis".
    Shubham, Abhishek Mathur.
      
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Cell-free mitochondrial DNA; Mitochondrial DNA; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.jns.2026.125920
  8. Arch Pharm Res. 2026 May 10.
    Modulation of mitochondrial DNA copy number: therapeutic potential of phytochemicals and plant extracts-a comprehensive review.
    Maria Rosaria Perri, Annamaria Cerantonio, Maria Grazia Cipriani, Ida Manna, Anna Aureli, Beatrice Marziani, Francesco Andreozzi, Gaia Chiara Mannino, Elettra Mancuso, Carolina Averta, Giancarlo Statti, Luigi Citrigno, Davide Mainieri.
      Mitochondrial DNA copy number (mtDNA-CN) is a critical marker of mitochondrial health and plays a key role in cellular bioenergetics. Alterations in mtDNA-CN have been associated with aging, metabolic disorders and neurodegenerative diseases. Recent studies have revealed that various plant-derived extracts, as well as the secondary metabolites they produce, known as phytochemicals, can modulate mtDNA-CN through mechanisms including the regulation of mitochondrial biogenesis, oxidative stress, and mtDNA repair. This review examines plant-derived extracts and phytochemical compounds from a wide range of plant species- including Ginkgo biloba, Crocus sativus, Curcumin and many others- able to modulate mtDNA dynamics, scavenging oxygen free radicals and improving antioxidant defense systems.
    Keywords:  Mitochondria; Mitochondrial DNA copy number; Mitochondrial function; Phytochemicals; Plant extracts
    DOI:  https://doi.org/10.1007/s12272-026-01620-1
  9. Oxid Med Cell Longev. 2026 ;2026(1): e5140711
    Skin Aging and Mitochondrial Dysfunction: Structural Changes, Mechanistic Insights, and Therapeutic Perspectives.
    Nathália Cardoso de Afonso Bonotto, Elize Musachio, Giulliano Danezi Felin, Giancarllo Danezi Felin, Carla Helena Augustin Schwanke, Ivana Beatrice Mânica da Cruz, Fernanda Barbisan.
      This narrative review discusses the relationship between structural changes in the skin and mitochondrial function during aging and evaluates emerging therapeutic interventions targeting mitochondrial dysfunction. An analysis of 49 scientific articles published between 2015 and 2025 was conducted using descriptors including "skin aging," "mitochondrial dysfunction," "oxidative stress," and "cutaneous senescence," and articles were retrieved from PubMed, Scopus, and ScienceDirect. Additional research was conducted using terms related to therapeutic interventions, including "mitochondrial therapies AND skin aging OR cutaneous aging." Original research articles were included based on thematic relevance, recency, and scientific rigor. The reviewed studies suggest that oxidative stress, mainly from mitochondrial metabolism, is a primary cause of skin cell senescence. Mitochondrial dysfunction emerges as a central mechanistic hub linking oxidative stress, mitochondrial genome instability, chronic low-grade inflammation (inflammaging), and the senescence-associated secretory phenotype (SASP) to age-related structural and functional skin alterations. Mitochondria maintain skin homeostasis through cell proliferation, differentiation, and genetic material synthesis. With advancing age, mitochondrial DNA copy number declines significantly, while reactive oxygen species production increases, thereby compromising cellular energy metabolism. Emerging mitochondrial-targeted therapeutic strategies, including nicotinamide adenine dinucleotide (NAD+) precursors, coenzyme Q10 supplementation, senolytics, and modulators of mitochondrial quality control, show promising effects on skin aging parameters in preclinical and early clinical studies. However, current evidence is based on small clinical trials with short follow-up periods, and long-term safety data remain limited. Therefore, while mitochondria are not the sole source of oxidants, growing evidence indicates that oxidative stress-driven mitochondrial dysfunction represents a priority pathogenic mechanism in skin aging. The clinical translation of mitochondrial-targeted therapies represents an innovative opportunity for anti-aging strategies, although the validation of standardized biomarkers and longitudinal safety investigations remains critical for clinical implementation.
    Keywords:  mitochondrial dysfunction; oxidative stress; skin aging; therapeutic approach
    DOI:  https://doi.org/10.1155/omcl/5140711
  10. Front Aging. 2026 ;7 1824237
    Sex differences in mitochondrial function in aging mouse skeletal muscle.
    Angelina Holcom, Ashley Liao, Kaitlyn G Holden, Anne M Bronikowski, Ashley E Webb.
       Introduction: Sex differences in lifespan and age-associated phenotypes are pervasive across species, yet the mechanisms remain poorly understood. Mitochondrial dysfunction is a major hallmark of aging, but whether skeletal muscle mitochondria age along sex specific trajectories remains incompletely defined.
    Methods: Here, we profiled mitochondrial bioenergetics and DNA integrity in flexor digitorum brevis (FDB) muscle from young (3-4 months) and aged (20-24 months) male and female C57BL/6 mice. We quantified cellular respiration in intact myofibers, measured mitochondrial DNA (mtDNA) copy number, and assessed expression of genes involved in mitochondrial dynamics, electron transport chain (ETC) function, and mtDNA maintenance.
    Results: Cellular respiration differed by sex at baseline and changed with age in a sex-dependent manner. Aged females exhibited a lower basal and ATP-linked respiration than aged males. In contrast, spare respiratory capacity increased in aged females relative to aged males, consistent with age- and sex-specific remodeling of the bioenergetic reserve. mtDNA copy number increased with age in both sexes, with a greater increase in mtDNA content in aged males. Gene-expression analyses revealed age- and/or sex-dependent changes, including lower Pink1 expression in females compared to males, an age-related increase in the mtDNA maintenance gene Polg2 only in males, though most genes were not significantly different. As an exploratory systemic readout, we additionally assessed DNA damage responsiveness in whole-blood leukocytes using the alkaline comet assay following oxidative challenge; young females exhibited greater induced DNA damage than young males.
    Discussion: Together, these data define sex- and age-associated mitochondrial remodeling in FDB and provide an initial assessment of sex-dependent inducible DNA damage responses in blood, underscoring the importance of sex as a biological variable in studies of aging.
    Keywords:  alkaline comet assay; flexor digitorum brevis (FDB); mitochondria bioenergetics; mitochondrial DNA copy number; sex differences; skeletal muscle aging
    DOI:  https://doi.org/10.3389/fragi.2026.1824237
  11. Int J Mol Sci. 2026 May 03. pii: 4096. [Epub ahead of print]27(9):
    Neurodegenerative Diseases in Children: A Comprehensive Review.
    Constantin Ailioaie, Laura Marinela Ailioaie, Cristinel Ionel Stan, Anca Sava, Dragos Andrei Chiran.
      Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a "rare-but-many" landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy-lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies.
    Keywords:  developmental regression; gene therapy; leukodystrophies; lysosomal storage disorders; mitochondrial diseases; neuroinflammation; oxidative stress; pediatric neurodegeneration; peroxisomal disorders; precision medicine
    DOI:  https://doi.org/10.3390/ijms27094096
  12. Mol Genet Metab. 2026 May 05. pii: S1096-7192(26)00424-5. [Epub ahead of print]148(3): 110141
    Patient experience informing outcomes and research in rare disease: Citrin deficiency as a case study.
    Yurika Asami, Li Eon Kuek, Su Kit Chew, Barbara Yu.
      The rapid expansion of therapies for rare diseases, including urea cycle disorders (UCDs), has intensified the need for endpoints that reflect meaningful benefit to patients. In rare inborn metabolic disorders, conventional clinical assessments and fragmented natural history data may not fully capture the daily disease burden. Citrin deficiency (CD) exemplifies this challenge: despite heterogeneous, age-dependent phenotypes, a "silent" or "adaptive" period is often described as largely asymptomatic based on clinical and biochemical measures. We present a patient-organization-led, patient-centered qualitative survey as a complementary approach to uncover "hidden" disease burden in a rare metabolic and urea cycle disorder. In an in-depth survey of seven adult CD patients, findings identified gaps between clinical descriptions and patient-reported disease burden. Fatigue and symptoms triggered by high carbohydrate intake emerged as key impacts on quality of life (QoL) among all surveyed patients. Other symptoms included under-recognized gastrointestinal (GI) issues, poor appetite, and psychological impacts. These findings contrasted with existing literature and questioned the concept of an asymptomatic adaptive phase. Although limited by the cohort size (n = 7), the current study illustrates how this approach can identify patient-important domains that standard clinical frameworks may under-capture. We propose that these domains should inform the development of fit-for-purpose patient-reported outcome measures (PROMs) and be integrated with relevant biochemical or molecular markers as endpoints for therapeutic studies and inform better research priorities and clinical management. More broadly, patient-organization-led qualitative surveying offers a scalable strategy to align translational efforts with outcomes that matter to patients across rare diseases.
    Keywords:  Citrin deficiency; Patient lived experience; Patient reported outcome measures; Patient-centered data; Rare disease patient organizations; Urea cycle disorders
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110141
  13. Biochim Biophys Acta Mol Cell Res. 2026 May 13. pii: S0167-4889(26)00056-X. [Epub ahead of print] 120158
    Mammalian mtDNA gene expression: Concepts learned from in vivo models.
    Diana Rubalcava-Gracia, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) expression is essential for oxidative phosphorylation (OXPHOS) and its in vivo regulation requires significant refinement. Here, we review key insights from mouse models carrying genetic modifications to the mtDNA expression machinery. While in vitro studies defined the basic machinery, mouse models reveal that mitochondrial transcription often exceeds immediate needs and may not be the primary rate-limiting step for OXPHOS biogenesis. Instead, mitochondria produce a transcript surplus regulated by nucleoid compaction and post-transcriptional stabilization. This apparent excess capacity is uncoupled from protein output under basal conditions but becomes critical during physiological stress or pathology. Using current and emerging genetic tools, researchers are now deciphering how regulatory layers coordinate to sustain systemic energy demands. These lessons highlight the importance of in vivo systems for identifying regulatory control points of mtDNA expression and developing targeted therapies for mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120158
  14. Nano Lett. 2026 May 11.
    Mitofusin-Decorated Extracellular Vesicles Enable Targeted Nucleic Acid Delivery to Mitochondria.
    Jiafeng Zhong, Luyao Wang, Wenjing Xuan, Xuehan Xu, Xing Chang, Jianjun Cheng, Chengjie Sun.
      Mitochondria-targeted therapies hold great promise for treating metabolic syndrome, neurodegeneration, and cancers associated with mitochondrial dysfunction or genetic mutations. However, its advancement is significantly limited by the lack of effective and biocompatible targeted delivery systems. Here, we introduce mitofusin-decorated extracellular vesicles (MFNEVs) as a natural-sourced nanoplatform for efficient mitochondrial delivery of various cytoplasm-sensitive macromolecular cargos. The surface-displayed mitofusin proteins MFN1 and MFN2 direct MFNEVs to localize to mitochondria, as confirmed by confocal imaging and gel electrophoresis analysis. In both in vitro and in vivo models, siRNA-loaded MFNEVs effectively reduce the expression of mitochondrial DNA-encoded genes. Moreover, sgRNA-loaded MFNEVs can achieve CRISPR-based mitochondrial gene editing, resulting in a decreased mitochondrial DNA content. Mechanistic studies further reveal that the delivery is facilitated by the cooperation of the mitochondrial fusion machinery. These findings establish the feasibility and versatility of MFNEVs as a promising delivery solution for mitochondrial therapeutics.
    Keywords:  CRISPR; extracellular vesicles; mitochondria-targeted delivery; mitofusin; siRNA
    DOI:  https://doi.org/10.1021/acs.nanolett.6c00233
  15. Annu Rev Genomics Hum Genet. 2026 May 11.
    How Studying Rare Disease Leads to Mechanistic Insights and Therapeutic Development: Lessons from Nonmammalian Models.
    Paige Hall, Michael Wangler, Jonathan Andrews.
      Though individually rare, rare diseases collectively affect nearly 1 out of 30 individuals, highlighting the continued need for and importance of research on these disorders. We argue that the recent work in identifying and diagnosing previously undiagnosed diseases is only the beginning. To meet this need, animal models have played an important role in studying rare and undiagnosed diseases by providing functional and biological information to validate candidate disease genes. Specifically, nonmammalian models like nematode worms (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio) provide significant advantages to the scientific community and have, unsurprisingly, been essential in many advances in the rare disease field and beyond. Given this success, new priorities are emerging on how to use these animal models to drive therapeutic-focused research. In this review, we discuss how these common nonmammalian models have pointed to new therapeutic directions and are used to both test and create therapies. Through the characterization of genetic mechanisms and emerging protocols like drug repurposing, animal models have never been as important to the rare disease field as they are now. Ongoing mechanistic discoveries and therapeutic advances not only have the potential to improve our management of rare disease but may also have implications for more common disorders across multiple areas of medicine.
    DOI:  https://doi.org/10.1146/annurev-genom-020525-025811
  16. Trends Cell Biol. 2026 May 13. pii: S0962-8924(26)00065-6. [Epub ahead of print]
    MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
    Nora Haggerty, Kentaro Nakamura, Hiromi Sesaki, Miho Iijima.
      Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed 'Mitochondrial Safeguard (MitoSafe)', in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.
    Keywords:  OMA1; PINK1; Parkin; dynamin-related GTPase; inflammation; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.007
  17. PLOS Glob Public Health. 2026 ;6(5): e0006435
    Rare diseases in children-Knowledge, experiences and challenges faced by pediatricians in Tanzania.
    Mariam Noorani, Mohamedraza Ebrahim, Francis Furia.
      Diagnosing and treating rare diseases in children is a major challenge for pediatricians globally. There is a lack of adequate knowledge of these conditions and diagnostic testing is not easily accessible, which frequently results in delays in care. The knowledge, experiences and challenges faced by pediatricians in Tanzania are not known. This study used a nationwide cross-sectional online survey to describe the knowledge of pediatricians in Tanzania on rare diseases, their experiences, and the challenges they face in treating these children. The survey tool was shared on the Pediatric Association of Tanzania WhatsApp group where most pediatricians are registered. 168 pediatricians completed the survey, giving a response rate of 52%. All of them had encountered a child with a presumed rare disease in their career, with 60% having seen one in the 6 months preceding the survey. The commonest presumed rare condition encountered was genetic/metabolic, and the most common difficulty (97%) encountered was lack of access to diagnostic testing. A third of respondents reported that rare diseases were taught in university and 60% felt unprepared to look after these children. Three quarter of respondents could not access to experts to advise them on management. Presumed rare diseases are commonly encountered by pediatricians in Tanzania, and there are challenges in diagnostic testing, gaps in training, lack of confidence in providing care and inability to access experts on rare disease management. To improve care of children with rare diseases, diagnostic testing should be made available, accessible and affordable. A review of medical training curricula should be done to incorporate rare disease education and skill development. Platforms and pathways to connect pediatricians with regional and global experts should be put in place to provide timely and appropriate care to children with rare diseases.
    DOI:  https://doi.org/10.1371/journal.pgph.0006435
  18. Eur J Hum Genet. 2026 May 14.
    Rare disease genomics in an era of human pangenomics and telomere-to-telomere genome references.
    Chiara Folland, Gavin Monahan, James Breen, Mridul Johari, Hardip R Patel, Gianina Ravenscroft.
      Despite considerable efforts investigating the genetic aetiology of rare diseases in the past decades, approximately 50% of cases remain without a genetic diagnosis. Many missing diagnoses can be attributed to the limitations of short-read sequencing (SRS), compounded by (mis)-alignment to incomplete and inaccurate reference genomes such as GRCh37/38. SRS cannot resolve many regions that are challenging to map, including large contiguous tandem repeats, segmental duplications (SDs), sites of complex structural variants (SV), or highly diverged population-specific loci. Long-read sequencing (LRS) technologies have delivered the first complete human genome assembly, T2T-CHM13. Compared to GRCh38, T2T-CHM13 resolves the remaining 8% of the genome, corrects structural errors and improves both SRS- and LRS-based read mapping and variant discovery. LRS has also facilitated the generation of high-quality, haplotype-resolved assemblies from globally diverse cohorts, enabling the construction of pangenome references for multiple ancestral groups. By representing more human genomic variation, a pangenome reference can improve mapping and variant calling accuracy. These new genome resources represent alternative reference paradigms that have the potential to uncover pathogenic variants underlying unsolved rare genetic diseases. Here, we examine the limitations of GRCh38 for rare disease variant discovery and explore how emerging resources like T2T-CHM13 and pangenomes can improve accuracy. We highlight key studies that have leveraged these references to improve diagnostic outcomes and discuss the potential for broader adoption. Finally, we consider the current barriers to research and clinical implementation and outline available resources and tools to expedite the transition to these new reference models.
    DOI:  https://doi.org/10.1038/s41431-026-02125-7
  19. J Cell Biol. 2026 Jun 01. pii: e202603198. [Epub ahead of print]225(6):
    PI(3)P regulates mitochondrial dynamics through EXC-5-dependent actin remodeling.
    Sneha Hegde, Marc Germain.
      Mitochondrial dynamics regulate mitochondrial activity through several pathways, but their coordination remains unclear. Zhao et al. (https://doi.org/10.1083/jcb.202508040) show that endosomal PI(3)P promotes CDC42-dependent actin polymerization on mitochondria, providing insight into the upstream signals regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1083/jcb.202603198
  20. Dev Cell. 2026 May 13. pii: S1534-5807(26)00123-1. [Epub ahead of print]61(5): 1146-1161.e8
    Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.
    Rajini Chandrasegaram, Sara Gottardo, Abhilesh Dhawanjewar, Antony M Hynes-Allen, Beitong Gao, Suvagata Roy Chowdhury, Luis-Carlos Tábara, Michele Frison, Stavroula Petridi, Patrick F Chinnery, Julien Prudent, Hansong Ma, Jelle van den Ameele.
      Mitochondrial DNA (mtDNA) exists in many copies per cell, with cell-to-cell variability in mutation load, which is known as heteroplasmy. Developmental and age-related expansion of heteroplasmic mtDNA mutations contributes to the pathogenesis of mitochondrial and neurodegenerative diseases. Here, we describe an approach for in situ sequence-specific detection of single mtDNA molecules (mtDNA-single-molecule fluorescent in situ hybridization [smFISH]). We apply this method to visualize and measure mtDNA and heteroplasmy levels in situ at single-cell resolution in whole-mount Drosophila tissue and cultured human cells. In Drosophila, we identify a somatic mtDNA bottleneck during neurogenesis. This amplifies heteroplasmy variability between neurons, as predicted by a mathematical bottleneck model, predisposing individual neurons to a high mutation load. However, both during neurogenesis and oogenesis, mtDNA segregation is accompanied by purifying selection, promoting wild-type (WT) over pathogenic mtDNA. mtDNA-smFISH thus elucidates how developmental cell-fate transitions, accompanied by changes in cell morphology, behavior, and metabolism, can shape the transmission and selection of deleterious mtDNA variants.
    Keywords:  Drosophila; bottleneck; heteroplasmy; mitochondria; mitochondrial DNA; mitochondrial disease; neurogenesis; oogenesis; purifying selection; single-molecule fluorescent in situ hybridization
    DOI:  https://doi.org/10.1016/j.devcel.2026.03.011
  21. Mol Biol Rep. 2026 May 12. pii: 745. [Epub ahead of print]53(1):
    Modeling human neurodegenerative disorders in Drosophila: strategies and translational opportunities.
    Shereen A Mohamed, Omnia A Badr.
      Drosophila melanogaster provides a genetically tractable and evolutionarily conserved platform for interrogating mechanisms of human neurodegeneration. This revised review critically evaluates how transgenic and genome-edited fly models expressing amyloid-beta, tau, alpha-synuclein, mutant huntingtin, and patient-relevant variants reproduce selective aspects of Alzheimer's disease, Parkinson's disease, and polyglutamine disorders, while also highlighting the boundaries of translational inference. We emphasize conserved pathogenic modules, including oxidative stress, mitochondrial dysfunction, impaired proteostasis, and stress signaling through Nrf2, JNK, and PINK1/Parkin, and distinguish robust mechanistic insights from findings that are primarily descriptive or overexpression-driven. We further discuss the specific contribution of Drosophila genetic tools such as GAL4/UAS, RNA interference, CRISPR-Cas9, and FLP/FRT-based mosaic analysis for dissecting cell-autonomous and non-cell-autonomous neurotoxicity. To improve usability, the manuscript now summarizes major disease models and natural compounds in dedicated tables, expands therapeutic discussion to include HDAC inhibitors and mitochondria/redox-directed small molecules, and outlines how fly studies can function within translational pipelines for variant interpretation, target prioritization, and preclinical triage before mammalian validation and human trials. Finally, we address key limitations of Drosophila relative to humans, including differences in metabolism, blood-brain barrier properties, immune complexity, and disease timescale, to provide a more balanced framework for using fly neurodegeneration models in precision medicine.
    Keywords:   Drosophila melanogaster ; Alzheimer’s disease; Antioxidants; Genetic modeling; Neurodegeneration; Oxidative stress; Parkinson’s disease; Precision medicine
    DOI:  https://doi.org/10.1007/s11033-026-11844-5
  22. Int J Mol Sci. 2026 Apr 27. pii: 3871. [Epub ahead of print]27(9):
    Mitochondria as an Integrative Hub of Cellular Homeostasis and Stress Response.
    Valentina Mihaylova, Eleonora Kovacheva, Maria Gevezova, Victoria Sarafian, Maria Kazakova.
      Mitochondria are increasingly recognized as multifunctional organelles that integrate metabolic, redox, immune, and cell fate signaling, thereby maintaining cellular and tissue homeostasis under physiological conditions. Beyond their classical role in ATP production, mitochondria act as central regulatory hubs coordinating adaptive responses to metabolic demands and environmental stress. These functions are sustained through tightly regulated quality control mechanisms, including mitochondrial biogenesis, dynamic fusion-fission remodeling, redox signaling, and selective removal of damaged organelles via mitophagy. Disruption of these processes compromises cellular resilience and contributes to disease initiation and progression. This review summarizes and critically evaluates current evidence on mitochondrial function in health and its dysregulation in pathological conditions, with a particular focus on rheumatoid arthritis (RA), ischemic stroke (IS), and autism spectrum disorder (ASD). Despite their distinct clinical manifestations, these disorders share convergent mitochondrial abnormalities, including metabolic reprogramming toward glycolysis, excessive or persistent reactive oxygen species production, impaired mitophagy, mitochondrial DNA-driven innate immune activation, and hypoxia-related stress. In RA, mitochondrial dysfunction sustains chronic inflammation and joint destruction; in IS, acute mitochondrial failure and reperfusion-associated oxidative stress drive neuronal injury; and in ASD, mitochondrial metabolic inflexibility and defective quality control contribute to chronic low-grade inflammation and neurodevelopmental vulnerability. A variety of methods for the assessment of mitochondrial function are available to study these pathological conditions. Collectively, these findings position mitochondrial dysfunction as a unifying pathogenic mechanism linking inflammatory, neurodegenerative, and neurodevelopmental processes. Targeting mitochondrial metabolism, redox balance, and quality control pathways therefore represents a promising cross-disease therapeutic strategy.
    Keywords:  autism spectrum disorder; ischemic stroke; mitochondrial function; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/ijms27093871
  23. Br J Clin Pharmacol. 2026 May 13. e70593
    Time to accelerate rare disease research: AI-powered in silico trials, digital twin-driven RCTs and decision-grade real-world evidence.
    Andrej Belančić, Elvira Meni Maria Gkrinia, Oscar Della Pasqua, Reecha Sofat, Dinko Vitezić, Robert Likić.
      
    Keywords:  clinical trials; digital twins; in silico trials; rare diseases; real‐world evidence
    DOI:  https://doi.org/10.1002/bcp.70593
  24. Stud Health Technol Inform. 2026 May 07. 335 89-95
    Flexible Data Integration for Genomics-Driven Decision Support in Rare Genetic Epilepsy.
    Ariadna Pérez Garriga, Philipp Honrath, Stefan Wolking, Beatrice Coldewey, Susann A Bozkir, Nils Freyer, Patrick May, Yvonne Weber, Rainer Röhrig, Myriam Lipprandt.
       BACKGROUND: Precision medicine for complex diseases like epilepsy requires integrating heterogeneous clinical and genomic data but interpreting numerous disease-associated genes remains challenging.
    OBJECTIVES: How can data from disparate biomedical sources be organized efficiently and flexibly to support precision medicine in early project stages in genetic epilepsy?
    METHODS: We applied a three-step system design approach tailored for academic medical research, considering project requirements, available resources, and technology selection.
    RESULTS: The EAV-hybrid model accommodated diverse clinical and genetic data while preserving flexibility for future expansion. Integration with cBioPortal enabled intuitive visualization and interpretation. The design supports future migration to standard CDMs such as OMOP or i2b2.
    CONCLUSION: A flexible, metadata-driven EAV-hybrid model supports rapid prototyping and structured data integration in early-stage precision medicine projects, providing an infrastructure for molecular boards and clinical decision-making for genetic epilepsies.
    Keywords:  Common Data Model; Data Management; Data Standardization; Epilepsy; Precision Medicine
    DOI:  https://doi.org/10.3233/SHTI260061
  25. Narra J. 2026 Apr;6(1): e3042
    Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.
    Meutia A Faradilla, Karina S Anastasya, Deasyka Yastani, Yohana Yohana, Endrico X Tungka, Suweino Suweino.
      Aging is the primary risk factor for major neurodegenerative disorders, yet the precise molecular links between biological aging and progressive neuronal loss remain complex. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, has emerged as a central converging mechanism driving both processes. This review aims to synthesize current evidence demonstrating how chronic redox imbalance drives cellular senescence and neuronal vulnerability through mitochondrial dysfunction, lipid peroxidation, and oxidative protein damage. These insights underscore how sustained oxidative insults promote the misfolding and aggregation of disease-defining proteins, including amyloid-beta in Alzheimer's disease and α-synuclein in Parkinson's disease, thereby amplifying neuroinflammation, synaptic dysfunction, and bioenergetic failure. Furthermore, antioxidant-based therapeutic strategies are critically reassessed, highlighting a paradigm shift from non-specific radical scavenging toward targeted modulation of endogenous defense systems, particularly NRF2 signaling and mitochondria-directed antioxidants. By integrating molecular mechanisms with translational perspectives, this review integrates molecular, cellular, and translational evidence to explain how oxidative stress links biological aging to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.
    Keywords:  Oxidative stress; aging; mitochondria; neurodegeneration; reactive oxygen species
    DOI:  https://doi.org/10.52225/narra.v6i1.3042
  26. Prog Neuropsychopharmacol Biol Psychiatry. 2026 May 08. pii: S0278-5846(26)00136-3. [Epub ahead of print]147 111739
    The cooccurrence of psychosis and emergent cognitive impairment/decline in rare genetic disorders: A scoping review.
    Mark A Colijn.
       OBJECTIVE: Cognitive impairment is a core feature of schizophrenia, and psychosis can occur in numerous types of dementia. Although rare genetic variation may underlie the development of psychosis or dementia in some individuals, no reviews to date have explored the spectrum of genetic disorders that have the potential to cause both. Given the clinical utility of characterizing the corresponding differential diagnosis, this scoping review sought to identify all rare genetic disorders that plausibly confer risk for both psychosis and cognitive decline.
    METHODS: This review involved consecutive literature searches using PubMed and Scopus. The first search combined terms related to psychosis, cognitive decline, and genetics, while the second was intended to find any additional articles that described the occurrence of psychotic symptoms among individuals diagnosed with the diseases (and related diseases) identified in the first search. After duplicates were removed, articles that provided individual-specific information pertaining to the development of both psychosis and new-onset cognitive impairment/decline were retained, provided there was no secondary explanation to account for the symptoms.
    RESULTS: The two searches ultimately yielded 151 and 230 eligible articles, respectively, corresponding to 52 genetic disorders/genetic disorder categories and 90 genes/variants. Although some are well-known to confer risk for both psychosis and dementia, others have only rarely been associated with either.
    CONCLUSION: This scoping review highlights the diverse array of genetic diseases that have the potential to cause both psychosis and new-onset cognitive impairment/decline. It also lays the groundwork for the completion of disease-specific systematic reviews on this topic.
    Keywords:  Cognitive dysfunction; Dementia; Genetic diseases; Genetics; Inborn; Neuropsychiatry; Psychotic disorders; Schizophrenia
    DOI:  https://doi.org/10.1016/j.pnpbp.2026.111739
  27. Seizure. 2026 Apr 17. pii: S1059-1311(26)00109-3. [Epub ahead of print]139 70-74
    Uridine-responsive epileptic encephalopathy: Precision treatment across the age spectrum - a case series.
    Gurdeep Sekhon, Ana Perez Caballero, Christin Eltze, Saskia B Wortmann, Usha Kini, Georgina Bird-Lieberman, Sarah Hughes, Kshitij Mankad, Nour Elkhateeb, Declan O'Rourke, Laila Selim, Martin Smith, Ingrid Watt-Coote, Samuel Shribman, Elaine Murphy, Clare Galtrey, James Davison, Amy McTague.
       INTRODUCTION: CAD deficiency (Type 50 early infantile epileptic encephalopathy) is a rare, yet treatable neurometabolic disorder characterised by refractory seizures, developmental delay, and dyserythropoietic anaemia. Timely recognition and treatment with uridine can dramatically alter the clinical course but remains challenging due to phenotypic variability and diagnostic limitations.
    CASE PRESENTATIONS: We describe five patients with biallelic pathogenic CAD variants, presenting across the age spectrum from neonatal period to adulthood. Common features included pharmacoresistant epilepsy, developmental delay, cerebellar atrophy, and dyserythropoietic anaemia with blood smear showing anisopoikilocytosis. Diagnosis was confirmed through trio whole exome or genome sequencing. Initiation of uridine monophosphate (UMP) supplementation in 4 patients led to rapid seizure control, improved neurodevelopmental outcomes, and normalisation of blood counts. The remaining patient, who could not access UMP, died following progressive neurological deterioration.
    CONCLUSIONS: CAD deficiency should be considered in patients with refractory epilepsy and unexplained anaemia. Early genetic diagnosis and initiation of uridine therapy can result in significant neurological and haematological improvement. Securing access to uridine is essential to improve outcomes in this otherwise devastating disorder.
    Keywords:  CAD deficiency; EIEE-50; Epilepsy genetics; Epileptic encephalopathy; Pharmacoresistant epilepsy; Uridine
    DOI:  https://doi.org/10.1016/j.seizure.2026.04.018
  28. Int J Equity Health. 2026 May 13.
    Moving beyond good intentions: a qualitative study exploring healthcare professionals' perspectives on delivering equitable prenatal testing in the English NHS.
    Michelle Peter, Clotilde Abe, Agnes Agyepong, Atinuke Awe, Rachael Buabeng, Morgan Daniel, Jane Fisher, Sasha Henriques, Kerry Leeson-Beevers, Lyn S Chitty, Melissa Hill.
       BACKGROUND: Prenatal testing (prenatal screening and diagnostic testing) is a central component of prenatal care in the UK. Healthcare professionals (HCPs) play a key role in guiding parents through the testing pathway. Against a backdrop where Black and racially minoritised parents are disproportionately impacted by maternal health inequalities, little is known about how HCPs working in prenatal testing services navigate the delivery of equitable care in everyday practice. Understanding HCP perspectives is essential, especially as prenatal testing technology advances.
    METHODS: We conducted semi-structured interviews with 30 HCPs who deliver prenatal testing across England. Interviews explored experiences of discussing prenatal testing with parents from Black and racially minoritised backgrounds, influences on delivering equitable care, and views on service improvement. Data were analysed using codebook thematic analysis informed by Critical Race Theory to examine how structural factors shaped practice.
    RESULTS: HCPs valued equitable care, making deliberate efforts to support parents' varying needs. However, four interrelated themes highlighted constraints on equitable delivery: unequal starting points for parents entering testing discussions; uneven clinical confidence and knowledge of genetics across the workforce; variability in support for culturally sensitive care; and reliance on informal, individual labour to address gaps in service design. These dynamics meant that equitable care was often pursued through personal adaptation rather than consistently supported systems.
    CONCLUSIONS: Providing equitable care cannot rely on individual effort. System-level investment in clinical education, service design, and organisational cultures that support culturally sensitive care is needed. With the expansion of prenatal genomics, addressing these structural conditions will be essential for ensuring the benefits of prenatal testing are realised equitably.
    Keywords:  Antenatal screening; Genetic testing; Health equity; Health inequalities; Healthcare professionals; Prenatal testing; Qualitative analysis; Race/ethnicity
    DOI:  https://doi.org/10.1186/s12939-026-02871-6
  29. J Nanobiotechnology. 2026 May 11.
    Gene therapy for liver diseases: methods, challenges and opportunities.
    Mengyao Yan, Qian Xiang.
      Gene therapy has emerged as a promising and pivotal strategy for addressing numerous genetic disorders that currently lack effective therapeutic options. For many other presently incurable conditions, including the majority of inherited metabolic liver diseases, gene therapy offers a realistic and transformative treatment modality. This review highlights recent advancements in gene delivery vectors targeting the liver-specifically hepatocytes-with a focus on strategies involving gene supplementation and gene editing, as well as notable progress achieved through RNA-based therapeutic agents. Several early trials utilizing lipid nanoparticle (LNP)-based and recombinant adeno-associated virus (rAAV)-mediated approaches for gene supplementation and editing in liver diseases have yielded encouraging results. For example, rAAV-mediated FIX supplementation (2 × 1013 genome copies/kg) achieves sustained therapeutic activity in a subset of HOPE-B trial participants with hemophilia B, and LNP-CRISPR editing of ANGPTL3 (0.5 mg/kg mRNA) produces marked reductions in LDL-C and triglycerides. However, several translational challenges have been identified, including unintended activation of the innate immune system and severe hepatotoxicity following high-dose vector administration. These concerns necessitate rigorous and ongoing safety monitoring. In this review, we summarize major advancements, current challenges, and future perspectives in the field of liver-directed gene therapy. Additionally, we highlight key limitations inherent to existing approaches and discuss potential strategies to overcome these barriers and improve therapeutic outcomes.
    Keywords:  Gene therapy; adeno-associated virus; immune barriers; lipid nanoparticle; liver diseases
    DOI:  https://doi.org/10.1186/s12951-026-04518-8
  30. Redox Biol. 2026 May 10. pii: S2213-2317(26)00206-5. [Epub ahead of print]94 104208
    Zinc dyshomeostasis, mitochondrial dysfunction, and their pathological cycle in ischemic stroke pathophysiology: Mechanisms and potential therapeutic targets.
    He Liu, Yuequan Zhu, Xiaokun Geng, Haiping Zhao, Yongmei Zhao.
      Ischemic stroke is a leading cause of global mortality and long-term neurological disability. Zinc, an essential trace element critical for neuronal survival within the central nervous system, becomes a key pathological mediator when its homeostasis is disrupted following ischemia. Mitochondria, which are essential for neuronal energy production and survival, are primary targets of zinc-induced toxicity. Excess zinc disrupts mitochondria through multiple mechanisms, causing significant structural damage (swelling and cristae remodeling), impairing dynamic balance (fission/fusion and mitophagy), disrupting oxidative respiratory chain function, reducing ATP production, inducing loss of membrane potential, and triggering oxidative stress responses. Notably, mitochondrial impairment during cerebral ischemia-reperfusion further promotes intracellular zinc accumulation by disrupting cytosolic zinc pools and calcium homeostasis, as well as impairing the interactions between mitochondria and other organelles including the endoplasmic reticulum and lysosomes, creating a vicious cycle that exacerbate ischemic damage. Due to the critical role of zinc ions, emerging zinc-related technologies such as the AggHX sensor, antioxidant zinc oxide nanoparticles and modern zinc chelation strategies offer promising diagnosing and therapeutic avenues for neurological disorders like cerebral ischemia. Meanwhile, the emergence of mitochondrial DNA editing tools marks a new era of precise mitochondrial therapy. Firstly, this review systematically traces the historical evolution of the understanding of zinc's dual roles in neural physiology and pathology, and subsequently summarizes the pathogenic interplay between zinc dyshomeostasis and mitochondrial dysfunction in ischemic stroke, highlighting the "zinc-mitochondria axis" as a potential therapeutic target. It also provides a comprehensive overview of recent advances in zinc-based technologies for neurological diseases, evaluating their opportunities and challenges in neuroprotection and clinical applications, aiming to provide novel insights for developing advanced therapeutic strategies.
    Keywords:  Ischemia and reperfusion; Mitochondria function; Mitochondria structure; Neuron; Zinc; Zinc transporter
    DOI:  https://doi.org/10.1016/j.redox.2026.104208
  31. Mech Ageing Dev. 2026 May 08. pii: S0047-6374(26)00043-6. [Epub ahead of print]231 112191
    Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
    YiFan Yan, Yuetong Li, Heng Ma.
      Mitochondria-lysosome contacts (MLCs) are emerging as a dynamic membrane interface that integrates organelle communication with cellular homeostasis. Rather than acting solely as intermediates of degradative trafficking, MLCs organize local calcium transfer, lipid exchange, Rab7-dependent contact remodeling, and mitochondrial quality control. These functions place MLCs at the intersection of mitochondrial fitness, lysosomal competence, metabolic adaptation, and stress signaling. Aging provides a particularly informative setting in which to examine this interface, because mitochondrial dysfunction and lysosomal decline co-emerge and reinforce one another during cellular aging. Current evidence suggests that aging does not simply increase or decrease MLCs, but instead remodels their dynamics, molecular composition, and functional output. Such remodeling may impair mitophagy, alter calcium and lipid coupling, amplify oxidative and inflammatory stress, and contribute to age-related disease phenotypes. In this review, we summarize the structural organization and regulatory logic of MLCs, examine their mechanistic roles in organelle homeostasis, and discuss how aging reshapes this interface in physiological and pathological contexts. We also highlight key methodological challenges and therapeutic opportunities for the field.
    Keywords:  Aging; Lysosome; Membrane contact sites; Mitochondria-lysosome contacts; Mitochondrial quality control; Organelle homeostasis
    DOI:  https://doi.org/10.1016/j.mad.2026.112191
  32. Trends Cell Biol. 2026 May 12. pii: S0962-8924(26)00066-8. [Epub ahead of print]
    AMPK: a master regulator of mitochondrial quality and quantity.
    Reuben J Shaw, Ian G Ganley, Julien Prudent, D Grahame Hardie.
      The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.
    Keywords:  endosymbiosis; mitochondrial biogenesis; mitochondrial fission; mitochondrial fusion; mitophagy; origin of eukaryotes
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.008
  33. FASEB J. 2026 May 31. 40(10): e71812
    Atf4a Regulates Mitochondrial Homeostasis Through Parkin-Mediated Mitophagy to Enhance Hypoxia Tolerance in Zebrafish (Danio rerio).
    Ranran Zhao, Jican Zhao, Weiyi Xia, Wanjuan Yu, Huihui Zhou, Xuan Wang, Kansen Mai, Gen He, Chengdong Liu.
      The Integrated Stress Response (ISR) is a vital cellular mechanism that regulates cell survival during various stress conditions, including hypoxia. Activating transcription factor 4 (ATF4) is recognized as a key regulator of ISR, however, its role in hypoxic stress responses remain underexplored. In the present study, we generated an Atf4a-deficient zebrafish model to investigate the role of Atf4a in hypoxia tolerance, mitochondrial homeostasis, and cellular stress adaptation. The results showed that atf4a knockout led to significant growth impairment, endoplasmic reticulum and mitochondrial dysfunction, and disrupted energy metabolism, particularly under hypoxic conditions. We observed an increase in mitochondrial DNA and impaired mitochondrial morphology in Atf4a-deficient zebrafish. Metabolomic analysis revealed significant alterations in the pentose phosphate pathway and TCA cycle following atf4a knockout. Additionally, we observed increased mitochondrial oxidative stress and reduced antioxidant capacity in atf4a mutants. Atf4a-deficiency also led to decreased expression of the mitophagy-related gene p62 and parkin. Atf4a transcriptionally regulates the expression of parkin, suggesting that Atf4a regulates mitochondrial homeostasis through parkin-mediated mitophagy in zebrafish. These results underscore the critical role of Atf4a in maintaining cellular homeostasis, mitochondrial integrity, and metabolic adaptation during hypoxic stress, highlighting its potential as a therapeutic target for stress-related diseases.
    Keywords:  ATF4; ISR; hypoxia; mitophagy; parkin
    DOI:  https://doi.org/10.1096/fj.202502855R
  34. Int J Mol Sci. 2026 Apr 29. pii: 3972. [Epub ahead of print]27(9):
    Platelet Mitochondrial Function, Physical Performance, and Body Composition in Older People Living with HIV: A Preliminary Study.
    Rosemary A Schuh, Sausan M Jaber, Krisann K Oursler, Alice S Ryan.
      Mitochondrial dysfunction is a hallmark of aging and age-related physical decline in people living with HIV (PLWH) who experience accelerated aging. This pilot study investigated the relationships between platelet mitochondrial function, physical performance, and body composition in older, sedentary PLWH compared with older, sedentary HIV-negative controls. Platelets have the potential to act as minimally invasive and easily accessible biomarkers for systemic mitochondrial bioenergetics and may serve as a practical biomarker in aging-related research. We analyzed correlations between mitochondrial parameters, protein levels, and measures of physical performance and body composition in a cohort of predominantly African American men (n = 7 PLWH, n = 7 controls). Body composition was assessed using dual-energy X-ray absorptiometry (DXA), and exercise capacity through VO2 peak and strength tests. Platelet mitochondrial bioenergetic parameters were measured by oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Key mitochondrial proteins SIRT3, COXII, DRP1, and OPA1 were evaluated by Western blotting. The PLWH and HIV-negative control groups were similar in age and cardiorespiratory fitness. In PLWH, basal OCR and ATP-linked respiration showed strong positive correlations with VO2 peak (r = 0.874, p < 0.05 and r = 0.862, p < 0.05, respectively) and negative correlations with BMI (r = -0.856, p < 0.05 and r = -0.849, p < 0.05, respectively). SIRT3 emerged as a potential key player, demonstrating strong positive correlations with basal OCR (r = 0.804, p < 0.05), ATP-linked respiration (r = 0.787, p < 0.05), and VO2 peak (r = 0.970, p < 0.001), and negative correlations with BMI (r = -0.830, p < 0.05) and fat mass (r = -0.827, p < 0.05) in PLWH. Analyses focused on within-group associations in PLWH because bioenergetic measures were obtained using different Seahorse platforms in PLWH and controls, precluding valid direct quantitative comparisons between groups. Our findings provide evidence for significant associations between platelet mitochondrial bioenergetics, specific mitochondrial proteins (particularly SIRT3), and key physical attributes in older, sedentary PLWH. These preliminary findings suggest that platelets may serve as minimally invasive biomarkers of systemic mitochondrial health, contribute to our understanding of mitochondrial function in HIV-associated accelerated aging, and inform future interventions to enhance mitochondrial function and improve health outcomes in this vulnerable population. However, results should be interpreted cautiously given the small sample size and exploratory design and should be considered hypothesis-generating rather than definitive. Larger, demographically more diverse studies that include HIV-negative controls are needed to validate these associations and determine their clinical relevance.
    Keywords:  SIRT3; aging in HIV; body composition; cardiorespiratory fitness; exercise; mitochondrial bioenergetics; physical performance; platelet mitochondrial function
    DOI:  https://doi.org/10.3390/ijms27093972
  35. Nat Med. 2026 May 15.
    Population-scale genomic medicine with the Hong Kong Genome Project.
    Hong Kong Genome Project
      The Hong Kong Genome Project (HKGP) aims to build a foundational resource for precision medicine in the Chinese population through large-scale genome sequencing and integrated analyses. Here we report findings from over 20,000 HKGP participants across two cohorts: a rare disease cohort including 2,227 patients with suspected genetic diseases and a population cohort including 18,261 participants undergoing genomic screening for medically actionable findings. The rare disease cohort achieved a diagnostic rate of 25%. When benchmarked against panels designed for European ancestries, the analysis revealed that 3.7% of the individuals in the population cohort had pathogenic or likely pathogenic variants associated with dominant disorders. While 48% of individuals were found to carry recessive disorder genes in the gene list based upon European ancestries, our analysis revealed that 38 additional clinically important genes would have been overlooked in the Chinese population. Pharmacogenomic analysis demonstrated that nearly all participants harbored at least one actionable phenotype, potentially informing nearly one million annual prescriptions in Hong Kong. The ongoing HKGP establishes a curated Hong Kong Chinese reference for clinically relevant genetic variation and serves as a blueprint for the implementation of precision medicine in underrepresented populations.
    DOI:  https://doi.org/10.1038/s41591-026-04410-w
  36. JIMD Rep. 2026 May;67 e70093
    Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.
    Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.
      Primary mitochondrial diseases frequently affect the central nervous system, yet the extent, distribution and progression of white matter hyperintensities (WMHs) remain insufficiently characterised, particularly in terms of quantitative volumetrics and longitudinal progression. Although WMHs are typically attributed to cerebral small-vessel disease, mitochondrial disorders may cause white matter injury through distinct vascular and metabolic mechanisms. We conducted a retrospective single-centre study at Turku University Hospital including 36 patients with mitochondrial disease, each with at least one brain MRI (73 images). Longitudinal data were available for 15 patients. Three-dimensional T1-weighted and FLAIR images (1.5/3 T) were analysed with the FDA-cleared cNeuro tool to obtain intracranial volume-normalised WMH and lesion volumes and an automated global Fazekas score. At baseline (median age 49 years), WMHs were present in all supratentorial regions. Over time, WMH volumes increased significantly in periventricular, deep and juxtacortical regions, while lesion progression was predominantly periventricular. Fazekas scores remained generally low and stable. In follow-up imaging, women and patients carrying the m.3243A>G variant showed a greater burden of WMHs and lesions, compared with men and those with other mitochondrial diagnoses. WMH load did not differ according to history of stroke-like episodes. Mitochondrial disease is associated with early and progressive WMH accumulation, particularly in individuals with the m.3243A>G variant, and the pattern exceeds what would be expected from conventional vascular risk factors alone. These findings support a disease-specific mechanism of white matter vulnerability and highlight the importance of quantitative MRI for monitoring progression in mitochondrial disease.
    Keywords:  disease progression; longitudinal imaging; mitochondrial disease; quantitative MRI; small‐vessel pathology; white matter hyperintensities
    DOI:  https://doi.org/10.1002/jmd2.70093
  37. Mitochondrion. 2026 May 13. pii: S1567-7249(26)00055-3. [Epub ahead of print] 102165
    Predicting recurrence risk of leigh syndrome using prenatal mtDNA heteroplasmy assessment.
    Maria Shishimorova, Hong Ma, Amy Koski, Crystal Van Dyken, Nuria Marti Gutierrez, Daniel Frana, Ying Li, Daniel Eyberg, Sergei Tevkin, Tomonari Hayama, Eunju Kang, Paula Amato, Kevin Havlin, Christopher Goodier, Roger Newman, Sally Shields, Shoukhrat Mitalipov.
      Predicting recurrence risk for mitochondrial DNA (mtDNA) disorders is challenging because heteroplasmy levels can shift during development. We examined whether prenatal heteroplasmy measurements predict postnatal outcomes for the pathogenic m.13513G > A variant associated with Leigh syndrome. In a longitudinal family-based study involving three naturally conceived pregnancies, mtDNA heteroplasmy was assessed by chorionic villus sampling at 10-12 weeks of gestation and, when available, amniocentesis at 16 weeks, with follow-up in neonatal and postnatal tissues. Prenatal heteroplasmy levels below ∼30% were associated with unaffected outcomes, whereas an affected sibling exhibited near-homoplasmic variant loads in critical organs. These findings suggest prenatal heteroplasmy assessment may inform recurrence risk for the mtDNA m.13513G > A disorder.
    Keywords:  Chorionic villus sampling; Heteroplasmy; Leigh syndrome; Mitochondrial DNA; Prenatal diagnosis
    DOI:  https://doi.org/10.1016/j.mito.2026.102165
  38. bioRxiv. 2026 Feb 27. pii: 2026.02.26.708316. [Epub ahead of print]
    Convergent effects of neurodevelopmental disorder-associated variants at mitochondria.
    Maxine I Robinette, Jada B Gundy, Xinyan Leng, Duc Duong, Ananth Shantaraman, Liang Shi, Elizabeth A Candelario, Anson Sing, Shubhangi Vibhor Garg, Weibo Niu, Nicholas T Seyfried, Steven A Sloan, Zhexing Wen, Joseph F Cubells, Erica Duncan, Jennifer G Mulle, Victor Faundez, Gary J Bassell, Ryan H Purcell.
      Investigations into the molecular pathogenesis of clinically defined neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD) and schizophrenia (SCZ) have produced evidence implicating dysfunctional mitochondrial metabolism. However, the functional connection between risk variants and mitochondrial proteins largely remains unclear. We tested the hypothesis that proteins encoded by NDD-associated copy number variants (CNVs) and SCZ risk genes are enriched within the mitochondrial interactome. We found that NDD- and SCZ-associated genes exhibit mitochondrial association comparable to their overlap with synaptic proteins, with interaction networks converging most strongly on mitochondrial translation. Two high-risk CNVs, the 3q29 deletion (3q29Del) and the 22q11.2 deletion (22q11Del), confer similar risks for ASD and SCZ and have independently been linked to mitochondrial phenotypes. To test whether these CNVs produce convergent effects on mitochondrial proteins in developing human neural tissue, we generated an isogenic series of 3q29Del and 22q11Del induced-pluripotent stem cells (iPSCs) and differentiated them into forebrain cortical organoids. Quantitative proteomic analysis showed high similarity in the profiles of dysregulated proteins in 3q29Del and 22q11Del compared to isogenic controls. Enrichment analysis of proteins altered in both variants revealed significant convergence on the mitochondrial ribosome and translation machinery. Furthermore, manipulation of mitochondrial translation elicited similar proteomic and functional responses in organoids and neural progenitor cells across both CNVs. These findings indicate that NDD-associated genes have rich interactions with mitochondrial proteins and that two of the strongest risk factors for NDDs may similarly disrupt neural mitochondrial metabolism through impaired mitochondrial translation.
    DOI:  https://doi.org/10.64898/2026.02.26.708316
  39. J Genet Couns. 2026 Jun;35(3): e70220
    Genetic counseling assistant-led education supports efficiency in rare disease care.
    Laura Duncan, Jessa Bidwell, Kayla Troe, Corinne Berg, Emily Toering, Gabrielle Eversole, Alyssa Knudson, Kaitlin Sikkink Brown, Carolyn R Rohrer Vitek, Yan Li, Filippo Pinto E Vairo, Jennifer Kemppainen.
      Genetic counseling assistants (GCAs) support genetic counselors (GCs) and genetics clinic workflows, but their potential roles in pretest genetic counseling for rare diseases have not been explored. A pilot within the Mayo Clinic Center for Individualized Medicine's Genetic Testing and Counseling Clinic (GTAC), which offers predefined tests for patients with rare disease, explored the impact of GCA pretest education on appointment time and patient questions. After training, GCAs met GTAC patients prior to the GC to provide scripted information on genetics concepts, the visit purpose, and the test including result types and disclosure plans. Data from the pilot and a control group were collected and analyzed using descriptive statistics and two-sided t-tests. Patient cohort characteristics did not differ between the two models. When a GCA provided pretest education, the GC spent an average of 11.2 minutes less with the patient during their session compared to visits completed solely by the GC (p < 0.0001). Total appointment time was not impacted by GCA education. Questions asked to GCAs were often not within GCA scope to answer (72.7%), and some patients asked repetitive questions to both the GC and GCA (63.2%). Reduction in GC time per patient could lead to increased accessibility by allowing additional patients to be seen in a day. Similar models may support GCA professional development while allowing GCs to remove repetitive education from their genetic counseling sessions, leading to less burnout and/or increased job satisfaction. Impact on administrative workflows, access, revenue, patient satisfaction and outcomes and GC/GCA satisfaction and benefits can continue to be explored when trialing models incorporating GCAs in pretest education roles.
    Keywords:  appointment time; genetic counseling assistant; genetic counselor; genetic testing; genetics services; intervention study; practice models; pretest; rare disease
    DOI:  https://doi.org/10.1002/jgc4.70220
  40. Am J Physiol Cell Physiol. 2026 May 13.
    Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
    Klaudia Sztolsztener, Thulasi Mahendran, David A Hood.
      Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR) and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either 1) CDDO, a LonP1 protease inhibitor, 2) GTPP, an HSP90 chaperone inhibitor, 3) CCCP, an energetic uncoupler, or 4) MB-10, an inhibitor of protein import, and responses were compared to those induced by acute contractile activity (ACA). LonP1 inhibition activated ATF4 and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of CHOP, indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, while MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity.
    Keywords:  integrated stress response; mitochondrial biogenesis; mitochondrial proteostasis; mitochondrial unfolded protein response; muscle contractile activity
    DOI:  https://doi.org/10.1152/ajpcell.00167.2026
  41. Int J Mol Sci. 2026 Apr 24. pii: 3785. [Epub ahead of print]27(9):
    Extracellular Vesicles Delivered a Functional ARG1 Enzyme and Restored Its Activity in a Mouse Model of ARG1-D Resulting in Improved Lifespan.
    Li-En Hsieh, Mafalda Cacciottolo, Michael J LeClaire, William Morrison, Bailey Murphy, Christy Lau, Kristi Elliott, Linda Marban, Minghao Sun.
      Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein-based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor's StealthXTM platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of their localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1-encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies, and the results showed that STX-Arg1-in EVs were non-toxic and able to restore arginase activities in the liver of Arg1-/- mice, which led to a lowered plasma arginine concentration similar to that in wild-type mice. Most importantly, Arg1-in EVs expanded the lifespan of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthXTM-engineered STX-Arg1-in EVs have a better safety profile due to the extremely low dosage and have great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement: Intracellular delivery of recombinant protein and improved llifespanare endpoints of successful enzyme replacement therapy for the treatment of ARG1-D. Using the StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed for the intracellular delivery of ARG1 protein in vitro and in vivo, with an improvement of lifespan in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with a low dose, setting the base for an improved therapeutic approach.
    Keywords:  arginase 1 deficiency; enzyme replacement therapy; extracellular vesicles (EVs); hyperargininemia
    DOI:  https://doi.org/10.3390/ijms27093785
  42. Br J Clin Pharmacol. 2026 May 13.
    Decoding RNA regulation: Challenges and opportunities for RNA-based therapies in Europe.
    Olivia C Lewis, Christine Leopold, Joyce M Hoek, Raymond M Schiffelers, Marie L De Bruin.
      RNA-based medicinal products represent a promising frontier in personalised medicine, offering sequence-specific disease targeting at various molecular levels, yet their clinical translation in the European Union (EU) may be hindered by regulatory uncertainty around definitions and evidence requirements; this study therefore aims to identify commonalities and differences in scientific and clinical characteristics of RNA-based therapeutics assessed by the European Medicines Agency to inform a classification framework supporting regulatory clarity and product development. A qualitative document analysis was conducted on 13 RNA-based therapeutics for non-infectious diseases that applied for EU marketing authorisation by March 2025, using EU regulatory documents including European Public Assessment Reports and Risk Management Plans to analyse descriptive, scientific and clinical characteristics, with data extraction validated via a dual-review process. Of the 13 products, 10 were approved, two refused and one withdrawn; they included five siRNAs, seven antisense oligonucleotides (ASOs) and one aptamer, primarily for rare diseases, with 12 acting through sequence-specific hybridisation to pre-mRNA or mRNA to suppress or modify protein production, often targeting liver diseases using delivery systems like GalNAc conjugation or lipid nanoparticles, while clinical challenges included limited efficacy data (e.g. small trials, surrogate endpoints) and recurring safety concerns including coagulation-related risks for ASOs, and notably risk profiles were not consistently linked to disease targets or RNA sequence. These findings highlight an opportunity for classification based on RNA mechanism and related chemical modifications conveying similar regulatory implications, suggesting that a structured framework could support knowledge pooling, which is especially useful for rare disease indications.
    Keywords:  RNA regulatory definitions; RNA regulatory framework; RNA safety concerns; RNA therapeutics; RNA‐based medicinal products; marketing authorisation EU; regulatory classification
    DOI:  https://doi.org/10.1002/bcp.70577
  43. Eur J Pharmacol. 2026 May 13. pii: S0014-2999(26)00457-7. [Epub ahead of print] 178975
    Characterization of mitochondrial dysfunction induced by BAX trigger site activator 1 in the ARPE-19 retinal pigment epithelial cell model.
    Toshihide Kashihara, Yuka Akiyama, Akane Morita, Saori Deguchi, Ryosuke Odaka, Tsutomu Nakahara.
      Mitochondrial dysfunction in the retinal pigment epithelium (RPE) is a key pathological feature of age-related macular degeneration (AMD). However, mechanistically defined experimental models that recapitulate stress-mediated mitochondrial injury remain limited. Bcl-2-associated X (BAX), a key pro-apoptotic effector, serves as a critical upstream regulator of mitochondrial outer membrane permeabilization. In this study, we systematically characterized mitochondrial dysfunction induced by BAX trigger site activator 1 (BTSA1), a selective small-molecule BAX activator, in ARPE-19 cells. Treatment with BTSA1 (3-60 μM) for 24 and 48 h induced a concentration- and time-dependent reduction in cell viability, accompanied by caspase-3 activation. Mitochondrial membrane potential, assessed via tetramethylrhodamine ethyl ester staining, was markedly reduced in a BAX-dependent manner and associated with increased reactive oxygen species production following prolonged exposure or at high concentrations. BTSA1 profoundly altered mitochondrial dynamics by promoting DRP1-mediated fission while suppressing fusion through MFN2 downregulation and stress-associated OPA1 processing, resulting in pronounced mitochondrial fragmentation. Furthermore, BAX activation elicited a biphasic response in mitochondrial quality control pathways: mild stress induced impaired autophagic flux and compensatory mitochondrial biogenesis, whereas severe stress triggered mitophagy accompanied by failure of biogenic compensation. These coordinated alterations closely mirror mitochondrial pathologies observed in the degenerating RPE in AMD. Collectively, our findings demonstrate that BAX activation by BTSA1 is sufficient to induce a comprehensive cascade of mitochondrial dysfunction. This system represents a mechanistically defined experimental model for dissecting BAX-mediated mitochondrial pathology and evaluating therapeutic strategies to preserve mitochondrial integrity in AMD.
    Keywords:  Age-related macular degeneration (AMD); BAX activation; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial quality control; Retinal pigment epithelium (RPE)
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178975
  44. Patterns (N Y). 2026 May 08. 7(5): 101535
    Centering the marginalized: AI-driven strategies for advancing health equity in rare disease care.
    Chaoyu Lei, Ying Zuo, Claudia Abreu Lopes, Jaimee Stuart, Benjamin Xu, T Y Alvin Liu, Thomas Ploug, Zilong Wang, Kang Dang, Kai Jin, Haoxuan Yu, Heaven Yeshaneh Tatere, Fanyi Kong, Ning Zhang, Lufa Zhang, Huifang Zhou.
      Rare diseases (RDs) affect 6%-8% of the global population but remain critically underserved. People living with an RD face misdiagnosis, limited treatment options, and inequitable access to specialized care. While artificial intelligence (AI) offers transformative potential in RD care, significant challenges remain. This perspective identifies five key dimensions to equitable AI application in RD care: data availability, algorithmic fairness, patient privacy, resource prioritization, and medical ethics. To address these barriers, strategies include enhancing data diversity through internationally harmonized repositories, leveraging synthetic data, and employing fairness-aware algorithms. Privacy-preserving methods safeguard sensitive genetic data while enabling collaborative research. Transparent resource-allocation frameworks and interdisciplinary governance ensure equitable distribution of AI-driven benefits, particularly in low- and middle-income countries. Ethical considerations, including patient-centered consent and dynamic risk assessments, are foundational to sustainable AI integration. By addressing these multidisciplinary challenges, AI can advance health equity, transforming RD care from fragmented and inequitable to inclusive and innovative. This paradigm shift aligns technological progress with the ethical imperative to ensure no patient is left behind in the promise of precision medicine.
    Keywords:  artificial intelligence; ethics; fairness; health equity; rare disease
    DOI:  https://doi.org/10.1016/j.patter.2026.101535
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