bims-polgdi Biomed News
on POLG disease
Issue of 2026–05–03
forty-one papers selected by
Luca Bolliger, lxBio
  1. Quality control of protein import into mammalian mitochondria.
  2. Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.
  3. Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
  4. Mild-cerebellar ataxia due to impaired mitochondrial function caused by the MSTO1 variations.
  5. The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.
  6. Transforming clinical trials in rare genetic diseases through telemedicine.
  7. Long-read MitoScope reveals tissue-resolved somatic mitochondrial variation and landscape of nuclear-embedded mitochondrial sequences.
  8. Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association.
  9. Cristae: bridging bioenergetic hubs and compartmental barriers in mitochondrial homeostasis.
  10. Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.
  11. Phenotypic heterogeneity within twins with MELAS with epilepsy: Case report.
  12. The Estrogen-Mitochondria Axis in Bipolar Disorder: From Fluctuating Hormones to Failing Bioenergetics.
  13. Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.
  14. RoundMi: A quantitative method to analyze mitochondrial morphology in mitotic cells.
  15. Mitochondrial metabolic dysfunction drives PANoptosis in retinal pigment epithelium during fungal endophthalmitis: emerging roles of the MITF-FBXW7 axis.
  16. Mitochondrial dysfunction in cerebrovascular diseases.
  17. Regulatory innovation for drug repurposing: Ten proposals to accelerate access and safety.
  18. Histone acetylation and methylation in rare diseases: from molecular mechanisms to clinical presentations.
  19. Structural and Functional Alterations of MAMs and Their Immunomodulatory Roles in Sepsis-Induced Lung Injury.
  20. Movement Disorders in Developmental and Epileptic Encephalopathies.
  21. Comprehensive genome sequencing associates elevated mitochondrial DNA and homoplasmy with early stage I of pancreatic cancer.
  22. Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
  23. Whole population cohorts versus sampled comparators designs for evaluating health and educational outcomes of children with inborn rare conditions: a simulation study.
  24. A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.
  25. Optimising rapid prenatal exome sequencing in the NHS genomic medicine service: the EXPRESS Synopsis.
  26. Benchmarking genetic birth prevalence estimates against newborn screening data.
  27. Zinc as a master regulator of intracellular organelle homeostasis.
  28. Leveraging MedlinePlus to Improve Health Information Access Among Patients and Caregivers: Systematic Literature Review.
  29. Mitochondria can spawn new 'organelles' - hinting at how modern cells evolved.
  30. The Mitochondrial-Autophagy Axis in MASLD: Mechanisms, Crosstalk, and Therapeutic Targets.
  31. Mechanistic insights and challenges in mitochondrial regulation of macrophage polarization and inflammatory responses.
  32. Brain Aging and the Pursuit of Longevity: Biological Mechanisms and Clinical Implications.
  33. Astragaloside IV delays vascular aging by enhancing mitochondrial fatty acid β-oxidation via the MLXIPL-PPARα/PGC-1α axis.
  34. Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation.
  35. Effects of exercise training on skeletal muscle function in patients with mitochondrial myopathy: a systematic review.
  36. Mitofusin 2 in Central Nervous System Disorders: Roles in Mitochondrial Dynamics and Therapeutic Implications.
  37. Alpha-Lipoic Acid and Biotin in Neurodegenerative Diseases: Convergent Mechanistic Insights from Preclinical Models to Clinical Perspectives.
  38. Selected Brain Metabolites and Mitochondrial DNA Copy Number as Potential Markers of Ongoing Neurodegeneration in Patients with Wolfram Syndrome.
  39. FGF12-Related Early-Onset Epileptic Encephalopathies: Therapeutic Response to Sodium Channel Blockers.
  40. The FOCUS model: A guide to promote patient partnership in clinical trial designs.
  41. Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
  1. Protein Sci. 2026 May;35(5): e70585
    Quality control of protein import into mammalian mitochondria.
    Madeleine Goldstein, Laurie Lee-Glover, Hilla Weidberg.
      Mitochondrial function depends on the continuous import of hundreds of nuclear-encoded proteins. Targeting and translocation of mitochondrial proteins is a multistep process that is inherently vulnerable to defects in cytosolic quality control systems as well as perturbations in mitochondrial protein import machinery and organelle function. Failure of mitochondrial protein import has dual consequences: it compromises mitochondrial biogenesis and activity, and it poses a cytosolic proteotoxic threat due to the accumulation of unimported precursor proteins. Accordingly, mitochondrial protein import defects are detrimental to cellular homeostasis and are associated with a wide range of disorders, including metabolic and neurodegenerative diseases. Cells therefore rely on layered quality control systems that monitor mitochondrial protein biogenesis and mitigate stress arising from mislocalized mitochondrial proteins. In this review, we summarize recent progress in understanding pathways that modulate mitochondrial protein import and the fate of unimported proteins in mammals. We highlight cytosolic and mitochondrial protein quality control mechanisms and discuss how import defects are translated into cellular stress responses and mitochondrial protective programs to restore cellular and mitochondrial homeostasis.
    Keywords:  Proteostasis; mitochondrial dysfunction; mitochondrial protein import; quality control mechanisms; stress responses
    DOI:  https://doi.org/10.1002/pro.70585
  2. Mol Psychiatry. 2026 Apr 29.
    Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.
    Samantha Corrà, Valeria Balmaceda, Carlo Viscomi.
      Mitochondrial diseases, caused by mutations in either mitochondrial or nuclear DNA, are highly complex genetic disorders characterized by faulty oxidative phosphorylation. Adeno-associated virus (AAV)-based gene therapy with its broad and customizable tissue tropism achieved through natural and engineered serotypes offers a highly effective platform for delivering therapeutic genes to affected tissues. However, the intricate genetics and biology of mitochondria present unique challenges for the development of AAV-based therapies. While gene replacement therapy remains a viable strategy for correcting nuclear gene defects, mutations in mtDNA require specialized approaches, such as mitochondrially targeted, RNA-free base editors and nucleases capable of precise editing within the mitochondrial genome. As an alternative, allotopic expression, which involves expressing mitochondrial genes from the nuclear genome, is currently being evaluated in clinical trials but remains controversial, due to issues related to mitochondrial import and functional integration in the respiratory complexes. The clinical translation of AAV-mediated therapies for mitochondrial diseases still confronts several interrelated challenges, including efficient targeting of multiple affected organs, scalable and cost-effective vector manufacturing, and minimizing vector-associated toxicity. By integrating advanced genome editing technologies with sophisticated vector engineering and delivery strategies, AAV-based gene therapy stands as a transformative approach for addressing the broad and heterogeneous spectrum of primary mitochondrial disorders. Continued progress in overcoming current biological and technical barriers will be essential to realize the full therapeutic potential of AAVs.
    DOI:  https://doi.org/10.1038/s41380-026-03570-y
  3. Nat Commun. 2026 Apr 30.
    Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
    Eleonora Centanini, Oliver Pain, Patrick F Chinnery, Alan Hodgkinson.
      Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-72649-5
  4. Front Neurosci. 2026 ;20 1775132
    Mild-cerebellar ataxia due to impaired mitochondrial function caused by the MSTO1 variations.
    Bin Wu, Jingwei Lv, Tong Shen, Bing Wen, Tan Wang.
       Background: MSTO1 encodes a regulator of mitochondrial fusion. Mutations in MSTO1 are linked to a rare mitochondrial disorder characterized by early-onset myopathy and cerebellar ataxia, with 31 cases reported globally to date, which underscores its exceptional rarity.
    Methods: We conducted comprehensive clinical, molecular, and biochemical investigations in a patient harboring novel MSTO1 variants.
    Results: We identified a patient presenting with adult-onset progressive ataxia and cerebellar atrophy who carried two novel compound heterozygous variants in the MSTO1 gene (c.756A>G, p.Glu252Glu; c.1339G>A, p.Glu447Lys). Brain MRI revealed marked cerebellar abnormalities, but the patient's clinical symptoms remained relatively mild with preserved daily function. This milder phenotype, characterized by adult onset and later disease presentation, contrasts with the more severe neurological deficits reported in a previously described case. Functional studies revealed significantly reduced MSTO1 protein expression, mtDNA depletion, and impaired mitochondrial function, as reflected by decreased mitochondrial membrane potential and respiratory capacity, suggesting a pathogenic role for these variants. Comparative analysis with fibroblasts from a previously reported case with MSTO1 mutation revealed notable differences in the severity of mitochondrial dysfunction, suggesting potential genotype-phenotype correlations.
    Conclusion: Our findings provide evidence linking the novel MSTO1 variants c.756A>G and c.1339G>A to mitochondrial dysfunction and broaden the phenotypic spectrum of MSTO1-related mitochondrial disorders to encompass a milder, adult-onset form of cerebellar ataxia. These results emphasize the importance of integrated clinical and functional approaches in evaluating variant pathogenicity and in elucidating the clinical and molecular heterogeneity of MSTO1-related mitochondrial disorders.
    Keywords:  MSTO1; MSTO1-related mitochondrial disorders; cerebellar ataxia; cerebellar atrophy; mitochondrial fusion
    DOI:  https://doi.org/10.3389/fnins.2026.1775132
  5. Mol Cell Biochem. 2026 Apr 27.
    The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.
    Mohamed A Raafat, Shaker Al-Hasnaawei, Hayjaa Mohaisen Mousa, Malathi Hanumanthayya, Samir Sahoo, S Prathiba, Gurjant Singh, Aashna Sinha.
      Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, remain leading causes of disability and premature death. Although they present with distinct clinical phenotypes, they converge on several pathogenic processes. Among these, mitochondrial dysfunction has emerged as a key driver of neurodegeneration, encompassing impaired bioenergetic capacity, disturbed calcium handling, altered mitochondrial dynamics, insufficient mitophagy, and excessive production of reactive oxygen species (ROS). This review provides a focused synthesis of the ways in which mitochondrial pathology contributes to neurodegeneration across major neurodegenerative disorders and summarizes therapeutic strategies designed to target mitochondria. We outline disease-relevant mitochondrial abnormalities and connect them to neuronal loss, synaptic failure, and neuroinflammatory cascades, with particular attention to mitochondrial ROS and inflammatory signaling linked to mitochondrial DNA. The manuscript further evaluates current and emerging interventions, including mitochondria-targeted antioxidants, mitochondrial transfer/transplantation, exercise, dietary approaches, and nanotechnology-enabled delivery systems. For each strategy, we consider the mechanistic rationale, key preclinical findings, and barriers to translation. Across experimental models, many of these approaches confer measurable neuroprotection-often reflected by lower oxidative burden, stabilization of mitochondrial membrane potential, and partial restoration of ATP production. However, clinical findings have been inconsistent, suggesting that efficacy depends strongly on disease stage, patient heterogeneity, and the specific mitochondrial defect being targeted. By integrating mechanistic insights with therapeutic evidence, this review offers a structured perspective on shared and disease-specific features of mitochondrial dysfunction and highlights priorities for advancing mitochondria-centered interventions toward meaningful clinical benefit.
    Keywords:  Mitochondria; Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative stress
    DOI:  https://doi.org/10.1007/s11010-026-05542-w
  6. J Community Genet. 2026 Apr 26. pii: 52. [Epub ahead of print]17(3):
    Transforming clinical trials in rare genetic diseases through telemedicine.
    Marco Crimi, Sebastiano Bianca.
      
    Keywords:  Artificial Intelligence; Clinical trials; EHealth; Rare genetic diseases; Remote Monitoring; Telemedicine
    DOI:  https://doi.org/10.1007/s12687-026-00887-7
  7. bioRxiv. 2026 Apr 15. pii: 2026.04.13.718259. [Epub ahead of print]
    Long-read MitoScope reveals tissue-resolved somatic mitochondrial variation and landscape of nuclear-embedded mitochondrial sequences.
    Christina Zakarian, Joshua D Smith, Chee Hong Wong, Christian D Frazar, Erica Ryke, Sean R McGee, Matthew Richardson, Jeffrey M Weiss, Katherine M Munson, Kendra Hoekzema, Taralynn Mack, Youngjun Kwon, Jeffrey Ou, Shane Neph, Min-Hwan Sohn, Anna Minkina, James T Bennett, Andrew B Stergachis, Evan E Eichler, Chia-Lin Wei.
      The mitochondrial genome (mtDNA), rich in repeats and prone to nuclear mitochondrial DNA segments (NUMTs), drives somatic mosaicism implicated in cancer, metabolic syndromes, and neurodegeneration, yet short-read sequencing yields incomplete catalogs, mapping artifacts, and false heteroplasmies. Here, we introduce MitoScope, a scalable long-read workflow to assemble mtDNA, perform high-fidelity variant calling, resolve heteroplasmy, and characterize NUMTs in benchmarking tissues from the Somatic Mosaicism Across Human Tissues (SMaHT) Network. MitoScope shows high sensitivity and precision, determines copy number, and uncovers low-frequency variants. We define an age- and tissue-dependent landscape of mtDNA mosaicism, including low-frequency pathogenic heteroplasmies, a bimodal heteroplasmy spectrum shaped by purifying selection, and age-accumulating deletions enriched for microhomology. Parallel profiling of NUMTs identifies high-confidence events with >2-fold more NUMTs than short-read surveys-with evidence of nonrandom trinucleotide contexts at breakpoints. These findings expose pervasive, tissue-resolved somatic mtDNA and NUMT instability with direct relevance for variant interpretation, aging, and human disease.
    DOI:  https://doi.org/10.64898/2026.04.13.718259
  8. Neurobiol Dis. 2026 Apr 24. pii: S0969-9961(26)00157-9. [Epub ahead of print]224 107412
    Analysis of mitochondrial DNA heteroplasmy in sporadic ALS suggests technical limitations rather than disease association.
    Philippe Codron, Valérie Desquiret, Delphine Prunier, Patrizia Amati-Bonneau, Viviane Nguefackngoune, Clara Rapenne, Louis Legoff, Julien Cassereau, Vincent Procaccio.
      Mitochondrial DNA (mtDNA) has received increasing attention in amyotrophic lateral sclerosis (ALS) following the recent report of recurrent low-heteroplasmy mtDNA variants in patients. Here, we performed mtDNA analysis on an independent cohort of 20 sporadic ALS patients using an in-house next-generation sequencing pipeline designed for diagnostics. Using standard filters, none of the previously reported low-heteroplasmy mtDNA variants were detected. These variants only appeared in the low-quality data and were present at similar rates in a large reference population without ALS, localizing to homopolymeric regions that are prone to sequencing errors. Our findings suggest that these low-level mtDNA variants are a result of the technical limitations of short-read next-generation sequencing rather than being associated with the disease.
    Keywords:  Amyotrophic lateral sclerosis; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.nbd.2026.107412
  9. Cell Death Dis. 2026 Apr 25.
    Cristae: bridging bioenergetic hubs and compartmental barriers in mitochondrial homeostasis.
    Jin Rao, Qian-Qian Wan, Lei Chen, Rong-Bing Tang, Daniya Killedar, Franklin Tay, Li-Na Niu.
      Mitochondrial cristae are intricately folded structures of the inner mitochondrial membrane that play essential roles in cellular energy production, metabolic regulation, and compartmentalization. Far from being passive folds, cristae are dynamic, functional entities central to mitochondrial bioenergetics. Their architecture maximizes membrane surface area and spatially organizes protein complexes to enhance oxidative phosphorylation and adenosine triphosphate (ATP) synthesis. The compartmentalized structure of cristae also establishes functional barriers that help maintain localized proton gradients, optimize metabolic reactions, and contribute to mitochondrial stability. These dual roles in energy transformation and spatial segregation underscore the importance of the cristae in supporting cellular homeostasis. The structural design and lipid composition of cristae with enrichment in cardiolipin also reflect their bacterial ancestry, revealing an evolutionary continuity from prokaryotic bioenergetic systems to eukaryotic organelles. Moreover, dynamic remodeling of cristae in response to stress, nutrient availability, and developmental cues highlights their adaptability in regulating mitochondrial performance and signaling pathways. Disruption of cristae architecture is increasingly implicated in neurodegenerative, cardiovascular, and metabolic diseases due to impaired ATP synthesis and compromised mitochondrial integrity. This review examines emerging insights into the organization, composition, and regulatory mechanisms of the cristae, emphasizing their role as both bioenergetic engines and protective compartments. Understanding the complex interplay between cristae structure and mitochondrial function may illuminate novel strategies for restoring mitochondrial health and targeting diseases linked to mitochondrial dysfunction. Cristae represent an evolutionary innovation that bridges structure and function, enabling the mitochondria to meet the multifaceted demands of the eukaryotic cell.
    DOI:  https://doi.org/10.1038/s41419-026-08779-x
  10. Cells. 2026 Apr 08. pii: 657. [Epub ahead of print]15(8):
    Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.
    Gianmarco Bertoni, Sara Ristori, Daniela Monti.
      Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.
    Keywords:  aging; geroscience; immunomodulation; immunosenescence; inflammaging; neurodegenerative diseases; neuroinflammation; senolytics; therapeutic strategies
    DOI:  https://doi.org/10.3390/cells15080657
  11. Medicine (Baltimore). 2026 May 01. 105(18): e47264
    Phenotypic heterogeneity within twins with MELAS with epilepsy: Case report.
    Huiru Wu, Yanling Wang, Qingxia Kong.
       RATIONALE: Mitochondrial encephalomyopathy with lactic acidemia and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder caused by mutations in mitochondrial DNA, most commonly the m.3243A>G variant. This mutation impairs oxidative phosphorylation, leading to inadequate cellular energy production, particularly in high-demand tissues such as the brain and muscles. The resultant energy deficit manifests as neurological and muscular dysfunction, including stroke-like episodes, seizures, and lactic acidosis.
    PATIENT CONCERNS: Twin brothers presented with heterogeneous clinical characteristics. The elder twin experienced seizures, blurred vision, hypertrichosis, exercise intolerance, and had learning difficulties since age 10. The younger twin developed hearing loss at age 12, followed by persistent epileptic seizures 3 months later. Both had a history of progressive neurological and multisystemic symptoms suggestive of a metabolic disorder.
    DIAGNOSES: Diagnostic evaluations included electroencephalography (EEG), which showed widespread mixed high-amplitude slow waves, and cranial magnetic resonance imaging, which revealed migratory lesions that changed with recurrent episodes. Genetic testing confirmed the m.3243A>G mutation in both twins. Their mother was identified as an asymptomatic carrier with an estimated heteroplasmy level of 30.79%.
    INTERVENTIONS: The elder twin was initially treated with acyclovir (antiviral) and methylprednisolone (anti-inflammatory) for suspected viral encephalitis, with symptomatic support. After genetic confirmation of MELAS, supportive therapies included coenzyme Q10, adenosine triphosphate disodium, levocarnitine, and arginine. During recurrent admissions for status epilepticus, antiepileptic regimens were maintained or adjusted, and imaging (magnetic resonance imaging/electroencephalogram) was repeatedly used for monitoring. His brother received similar interventions - levetiracetam, coenzyme Q10, and adenosine triphosphate disodium - upon diagnosis, with additional management for seizures, headaches, and gastrointestinal symptoms.
    OUTCOMES: Both twins were definitively diagnosed with MELAS syndrome. The elder twin was diagnosed first based on clinical and genetic findings, while the younger twin was diagnosed after the emergence of hearing loss and seizures. The condition highlights the progressive and variable nature of MELAS.
    LESSONS: The case underscores the significant phenotypic heterogeneity of MELAS, which often leads to misdiagnosis or delayed diagnosis. Early genetic testing is critical for accurate identification and prompt intervention. Family screening is recommended due to the maternal inheritance pattern, and tailored management should address the multifaceted clinical manifestations.
    Keywords:  MELAS; epilepsy; gene mutation; m.3243A>G; treatment; twins
    DOI:  https://doi.org/10.1097/MD.0000000000047264
  12. Biol Psychiatry Glob Open Sci. 2026 Jul;6(4): 100723
    The Estrogen-Mitochondria Axis in Bipolar Disorder: From Fluctuating Hormones to Failing Bioenergetics.
    Kassandra A Zachos, Kiana Behravan, Jude Demyati, Ana C Andreazza.
      Bipolar disorder (BD) is a psychiatric illness marked by fluctuating mood states and substantial systemic consequences, including dysregulated bioenergetics, immune modulations, and significant metabolic dysfunction. Although BD affects males and females at comparable rates, the literature indicates that the symptomatology and course of the disorder can differ between sexes. Females with BD are more likely to exhibit rapid cycling and depressive symptoms, whereas in males BD is more frequently associated with reckless behavior and hallucinations. A plausible mechanism for these symptomatology differences may be marked by the estrogen-mitochondria axis, which reflects the bioenergetic consequences of fluctuating estrogen levels on mitochondrial biogenesis (MB). Estrogen constitutes a family of steroid hormones that have critical regulatory roles in many physiological processes, including reproduction, metabolism, and immune regulation. In the context of bioenergetics, estrogen supports mitochondrial function in neural tissue by promoting oxidative phosphorylation, reducing oxidative stress, and regulating MB. In this literature review, we examine evidence linking estrogen fluctuation to periods of psychiatric vulnerability across the life span in females with BD. There is a particular focus on the mechanistic role of estrogen modulating MB, the existing experimental and preclinical evidence underlying this mechanism, and the evaluation of current pharmacological and nutraceutical therapeutics that have the potential to modulate this axis. Finally, we discuss the clinical and future therapeutic implications for behavioral symptomatology across the life span of females with BD. While this review focuses solely on literature on BD, the plausibility of investigating this mechanism extends to other mood disorders and psychiatric diseases.
    Keywords:  Bipolar disorder; Estrogen; Hormones; Mitochondria; Mitochondrial biogenesis; Psychiatry
    DOI:  https://doi.org/10.1016/j.bpsgos.2026.100723
  13. J Med Genet. 2026 Apr 29. pii: jmg-2025-111289. [Epub ahead of print]
    Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.
    Jamie M Ellingford, Erik Waskiewicz, Ashley J Pritchard, Javier Lopez, Rebecca Morgan, Emily Ley, Matt Lyon, Alona Sosinsky, Dalia Kasperaviciute, Joo Wook Ahn.
       BACKGROUND: Establishing best practice recommendations helps to increase consistency, equity and innovation in clinical genomics services. Bioinformatics approaches are a core component of clinical genomics services that use high-throughput genomic sequencing applied in the diagnosis of rare disorders and cancer. While a broad range of international recommendations exist for genomic diagnostic testing and genetic variant classification, the current UK-specific best practice recommendations for bioinformatics approaches applied in this context are outdated.
    METHODS: We assembled a team of bioinformaticians and scientists with diverse expertise in rare disease and cancer genomics applied in clinical diagnostics within the UK National Health Service. Through structured discussion, polls and surveys, we developed an updated set of best practice recommendations for bioinformatics approaches applied to high-throughput genomic sequencing in clinical genomic testing.
    RESULTS: We provide best practice recommendations across the spectrum of activities within a clinical genomics bioinformatics pipeline, including quality control, primary, secondary and tertiary analysis approaches and shared knowledge bases. We also comment on issues related to software development and maintenance. The recommendations can be applied to multiple sequencing technologies and encompass both targeted and whole genome sequencing approaches applied to germline and tumour DNA samples.
    CONCLUSION: The best practice recommendations outlined in this study provide a national framework for adoption and innovation of bioinformatics approaches across diverse clinical genomic testing strategies in the UK National Health Service.
    Keywords:  Genetics, Medical; Genomics; Human Genetics; Sequence Analysis, DNA
    DOI:  https://doi.org/10.1136/jmg-2025-111289
  14. FEBS Open Bio. 2026 May 01.
    RoundMi: A quantitative method to analyze mitochondrial morphology in mitotic cells.
    Elmira Parvindokht Bararpour, Christine Volmert, Valentina Piano.
      Mitochondrial morphology is a key readout of cellular physiology and pathophysiology, yet its quantitative analysis in mitotic cells remains technically demanding due to their rounded, three-dimensional architecture. Volumetric imaging approaches, while comprehensive, require extensive Z-stack acquisition, high computational resources, and specialized image analysis expertise, collectively limiting throughput and accessibility. Here, we present RoundMi, a streamlined workflow for rapid, quantitative analysis of mitochondrial morphology in mitotic cells using single focal plane imaging. RoundMi integrates automated preprocessing via the Nellie plugin in Napari with downstream segmentation and quantification in MitoSkel. Focal plane selection is guided by DNA staining and mitochondrial signal to capture representative morphological features while minimizing acquisition time and phototoxicity. We validated RoundMi in mouse embryonic fibroblasts (MEFs) and HeLa cells, demonstrating robust detection of established morphological differences between wild-type and DRP1-deficient cells in both interphase and mitosis. Benchmarking against volumetric methods, including deconvolution and maximum intensity projection, confirmed that single-plane analysis provides a reliable proxy for mitochondrial morphology while avoiding projection-induced artifacts and substantially reducing computational demand. RoundMi is applicable across multiple cell types and compatible with live-cell imaging, offering a versatile, high-throughput solution for mitochondrial morphology analysis in dividing cells.
    Keywords:  image‐based tool for organelle analysis; mitochondria; mitochondrial morphology analysis; mitosis
    DOI:  https://doi.org/10.1002/2211-5463.70257
  15. Front Immunol. 2026 ;17 1826337
    Mitochondrial metabolic dysfunction drives PANoptosis in retinal pigment epithelium during fungal endophthalmitis: emerging roles of the MITF-FBXW7 axis.
    Xiaohan Zhang, Jinfeng Zhang, Xuesong Lin.
      Fungal endophthalmitis (FE), although less common than bacterial endophthalmitis, carries a disproportionately high risk of irreversible blindness. Clinical observations show that some patients continue to experience progressive visual loss even after successful microbiological clearance, suggesting that disease outcomes are strongly influenced by excessive host immune-inflammatory injury rather than pathogen burden alone. Focusing on the retinal pigment epithelium (RPE), a key component of the blood-retinal barrier, this review summarizes recent advances in intraocular microenvironmental alterations, RPE immune responses, and the remodeling of cell death pathways during FE pathogenesis. We outline a conceptual framework centered on a "metabolism-immunity-death" axis. In this model, fungal infection induces mitochondrial metabolic reprogramming and dynamic imbalance in RPE cells, which can be associated with cytosolic leakage of mitochondrial DNA (mtDNA). As a danger-associated molecular pattern, mtDNA may activate the Z-DNA binding protein 1 (ZBP1) sensor, promote PANoptosome assembly and coordinate inflammatory cell death programs including pyroptosis, apoptosis, and necroptosis. We further highlight the regulatory GSK3β-MITF-FBXW7 axis and discuss how its dysregulation may connect impaired metabolic adaptation with irreversible RPE PANoptosis. Finally, potential translational implications of host-directed therapy (HDT) are discussed, including the use of cell-free mtDNA as an early biomarker and therapeutic strategies that combine metabolic protection with antifungal treatment. Collectively, this review provides a mechanistic perspective on the poor visual outcomes of FE and identifies potential targets for retinoprotective intervention.
    Keywords:  PANoptosis; ZBP1; fungal endophthalmitis; host-directed therapy; mitochondrial homeostasis; retinal pigment epithelium
    DOI:  https://doi.org/10.3389/fimmu.2026.1826337
  16. Trends Mol Med. 2026 Apr 30. pii: S1471-4914(26)00084-5. [Epub ahead of print]
    Mitochondrial dysfunction in cerebrovascular diseases.
    Fabio Marcheggiani, Ilaria Nunzi, Loredana Rao, Nada Dhaouadi, Salvatore Nesci, Paolo Pinton, Saverio Marchi.
      Mitochondria are central regulators of cerebrovascular health through their control of energy metabolism, Ca2+ homeostasis, and redox signaling, and their dysfunction represents a convergent pathogenic mechanism across cerebrovascular diseases. In ischemic stroke, mitochondrial failure exacerbates neuronal injury via permeability transition pore opening, oxidative stress, and bioenergetic collapse, while altered mitochondrial dynamics and the release of mitochondrial damage-associated molecular patterns amplify neuroinflammation during reperfusion. Beyond stroke, mitochondrial dysfunction contributes to intracranial aneurysms, atherosclerotic stenosis, and vascular malformations, where oxidative stress, mitochondrial DNA instability, and cell type-specific metabolic reprogramming drive vascular remodeling and lesion progression. In this review, we integrate recent evidence highlighting context- and stage-dependent roles of mitochondria in cerebrovascular pathology and discuss implications for biomarker discovery, therapeutic targeting, and translational strategies.
    Keywords:  cerebral malformations; inflammation; mitochondria; mitochondrial calcium uniporter; permeability transition pore; stroke
    DOI:  https://doi.org/10.1016/j.molmed.2026.04.002
  17. Drug Discov Today. 2026 Apr 24. pii: S1359-6446(26)00087-5. [Epub ahead of print] 104682
    Regulatory innovation for drug repurposing: Ten proposals to accelerate access and safety.
    Sara Pintado, Adelaide Fernandes, Esther A M Bührman, Joanna IntHout, Sofia Oliveira-Martins.
      Despite increasing efforts and incentives to address the critical lack of treatments for rare diseases, a substantial gap persists between patient needs and available therapies. Drug repurposing is a promising strategy in this field; nevertheless, it has not yet translated into a substantial increase in approved medicines. Although several EU regulatory pathways exist, none is tailored to drug repurposing, resulting in a complex landscape, particularly for nonprofit organisations. While there is no silver bullet, this article presents ten regulatory proposals to foster dialogue with decision-makers to tackle bottlenecks in areas of unmet medical need through a collaborative model with aligned incentives for all stakeholders. These proposals are based on published literature and the authors' experience in the SIMPATHIC project.
    Keywords:  European regulatory framework; drug approval; drug repurposing; orphan drugs; policy recommendations; rare diseases; real-world evidence
    DOI:  https://doi.org/10.1016/j.drudis.2026.104682
  18. Front Cell Dev Biol. 2026 ;14 1777625
    Histone acetylation and methylation in rare diseases: from molecular mechanisms to clinical presentations.
    Burcu Akman, Semra Gürsoy, Pınar Gençpınar, Ayşe İpek Polat, Ayşe Semra Hız, Yavuz Oktay, Tahsin Stefan Barakat, Uğur Özbek, Serap Erkek-Ozhan.
      Rare diseases, which collectively affecting millions of people worldwide, present unique diagnostic and therapeutic challenges due to their low prevalence and phenotypic heterogeneity. The importance of epigenetic deregulations in the pathophysiology of rare diseases has been highlighted by recent research on neurodevelopmental diseases and congenital malformation syndromes. Among these, abnormalities in histone modifications (especially lysine methylation and acetylation) have emerged as one of the key mechanisms underlying disease phenotypes. Histone-modifying enzyme mutations result in a variety of developmental diseases, including Kabuki, Rubinstein-Taybi and Weaver syndromes, often manifesting as cognitive impairments, craniofacial abnormalities and growth deficiencies. This review explores the functional convergence of genes encoding histone modifiers and their roles in chromatin regulation. It also analyzes the distribution of variants in these genes and their association with overlapping phenotypes across rare diseases. The findings highlight how different variants within the same gene can result in diverse phenotypic outcomes, and how variants in distinct genes may manifest convergent phenotypes underscoring the interconnected nature of epigenetic deregulations and their implications for understanding genotype-phenotype relationships. By focusing on the subunits of key histone-modifying complexes, we also systematically mapped associated Mendelian phenotypes and highlighted a subset of genes not yet linked to defined syndromes but showing strong intolerance to loss-of-function variants, suggesting their potential involvement in undiagnosed or emerging neurodevelopmental disorders.
    Keywords:  chromatin modifiers; chromatinopathies; epigenetics; neurodevelopment; rare disease
    DOI:  https://doi.org/10.3389/fcell.2026.1777625
  19. J Immunol Res. 2026 ;2026(1): e9888339
    Structural and Functional Alterations of MAMs and Their Immunomodulatory Roles in Sepsis-Induced Lung Injury.
    Yihao Wang, Jingran Yang, Xia Li.
       BACKGROUND: Sepsis-induced acute lung injury (SI-ALI) is a major cause of morbidity and mortality among septic patients. Recent evidence highlights the role of mitochondria-associated membranes (MAMs)-specialized contact sites between the endoplasmic reticulum (ER) and mitochondria-in regulating calcium signaling, lipid metabolism, energy homeostasis, and immune responses. Structural and functional alterations of MAMs are increasingly recognized as critical contributors to the pathogenesis of SI-ALI.
    OBJECTIVES: This review aims to summarize the structural and functional characteristics of MAMs, elucidate their alterations and immunoregulatory roles in sepsis-induced lung injury, and discuss potential therapeutic strategies targeting MAMs to mitigate pulmonary damage.
    METHODS: A comprehensive literature review was conducted using recent studies focused on the molecular structure, signaling mechanisms, and pathological changes of MAMs in sepsis and related inflammatory diseases. Emphasis was placed on calcium signaling, mitochondrial dysfunction, oxidative stress, and inflammasome activation.
    RESULTS: MAMs maintain close ER-mitochondria contacts (10-30 nm) through key proteins such as inositol 1,4,5-trisphosphate receptor (IP3R), glucose-regulated protein 75 (GRP75), voltage-dependent anion channel (VDAC), and mitofusin-2 (MFN2). During sepsis, oxidative stress and inflammatory cytokines disrupt these contacts, leading to impaired calcium transfer, mitochondrial dysfunction, and energy deficiency. Dysregulated MAMs promote NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, excessive reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) release, thereby amplifying inflammatory cascades and immune cell apoptosis. Therapeutic strategies that restore MAM integrity-such as upregulating MFN2, activating ER autophagy, or modulating calcium transport proteins-have shown potential to attenuate lung injury by improving mitochondrial metabolism and reducing oxidative stress.
    CONCLUSIONS: MAMs play essential roles in maintaining intracellular homeostasis and immune balance. Their structural and functional disruption contributes significantly to the progression of SI-ALI. Targeting MAMs offers promising therapeutic opportunities for preventing and treating sepsis-induced lung injury, although further mechanistic and clinical studies are warranted to translate these findings into practice.
    Keywords:  MAMs; endoplasmic reticulum; immune regulation; inflammatory response; mitochondria; septic lung injury; structural and functional changes
    DOI:  https://doi.org/10.1155/jimr/9888339
  20. Mov Disord Clin Pract. 2026 May 01.
    Movement Disorders in Developmental and Epileptic Encephalopathies.
    Shekeeb Mohammad, Darius Ebrahimi-Fakhari, Hugo Morales-Briceno.
       BACKGROUND: Monogenic developmental and epileptic encephalopathies (DEE) frequently feature co-occurring movement disorders. Gene discovery has expanded epilepsy-dyskinesia syndromes (EDS) from classic associations such as stereotypies in Rett syndrome to PRRT2-related infantile seizures with paroxysmal dyskinesia and crouched gait in SCN1A-associated Dravet syndrome.
    OBJECTIVES: To outline the movement disorders spectrum in EDS, propose a pragmatic syndrome-based clinical framework, group implicated genes into mechanistic categories, highlight selected genotype-phenotype correlations, and summarize symptomatic and precision therapeutic options.
    METHODS: A non-systematic, structured literature review identified monogenic disorders reported with EDS, grouping publications into four tiers: multi-etiology cohorts; small series and narrative/systematic reviews; single-gene or pathway-focused reports; and mechanistic/therapeutic studies.
    RESULTS: Eight cohort studies and multiple tier 2-3 series and reviews yielded 245 single-gene associations, most mapping to ion channel and synaptic signaling pathways. Across DEE cohorts, movement disorders occurred in roughly one-quarter to over one-half of patients, were often hyperkinetic (notably dystonia and stereotypies), and frequently combined multiple phenomenologies. We grouped clinical presentations into early and late infantile-onset EDS, Rett and Rett-like syndromes, paroxysmal/episodic and relapsing-remitting disorders, disorders with severe acute motor exacerbations, and hypokinetic/progressive phenotypes. Treatments are guided by gene- and mechanism-informed strategies including sodium-channel blockers, glutamatergic modulators, ketogenic diet, agents for paroxysmal dyskinesias, and deep brain stimulation in life-threatening crises.
    CONCLUSIONS: Movement disorders are common, often severe, and genetically heterogeneous across EDS. A syndrome-based approach integrating clinical features, neuroimaging, and broad genetic testing (including copy number variants and repeat expansions) can guide symptomatic management and emerging precision therapies.
    Keywords:  DEE; dyskinesia; epilepsy
    DOI:  https://doi.org/10.1002/mdc3.70641
  21. iScience. 2026 May 15. 29(5): 115453
    Comprehensive genome sequencing associates elevated mitochondrial DNA and homoplasmy with early stage I of pancreatic cancer.
    Appolinaire A Olou, Wesley Tom, M Rohan Fernando.
      Mitochondrial genome (mtDNA) presents higher fold mutation rates in cancers, creating heteroplasmy. While mtDNA mutations are drivers of cancers, heteroplasmic mutations appear theoretically unlikely drivers. However, whether high homoplasmy can characterize the early stage of cancers, along with high mtDNA genome coverage, has not yet been explored. Here, we directly profile stage I treatment naive pancreatic cancer patients' cfDNA using high throughput genome sequencing technology. Our analysis uncovered an elevated mitochondrial, not nuclear, genome coverage, correlating with high homoplasmy and rates of single-nucleotide variants. Heteroplasmy is the most expected and common biologically relevant mitochondrial genomic state in cells, but it can disrupt cellular phenotype and fitness. Conversely, homoplasmy is uncommon but can be selected for in certain cellular contexts. The high mtDNA coverage, along with a high mutation load at stage I of this cancer, concomitantly with a high homoplasmy, argues that mtDNA homoplasmy and its associated mutations accumulated non-passively.
    Keywords:  biological sciences; omics
    DOI:  https://doi.org/10.1016/j.isci.2026.115453
  22. Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):
    Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
    Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.
      Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication. In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.
    DOI:  https://doi.org/10.1093/nar/gkag233
  23. J Clin Epidemiol. 2026 Apr 28. pii: S0895-4356(26)00169-1. [Epub ahead of print] 112294
    Whole population cohorts versus sampled comparators designs for evaluating health and educational outcomes of children with inborn rare conditions: a simulation study.
    Joachim Tan, Milagros Ruiz Nishiki, Mario Cortina-Borja, Rachel L Knowles, Katie Harron, Catherine Peters, Pia Hardelid.
       OBJECTIVE: Linked administrative data covering whole populations are fundamental resources for longitudinal studies of children with rare conditions (cases) and unaffected peers (comparators). Data minimisation regulations sometimes limit the number of sampled comparators per case (hereafter abbreviated SCn) for research, with unknown impact on study findings.
    STUDY DESIGN AND SETTING: Using Monte Carlo draws, we simulated data from 100,000 children with and without an exemplar condition, congenital hypothyroidism (CHT), with sex and comorbidity as covariates. Three illustrative outcomes (Y: Maths tests standardised marks at age 11 years (z-score); L: achieving expected Maths attainment (binary); T: months to neurodevelopmental disorder diagnosis) were modelled as linear combinations of CHT, sex and comorbidity. Varying parameters (comorbidity prevalence; comorbidity-CHT association; CHT effect on Y, L, and T) factorially produced 36 data-generating mechanisms (DGMs). Three sizes of CHT effect were explored: small (z-score ≤|0.03|, log odds/hazard ratios ≤|0.41|); medium (z-score=|0.3|, log odds/hazard ratios ≥|0.74|); large (z-score ≥|0.6|, log odds/hazard ratios ≥|1.6|). Summary measures of regression coefficients, standard errors (SEs) and p-values from 1000 simulations were used to evaluate statistical power (percentage of p-values ≤0.05), precision (relative variance) and bias (mean distance from true effect), comparing various SCn (where n=5, 10, 15, 25, 50 and 100) versus full cohort (FC). Percentage differences of ≤2% and 2%-5% (from FC value) were considered non-inferior and satisfactory respectively.
    RESULTS: Mean p-values for SC25 generally deviated ≤5% versus FC with medium effects, and ≤2% for large effects across all DGMs. For Y, L and T, none of the SCn nor FC had power ≥80% with small or medium effects, whilst all SCn had sufficient power with large effects. Compared with FC, precision for SC25 decreased by 1.3-5.0% for Y, 5.5-7.4% for L, and 8.6-10.6% for T in one DGM (comorbidity prevalence=0.001 and CHT was 10× more common in those with comorbidity versus those without). No association between SCn and bias was discernible throughout.
    CONCLUSIONS: SC25 provided comparable performance as FC for rare disease studies under several typical scenarios, but small effects posed challenges, notwithstanding sampling. This approach facilitates cost-effective recommendations for study design where whole-population data are not available.
    Keywords:  Simulation; cohort studies; congenital hypothyroidism; rare diseases; sampling; study design
    DOI:  https://doi.org/10.1016/j.jclinepi.2026.112294
  24. bioRxiv. 2026 Apr 17. pii: 2026.04.16.717704. [Epub ahead of print]
    A robust workflow for 3D imaging of human mitochondria using cryo-electron tomography.
    Akhil Gargey Iragavarapu, Oleg Artemchuk, Daija Bobe, Anna C Ratliff, Evgeny Pavlov, Halil Aydin.
      Mitochondria are dynamic signaling organelles that transduce metabolic and biochemical cues to facilitate cellular adaptation. Their complex structure and dynamics are essential for integrating metabolic pathways, responding to stressors, and communicating inter- and intra-cellular signals. While optimal mitochondrial activity is frequently linked to cellular and organismal health-influencing processes ranging from metabolism and regulated cell death to differentiation and growth-the mechanistic links between mitochondrial dysfunction and cellular defects leading to human disease remain incompletely understood. Understanding how mitochondrial shape and function are linked is crucial for deciphering the regulatory mechanisms of cell survival and fate. Here, we present a molecular resolution cryo-electron tomography (cryo-ET) imaging and image analysis platform to investigate the structure of isolated human mitochondria under different conditions. We describe optimized protocols for isolating mitochondria from human cells, vitrifying these samples with high-pressure freezing (HPF) using the waffle method, cryo-focused ion beam (cryo-FIB) milling to generate thin sections (lamellae), and imaging with cryo-transmission electron microscopy (cryo-TEM). This is complemented by a robust downstream processing pipeline for tilt-series alignment, tomogram reconstruction, and three-dimensional (3D) segmentation of tomograms using the latest state-of-the-art algorithms. With some variations, this versatile workflow is adaptable to other subcellular compartments for structural studies in isolation or within intact cells. Furthermore, our protocols provide a critical foundation for investigating the in-situ structure of protein machineries that govern key cellular processes.
    DOI:  https://doi.org/10.64898/2026.04.16.717704
  25. Health Soc Care Deliv Res. 2026 Apr;14(14): 1-40
    Optimising rapid prenatal exome sequencing in the NHS genomic medicine service: the EXPRESS Synopsis.
    Melissa Hill, Michelle Peter, Morgan Daniel, Hannah McInnes-Dean, Rema Ramakrishnan, Emma Smith, Holly Walton, Laura Blackburn, Jane Fisher, Naomi J Fulop, Marian Knight, Caroline Lafarge, Kerry Leeson-Beevers, Rhiannon Mellis, Stephen Morris, Michael Parker, Sophie Peet, Dagmar Tapon, Wing Han Wu, Sarah L Wynn, Lyn S Chitty.
       Background: Prenatal exome sequencing for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the National Health Service Genomic Medicine Service.
    Objective: To evaluate the new prenatal exome sequencing service to provide evidence that will inform improvements to quality of care and equity of access for parents having prenatal tests.
    Design and methods: Our theoretically driven, multi-site, convergent parallel mixed-methods study design combined qualitative analyses of the service, stakeholder perspectives and ethical considerations with quantitative analyses of staff experiences, clinical outcomes and cost-effectiveness. Our final data set included interviews with parents offered prenatal exome sequencing (n = 48) and professionals (n = 63), surveys with professionals (n = 159) and data from prenatal exome sequencing testing referrals between October 2021 and June 2022 (413 referrals and 241 prenatal exome sequencing tests) linked to National Congenital Anomaly and Rare Disease Registration Service data and the Maternity Services Data Set. The study had oversight from a Steering Group and a Patient and Public Involvement Advisory Group. The Patient and Public Involvement Advisory Group contributed to study design, developing study materials and interpreting findings.
    Results: Parents and professionals welcomed the introduction of a national prenatal exome sequencing service. Parents need emotional support across the testing journey, including follow-up care. A newly developed prenatal sequencing animation increased self-reported and objective knowledge of prenatal exome sequencing. Good communication and close working between genetics, fetal medicine and laboratory teams has supported successful implementation. Challenges for service delivery included increased administrative time and gaps in genomics education, particularly for midwives and fetal medicine clinicians. Local implementation varied in leadership, staffing and approaches to multidisciplinary team working. Ethical issues centred on barriers for equity of access and the intersecting timelines of prenatal exome sequencing testing and termination of pregnancy laws. Between October 2021 and June 2022, the diagnostic yield for prenatal exome sequencing was 35% (85/241) with a median turnaround time of 15 days to the final report. For 85 women who had a diagnosis, 40% had a termination of pregnancy, 18% had a stillbirth and 42% had a live birth. For women with a no findings result, 18% had a termination of pregnancy, 5% had a stillbirth and 78% had a live birth. The median gestational age at termination was 26 weeks. Total National Health Service costs for the 413 cases in the study period, with the most common staffing model, was £962,727 (£775,454 to £1,204,027, 95% credibility interval), or £2331 per case referred and £3592 per case that proceeded with testing.
    Limitations: Our parent interview sample lacked diversity, with most being White/White British and educated to degree level or above. Details on prenatal exome sequencing service pathways from smaller units have not been captured. Assessment of variation in outcomes was restricted by the relatively small sample size of prenatal exome sequencing tests in the study period.
    Conclusions: This is the first study to explore the implementation of the national prenatal exome sequencing service in England. Our findings will inform the evolving prenatal exome sequencing service to ensure equity of access, high standards of care and benefits for all parents.
    Future work: Future research should include gathering the views and experiences from parents from diverse backgrounds, evaluating the prenatal sequencing animation in clinical practice and building on EXPRESS to identify and agree optimal care pathways that will ensure equity of access for all parents.
    Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number NIHR127829.
    Keywords:  COST-EFFECTIVENESS; ETHICS; GENOMICS; IMPLEMENTATION; MAJOR SYSTEM CHANGE; MIXED-METHODS; PRENATAL EXOME SEQUENCING
    DOI:  https://doi.org/10.3310/GJLC0716
  26. Am J Hum Genet. 2026 Apr 24. pii: S0002-9297(26)00152-7. [Epub ahead of print]
    Benchmarking genetic birth prevalence estimates against newborn screening data.
    Michael C Sierant, Nicholas Knoblauch, Evan Witt, Daniel Gaffney, Sara L Pulit, Arthur Wuster.
      Accurate prevalence estimates for rare congenital conditions are critical for understanding disease epidemiology and enabling drug development. They inform public health investment, identify communities with high disease burden or underdiagnosis, and highlight unmet clinical need. Large biobanks have enabled genetics-based models to estimate disease prevalence. Autosomal-recessive (AR) diseases are particularly suited to this approach, as birth prevalence can be inferred from pathogenic allele frequency in unaffected populations; however, this approach has not been validated against real-world clinical datasets at scale. Newborn screening (NBS), which tests for neonatal diseases using quantitative diagnostic methods, provides a uniquely robust comparator for birth prevalence with low ascertainment bias, large sample size, and low diagnostic variability. With the objective of benchmarking a commonly used approach for determining disease prevalence, we applied a genetic model to estimate birth prevalence for 28 AR diseases from NBS panels and compared them with reported birth prevalence from 23 million newborns in the United States. We found that concordance between the genetic estimate and NBS was impacted by the source of allele frequency estimates, ancestry-matching methodology, and pathogenic variant inclusion criteria. Incorporating these refinements, we demonstrate that a genetics-first approach can provide first-order estimates of AR disease birth prevalence for 25 of 28 NBS diseases (89%). However, we note a general underestimate of the genetic prevalence, suggesting that identifying additional sources of pathogenicity would improve concordance with NBS. Further, we assessed the impact of epidemiological and genetic variables, highlighting diseases where genetic prevalence estimates may not be accurate.
    Keywords:  ancestry-informed prevalence; autosomal-recessive disease; demographic weighting; genetic birth prevalence; genetic epidemiology; method benchmarking; newborn screening; rare-disease epidemiology
    DOI:  https://doi.org/10.1016/j.ajhg.2026.04.002
  27. Exp Mol Med. 2026 May 01.
    Zinc as a master regulator of intracellular organelle homeostasis.
    Sofia Brito, Jiyoon Kim, Bum-Ho Bin.
      Zinc (Zn²⁺) is an essential trace element that supports a vast array of cellular processes, including enzymatic catalysis, gene expression, immune regulation and signaling. Its unique redox-inert properties and ability to bind diverse proteins make it indispensable for cellular homeostasis. Zinc is dynamically distributed within cells, where its compartmentalization across organelles, such as the nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, lysosomes, endosomes and peroxisomes, enables specialized functions crucial for organelle integrity and interorganelle communication. The present Review provides a comprehensive account of organelle-specific zinc homeostasis, highlighting the intricate roles of zinc transporters, metallothioneins and metallochaperones in regulating zinc flux and buffering. Here we discuss how zinc modulates structural and enzymatic processes, stress responses, redox balance and signaling pathways within each organelle. We then provide an integrated overview of how its dysregulation contributes to diverse molecular dysfunctions and pathologies including neurodegeneration, cancer, metabolic disorders and aging. We further examine emerging therapeutic strategies aimed at restoring zinc homeostasis, including supplementation and bioengineered, organelle-targeted delivery systems, as well as advanced tools for visualizing zinc dynamics at subcellular resolution. Together, these insights demonstrate the crucial role of zinc as a compartmentalized regulator of cellular health and a promising target for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s12276-026-01706-2
  28. JMIR Med Inform. 2026 Apr 27. 14 e79416
    Leveraging MedlinePlus to Improve Health Information Access Among Patients and Caregivers: Systematic Literature Review.
    Fei Yu, Xiaomeng Wang, Jia Liu, Tian Wang, Siobahn Day Grady, Lixin Song.
       Background: MedlinePlus, developed by the National Library of Medicine (NLM) in the United States, is one of the most widely used, authoritative, consumer-grade health information resources on the web. Although extensively used and discussed in scholarly work for health literacy and patient education, it is unclear how MedlinePlus has been integrated into clinical care or embedded within health informatics applications.
    Objective: This study aimed to understand how MedlinePlus has supported patients and caregivers by increasing access to health information for clinical care and illness management. The insights on this topic will inform the design and development of patient-facing digital health intervention tools for improved health communication, decision engagement, informed decision-making, and health outcomes.
    Methods: We conducted a systematic literature review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. First, we developed a comprehensive literature search strategy, searched 9 citation databases, and aggregated and deduplicated search results before importing them into Covidence for manual screening using predefined inclusion and exclusion criteria. Second, reviewers independently assessed all studies at the title-abstract and full-text levels, resolving discrepancies through ongoing discussions. Third, we applied the PICO (problem/population, intervention, comparison, and outcome) and the Collaborative Chronic Care Model as guiding frameworks for data extraction and analysis. All included studies underwent quality assessment using the Mixed Methods Appraisal Tool.
    Results: In total, 28 studies reported in 27 sources met our inclusion criteria. We categorized the extracted data into 4 areas. First, regarding bibliometrics, the studies were reported between 2004 and 2024, with 2010 having the highest number of studies. Of these studies, 25 were conducted in the United States, 2 were conducted in Iran, and 1 was conducted in Argentina. Health informatics journals and conference proceedings, as well as library science journals, were prominent publishing venues. The NLM funded half of the studies. Second, regarding participants, most studies focused on outpatients. Other participant roles included physicians, nurses, hospital staff, pharmacists, and librarians. Fewer than half of the studies addressed the social determinants of health. Third, regarding intervention, most studies implemented MedlinePlus information interventions within clinical settings. Other interventions occurred in community pharmacies, community organizations, libraries, online health platforms, or patient portals. Fourth, regarding outcome, only 4 studies assessed clinical outcomes, and the findings were mixed and inconsistent. However, 24 of 28 studies reported positive nonclinical outcomes, including improved attitudes toward and satisfaction with MedlinePlus and enhancements in patients' information-seeking behaviors, confidence, and willingness to engage in decision-making, physician-patient communication, self-management, and self-efficacy.
    Conclusions: This systematic literature review is the first comprehensive examination of how MedlinePlus has been integrated into clinical care, supporting patients and caregivers with enhanced access to health information. Our findings offer evidence and insights through the Collaborative Chronic Care Model lens and can guide the development of digital health interventions to improve patient health.
    Keywords:  MedlinePlus; health information access; information intervention; information prescription; patients and caregivers; systematic literature review
    DOI:  https://doi.org/10.2196/79416
  29. Nature. 2026 Apr 27.
    Mitochondria can spawn new 'organelles' - hinting at how modern cells evolved.
    Viviane Callier.
      
    Keywords:  Cell biology; Evolution; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-01295-0
  30. Compr Physiol. 2026 Jun;16(3): e70155
    The Mitochondrial-Autophagy Axis in MASLD: Mechanisms, Crosstalk, and Therapeutic Targets.
    Gaurab Bhaduri, Anchin Kalia, Banshi Saboo, Sanjay Bandyopadhyay.
       BACKGROUND: This review seeks to integrate contemporary evidence regarding mitochondrial dysfunction and autophagic regulation in metabolic dysfunction associated steatotic liver disease (MASLD), elucidating mechanistic pathways, indigenous determinants, and emerging therapeutic targets.
    METHODS: A thorough search was performed in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar. Research publications on mitochondrial activity, oxidative phosphorylation, fatty acid oxidation, mitophagy, lipophagy, and associated autophagic pathways in MASLD or MASH were incorporated.
    RESULTS: This review integrates findings that show mitochondrial dysfunction is a key mediator of MASLD progression. Mitochondrial dysfunction due to fatty acid oxidation, electron transport chain uncoupling, increased reactive oxygen species, and was found to be associated with steatosis, inflammation, and fibrosis. Simultaneous inhibition of autophagy, including lipophagy and mitophagy, contributes to lipid accumulation and persistence of dysfunctional mitochondria. Novel mediators of MASLD progression include gut dysbiosis, ferroptosis, and mitoDAMP signaling.
    CONCLUSION: In summary, the results indicate that mitochondrial dysfunction and autophagy dysregulation are interdependent mediators of MASLD pathogenesis. Their interaction mediates metabolic overload to oxidative stress, inflammation, and fibrotic remodeling. The understanding of these mechanisms provides a common platform for MASLD progression and suggests mitochondrial quality control, autophagy modulation, and associated metabolic pathways as promising targets for future MASLD therapeutic and preventive strategies.
    Keywords:  autophagy; lipotoxicity; liver fibrosis; metabolic dysfunction–associated steatotic liver disease (MASLD); mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1002/cph4.70155
  31. Front Physiol. 2026 ;17 1768672
    Mechanistic insights and challenges in mitochondrial regulation of macrophage polarization and inflammatory responses.
    Xinran Liu, Renping Liu.
      Inflammation has a dual nature; excessive or uncontrolled inflammation can trigger metabolic inflammatory diseases, in which immune cells, especially macrophages, play a crucial role. Mitochondria, as the core of cellular energy metabolism, are closely related to macrophage polarization and inflammation regulation. Mitochondrial dysfunction can trigger inflammatory responses through the activation of multiple signaling pathways, involving multiple signaling pathways, including Cyclic GMP-AMP Synthase - Stimulator of Interferon Genes 1, inflammasomes, and Retinoic acid-Inducible Gene I (RIG-I). Currently, the role of mitochondria in regulating inflammatory responses is increasingly prominent; however, current research still faces many challenges, such as a lack of mechanistic connections, unclear details of key molecules, insufficiently refined experimental strategies, and difficulties in clinical translation. Future research needs to leverage advanced technologies to delve deeper into the mechanisms, improve the bioavailability and tissue-specific delivery of mitochondrial-targeted drugs, establish personalized evaluation criteria, and promote interdisciplinary innovation to facilitate the transition of mitochondrial-targeted therapy from basic research to clinical application.
    Keywords:  inflammation; macrophage polarization; macrophages; metabolism; mitochondrial-regulated inflammation mechanisms
    DOI:  https://doi.org/10.3389/fphys.2026.1768672
  32. Aging Dis. 2026 Apr 15.
    Brain Aging and the Pursuit of Longevity: Biological Mechanisms and Clinical Implications.
    Myung-Hoon Han, Shin-Woong Ko, Seong-Ho Koh.
      Brain aging is an inevitable but modifiable process in which cellular, molecular, and systemic alterations converge on the central nervous system to determine cognitive health span. Much of the existing literature examines the biological mechanisms of aging, the distinction between normal and pathological brain aging, and lifestyle or pharmacological interventions as separate domains, with few integrative analyses connecting these elements into a clinically relevant conceptual framework. This knowledge gap limits the effective translation of geroscience advances into practical, lifespan-oriented strategies for prevention and care. This review aims to: (1) distinguish systemic aging from cognitive frailty within a brain-oriented clinical framework; (2) summarize key molecular mechanisms of brain aging, including telomere shortening, genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction; (3) contrast clinical features of normal brain aging with neurodegenerative disease; and (4) evaluate emerging therapeutic strategies, including senolytics, gene modulation, and nutrient-sensing pathway regulation, while critically appraising the translational readiness of each. Integrating proactive lifestyle measures with advances in geroscience may provide a cohesive framework for promoting not only longer life but also healthier brain aging, although most interventional evidence to date remains preclinical, and substantial translational gaps must be addressed before these strategies can be validated in clinical practice.
    DOI:  https://doi.org/10.14336/AD.2026.0269
  33. Phytomedicine. 2026 Apr 15. pii: S0944-7113(26)00417-4. [Epub ahead of print]156 158183
    Astragaloside IV delays vascular aging by enhancing mitochondrial fatty acid β-oxidation via the MLXIPL-PPARα/PGC-1α axis.
    Xiangyu Chen, Xiaodie Chen, Nan Xiao, Yutong Yang, Chenghui Li, Yanbin Pan, Huiqun Huang, Xiaodong Duan, Yongan Deng, Chengkai Chen, Shuting Zeng, Simin Yang, Yixuan Huang, Danping Huang, Yubin Yang, Zunpeng Shu, Li Zhang.
       BACKGROUND: Mitochondrial dysfunction and the dysregulation of lipid metabolism are significant contributors to vascular aging, which in turn raises the risk of age-related cardiovascular diseases (CVDs). Buyang Huanwu decoction (BHD), a traditional formula widely used for treating CVDs, has not been thoroughly investigated in terms of its active components and the molecular mechanisms by which it may delay vascular aging.
    PURPOSE: This study aims to investigate the effects and mechanisms of BHD and its primary active component, Astragaloside IV (AS-IV), in mitigating vascular aging, focusing on mitochondrial function and lipid metabolism.
    METHODS: Experiments were conducted using naturally aged mice and a D-galactose-induced model of vascular smooth muscle cells (VSMCs) senescence. Vascular aging was evaluated through aortic histopathology, assessment of senescence markers and senescence-associated secretory phenotype (SASP) factors. Transcriptomics and lipidomics analyses were employed to uncover critical pathways and identify differential lipid profiles. Mitochondrial structure and function were examined using transmission electron microscopy (TEM), Mitochondrial DNA (mtDNA) copy number, and mitochondrial membrane potential (MMP). The molecular mechanisms were further validated through molecular biology and MLX Interacting Protein-Like (MLXIPL) knockdown and overexpression techniques.
    RESULTS: Both BHD and AS-IV improved age-related vascular morphological changes, mitigated elastic fiber disruption, diminished collagen deposition, and downregulated senescence markers along with SASP factors. Transcriptomic analysis identified MLXIPL as a key transcription factor, emphasizing the involvement of the peroxisome proliferator-activated receptor (PPAR) signaling pathway and mitochondrial fatty acid β-oxidation as critical processes. Lipidomic profiling indicated reduced serum acylcarnitine levels in aged mice, suggesting compromised fatty acid β-oxidation. Both BHD and AS-IV were found to suppress MLXIPL, activate PPARα, increase mtDNA copy number, enhance MMP, improve mitochondrial ultrastructure, and upregulate the expression of key genes and proteins associated with mitochondrial biogenesis and fatty acid β-oxidation. Co-immunoprecipitation assays confirmed that AS-IV facilitated PPARα-PGC-1α interaction. Functional validation established that MLXIPL knockdown produced a stronger effect than AS-IV, whereas MLXIPL overexpression negated the beneficial effects of AS-IV on mitochondrial function, lipid accumulation, and cellular senescence.
    CONCLUSION: BHD and its active component AS-IV delay vascular aging by inhibiting MLXIPL, thereby activating the PPARα/PGC-1α signaling pathway to promote mitochondrial fatty acid β-oxidation and reduce lipid accumulation. This elucidates a mechanistic basis for BHD's traditional use and highlights AS-IV as a key active principle with therapeutic potential.
    Keywords:  Astragaloside IV; Buyang Huanwu decoction; Fatty acid β-oxidation; Lipid metabolism; Mitochondrial biogenesis; Vascular aging
    DOI:  https://doi.org/10.1016/j.phymed.2026.158183
  34. Cells. 2026 Apr 19. pii: 720. [Epub ahead of print]15(8):
    Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation.
    Amer Elias, Shani Stern.
      Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood-brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson's disease, Huntington's disease, and Alzheimer's disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.
    Keywords:  Adeno-Associated Virus (AAV); Blood–Brain Barrier (BBB); CRISPR-Cas; Central Nervous System (CNS); base editing; exosomes; gene editing; neurological disorders; precision medicine; prime editing
    DOI:  https://doi.org/10.3390/cells15080720
  35. Front Sports Act Living. 2026 ;8 1710264
    Effects of exercise training on skeletal muscle function in patients with mitochondrial myopathy: a systematic review.
    Qiliang Wan, Yi Ding, Wenduo Liu, Kun Yang.
       Background: Mitochondrial myopathy (MM) is a group of rare, progressive muscle disorders characterized by impaired oxidative phosphorylation due to mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations, leading to exercise intolerance, muscle weakness, and metabolic dysfunction. Although exercise is increasingly recognized for its capacity to enhance mitochondrial function and muscle performance, the specific effects of different exercise prescriptions (in terms of modality, intensity, and duration) on MM and their phenotype-specific outcomes remain heterogeneous. This study systematically investigates how various exercise types influence mitochondrial function, muscle performance, and clinical outcomes across MM subtypes.
    Methods: Databases including PubMed, Web of Science, Embase, and Scopus were searched from 1990 to September 2025. Clinical trials involving exercise interventions in MM patients were included, with outcomes covering exercise capacity, muscle function, mitochondrial markers, and metabolic indices. Risk of bias was assessed using Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2) and Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I V2), and methodological quality was appraised with the Mixed Methods Appraisal Tool (MMAT).
    Results: Fifteen studies (1 randomized controlled trial and 14 non-randomized trials) including a total of 157 MM patients (sample size per study: 4-20) were analyzed. Moderate-intensity aerobic and resistance exercise consistently improved maximal oxygen uptake (VO2 max), maximal workload (W max), muscle strength, and mitochondrial enzyme activity, with no consistent group-level increases observed in creatine kinase (CK) levels or mtDNA mutation burden. Aerobic training enhanced oxidative capacity, phosphocreatine (PCr) recovery, and antioxidant defense, while resistance training improved muscle strength, satellite cell activation, and reduced cytochrome c oxidase (COX)-deficient fibers. Combined regimens yielded additive benefits. Most interventions lasted 8-14 weeks, 3-5 sessions per week. Phenotype-specific responses were evident: patients with large-scale deletions or m.3243A>G mutations showed favorable adaptation, whereas other point mutations or microdeletions displayed variable or adverse responses.
    Conclusion: Moderate-intensity, phenotype-specific exercise prescriptions, especially those integrating both aerobic and resistance components, may enhance mitochondrial and muscular function in patients with mitochondrial myopathy while reducing the likelihood of adverse effects. However, larger controlled trials are needed to confirm long-term efficacy and to clarify potential risk profiles.
    Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251145502, PROSPERO CRD420251145502.
    Keywords:  exercise intervention; exercise recommendations; mitochondrial function; mitochondrial myopathy; pathological mechanisms
    DOI:  https://doi.org/10.3389/fspor.2026.1710264
  36. Neurochem Int. 2026 Apr 24. pii: S0197-0186(26)00055-0. [Epub ahead of print] 106164
    Mitofusin 2 in Central Nervous System Disorders: Roles in Mitochondrial Dynamics and Therapeutic Implications.
    Li Tang, Jiehao Huang, Rui Xia, Wei Xu, Juan Li, Mu Zhang.
      Mitochondrial dynamics have been increasingly recognized as a central determinant in the pathogenesis of central nervous system (CNS) disorders. Mitofusin 2 (MFN2), a critical mitochondrial fusion protein, preserves mitochondrial network integrity and participates in fission, mitophagy, and axonal transport, thereby maintaining neuronal function and energy homeostasis. Structural features of MFN2 underpin its diverse regulatory roles, whereas MFN2 deficiency leads to mitochondrial fragmentation, metabolic dysfunction, oxidative stress, and neuronal impairment. This review summarizes the molecular mechanisms of MFN2 in the CNS and its impact on neuronal survival, synaptic function, and signaling pathways. In addition, we highlight potential MFN2-targeted interventions, including natural compounds, pharmacological agents, and emerging small-molecule activators, while also discussing disease-specific mechanisms and translational challenges such as endoplasmic reticulum (ER)-mitochondria communication abnormalities and blood-brain barrier permeability.
    Keywords:  Central nervous system disorders; MFN2 activators; Mitochondrial dynamics; Mitofusin 2
    DOI:  https://doi.org/10.1016/j.neuint.2026.106164
  37. Neurol Int. 2026 Mar 26. pii: 64. [Epub ahead of print]18(4):
    Alpha-Lipoic Acid and Biotin in Neurodegenerative Diseases: Convergent Mechanistic Insights from Preclinical Models to Clinical Perspectives.
    Asdrubal Aguilera-Méndez, Karel Aguilera-Manuel, Alfredo Saavedra-Molina, Patricia Ríos-Chávez, Santiago Villafaña, Renato Nieto-Aguilar, Daniel Godínez-Hernández, Daniel Ortega-Cuellar, Zoraya Palomera-Sanchez, Marcia Gauthereau-Torres.
       BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, represent a major global health burden and share convergent pathogenic mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, calcium imbalance, and neuronal loss. Despite advances in symptomatic management, effective disease-modifying therapies remain limited.
    OBJECTIVES: This review aims to critically synthesize mechanistic, preclinical, and clinical evidence on α-lipoic acid and biotin as candidate neuroprotective agents in neurodegenerative diseases, with emphasis on shared signaling pathways, therapeutic potential, generally favorable safety profiles, and translational limitations.
    METHODS: A narrative and integrative review was conducted, encompassing mechanistic studies, preclinical experimental models, and clinical trials and observational studies evaluating ALA and biotin in neurodegenerative diseases. The evidence was qualitatively analyzed with attention to biological plausibility, consistency across models, and clinical relevance.
    RESULTS: ALA and biotin modulate key cellular pathways implicated in neurodegeneration, including mitochondrial metabolism, redox homeostasis, inflammatory signaling, and neurovascular function. Preclinical studies consistently report beneficial effects on mitochondrial efficiency, oxidative stress, and neuroinflammatory markers. In contrast, clinical evidence remains heterogeneous, with more extensive evaluation of biotin in progressive multiple sclerosis and more limited or exploratory findings for ALA across neurodegenerative disorders.
    CONCLUSIONS: ALA and biotin exhibit mechanistic convergence across pathways relevant to neurodegeneration and generally favorable safety profiles. Although current evidence supports their biological plausibility as adjunctive or exploratory therapeutic strategies, clinical outcomes remain inconsistent and appear to be influenced by dosing regimens, disease stage at intervention, and endpoint selection. Well-designed clinical studies are required to define their efficacy, optimal dosing, and disease-specific applicability.
    Keywords:  biotin; neurodegenerative disease; α-lipoic acid
    DOI:  https://doi.org/10.3390/neurolint18040064
  38. Metabolites. 2026 Apr 20. pii: 281. [Epub ahead of print]16(4):
    Selected Brain Metabolites and Mitochondrial DNA Copy Number as Potential Markers of Ongoing Neurodegeneration in Patients with Wolfram Syndrome.
    Ewa Zmysłowska-Polakowska, Tomasz Płoszaj, Sebastian Skoczylas, Julia Grzybowska-Adamowicz, Dobromiła Barańska, Katarzyna Matera, Aleksandra Palatyńska-Ulatowska, Wojciech Młynarski, Agnieszka Zmysłowska, Michal Ciborowski.
      Background: Wolfram syndrome (WFS) is a rare neurodegenerative disease that is genetically determined and inherited in an autosomal recessive manner. Although the first clinical symptom appearing in early childhood is diabetes mellitus, subsequent symptoms are associated with optic nerve atrophy, followed by central nervous system atrophy. Methods: The aim of the study was to analyse magnetic resonance images (MRI) of the brain in combination with single-voxel magnetic resonance spectroscopy (MRS) and to assess the copy number of mitochondrial DNA (mtDNA-CN) in 10 patients with WFS compared with a control group of 17 healthy individuals. Results: A significant decrease in the amount of selected metabolites was observed in WFS patients compared to controls in all assessed brain regions (pons, cerebellum, white matter, thalamus, and hippocampus). For three metabolites, Glutamate (Glu), Glutamate + Glutamine (Glx) and total N-acetylaspartate (TNAA), significant differences in concentrations were found between the study groups in almost all matrices evaluating specific areas of the brain (p < 0.011), with the exception of a trend toward reduced TNAA in the hippocampus (p = 0.065). In addition, patients with WFS had a significant decrease in the mitochondrial-to-nuclear DNA ratio compared to controls (p < 0.0003). Some metabolites, such as N-acetylaspartate and total N-acetylaspartate, showed strong correlations with specific regions of the visual pathway on MRI scans in patients with WFS. Conclusions: Selected brain metabolites and mtDNA-CN may become potential markers of WFS, and the results of this study may be used to define indicators for future therapeutic strategies.
    Keywords:  MRS; Wolfram syndrome; markers; mtDNA copy number; neurodegeneration
    DOI:  https://doi.org/10.3390/metabo16040281
  39. Am J Med Genet A. 2026 Apr 29.
    FGF12-Related Early-Onset Epileptic Encephalopathies: Therapeutic Response to Sodium Channel Blockers.
    Fatimah Aldurayhim, Sulman Basit, Shahid Bashir, Yousef Hussain Housawi, Ali Mir.
      Developmental and epileptic encephalopathies (DEEs) comprise a clinically and genetically heterogeneous group of severe neurodevelopmental disorders, frequently caused by pathogenic variants in genes encoding neuronal ion channels or synaptic proteins. The fibroblast growth-factor 12 (FGF12) encodes a binding protein for voltage-gated sodium channels. Variants in FGF12 have recently been associated with autosomal dominant DEEs characterized by early-onset epilepsy and neurodevelopmental impairment. We report three patients with a duplication involving exons 1-4 of FGF12 on chromosome 3q28-q29 and systematically review 24 previously published cases of FGF12-related DEE. Clinical features, electroencephalographic findings, neuroimaging data, and responses to anti-seizure medications (ASMs) were analyzed across a total cohort of 27 patients. Eighteen patients carried FGF12 missense variants, including the recurrent pathogenic p.Arg114His variant (n = 14), p.Gly112Ser (n = 2), p.Glu87Lys (n = 1), and one exon 4 missense variant (chr3:g.192335434C>T). Nine patients had copy number duplications involving FGF12. Seizure onset ranged from 1 day to 4 years of age, with 54.1% presenting in the neonatal period. Tonic seizures were the most common seizure type, and 79.1% of patients exhibited moderate to severe intellectual disability. Brain MRI showed mild cerebral and/or cerebellar atrophy in 41.6% of cases. Across reported cases, variable responsiveness to ASMs was observed, with sodium channel blockers including carbamazepine and phenytoin frequently associated with seizure reduction. This study expands the clinical and genetic spectrum of FGF12-related DEE and highlights considerable phenotypic variability across variant types. While treatment responses were heterogeneous, sodium channel blockers were commonly associated with clinical improvement. These findings support cautious consideration of sodium channel targeting therapies in FGF12-DEE and underscore the need for systematic studies to better define genotype treatment relationships.
    Keywords:   FGF12 ; FHF1 ; DEE; Na channel blockers; anti‐seizure medications; developmental epileptic encephalopathy; epilepsy; intellectual disability
    DOI:  https://doi.org/10.1002/ajmg.a.70182
  40. J Clin Transl Sci. 2026 ;10(1): e77
    The FOCUS model: A guide to promote patient partnership in clinical trial designs.
    Jennifer Catena Davis, Patrick Corr, Amy Raymond, Sabrina Figueiredo.
       Background: Evidence suggests that partnerships between researchers and patient communities result in clinical trials that better reflect the patient experience, but there are few documented and successful models of such partnerships. Within the clinical research landscape, the Duchenne Muscular Dystrophy (DMD) community has emerged as a positive outlier in this regard, having engaged in a research partnership over multiple years and in the approval of several disease-modifying therapies where there were previously none.
    Methodology: The successful partnership factors observed in the DMD community were mapped onto the three levels of the Behavior Change Wheel framework. This mapping created an academic model of patient community readiness for research partnerships. The academic model was further translated into a user-friendly, pragmatic model and blueprint.
    Results: The FOCUS Model outlines the development of a research partnership from the ground up, where each theme represents an essential component of the partnership structure. Accompanying this model is a discussion guide that communities can use in meetings or workshops to assess and enhance their readiness for research partnerships.
    Conclusions: The FOCUS model and its blueprint offer generalizable approaches that other rare disease patient communities can leverage to foster effective and lasting partnerships with scientific, medical, and regulatory stakeholders. The approach proposed in this study has the potential to help both the clinical research community and rare disease patient communities overcome typical barriers to rare disease clinical development.
    Keywords:  Duchenne muscular dystrophy; Patient-researcher partnerships; clinical drug development; clinical trials; rare disease
    DOI:  https://doi.org/10.1017/cts.2026.10719
  41. bioRxiv. 2026 Apr 17. pii: 2026.04.14.718012. [Epub ahead of print]
    Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
    Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.
      Cardiolipin (CL) is a four-chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of mitochondrial inner membrane structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.
    DOI:  https://doi.org/10.64898/2026.04.14.718012
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