bims-polgdi Biomed News
on POLG disease
Issue of 2026–06–28
fifty-five papers selected by
Luca Bolliger, lxBio
  1. Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
  2. Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
  3. Paradoxical hypolibido in a hyperandrogenic male with POLG-related mitochondrial disease.
  4. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  5. Activity of DNA- and RNA-Guided Prokaryotic Argonautes in Human Mitochondria.
  6. Evolving landscape of drug development for pediatric rare diseases-from successes to strategies for addressing unmet needs.
  7. Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.
  8. Building Equity Into Rare Disease Research Through Biobanking: Lessons From PIK3CA-Related Overgrowth Spectrum Disorders.
  9. Sensory decline in aging and neurodegeneration: A mitochondrial perspective.
  10. Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
  11. Bibliometric Analysis of Research Hotspots and Emerging Trends in Mitochondrial DNA and Atherosclerosis (2004-2025).
  12. Mitochondrial Dysfunction in Autism and Attention-Deficit/Hyperactivity Disorder: Evidence from Genetic, Biochemical, and Neuroimaging Approaches.
  13. Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
  14. Artificial Intelligence in Rare Diseases: Workflow-Integrated Precision Kidney Care.
  15. The impact of China's drug regulatory reform on access to orphan drugs: a cross-sectional study of diseases listed in the rare disease catalog.
  16. Reduced Mitochondrial DNA Copy Number and Telomere Length in Essential Tremor Patients: Evidence from an Age- and Sex-Adjusted Cross-Sectional Case-Control Study.
  17. Interplay of Mitochondrial Dynamics, Nutrition, and Vitamins: Evidence From Experimental and Human Studies With Implications for Women's Health.
  18. Causal associations between mitochondrial DNA copy number and gastrointestinal diseases: A Mendelian randomization study.
  19. Multi-ancestry analysis of POLG variants in Parkinson's disease.
  20. Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
  21. Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.
  22. European Reference Networks as core health structures where referring genetic newborn screening positive infants: an innovative operational research framework.
  23. Ginkgo Biloba Extract Ameliorates Age-Related Mitochondrial Deficits in Human iPSCs and Their Derived Neurons and Astrocytes.
  24. Mitochondrial quality control in health and disease: Updates 2026.
  25. Diagnostic yield of long-read sequencing for rare diseases: a systematic review.
  26. Sex representation in trials relative to indication-specific disease burden in FDA-approved drugs (2015-2023).
  27. After the Diagnosis.
  28. Large-language-models for pediatric diagnosis: Performance evaluation using real-world clinical notes from common and rare cases.
  29. Mitochondria-Targeting microRNAs (mitomiRs): Potential Mediators of Environmental Mitoepigenetics in Mammalian Spermatogenesis.
  30. The TOM Complex in the Outer Membrane of Mitochondria: A Supramolecular Assembly for Protein Import.
  31. Capsule-enhanced hierarchical vision transformers for rare disease classification from medical images.
  32. Proteolytic coordination of the OXPHOS Life Cycle.
  33. The multifaceted inducers of cellular senescence.
  34. Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.
  35. Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.
  36. Cardiomyopathy and mitochondrial encephalomyopathy in a female child associated with a heterozygous X-linked AIFM1 variant.
  37. Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
  38. Ketogenic diet therapy in pyruvate dehydrogenase deficiency: Global clinical practice from literature and survey data.
  39. Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases.
  40. Metabolic Brain Disorders: Prodromes, Symptoms, and Syndromes.
  41. Stem cell-derived extracellular vesicles for rare diseases: A clinical‑bottleneck‑to‑mechanism framework for translation.
  42. A Fat Chance at Neuroprotection: Ketogenic Diet and Parkinson's Disease.
  43. STELLAR: A flexible ensemble learning framework integrating rare variants to enhance polygenic risk prediction.
  44. Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.
  45. Methodological Advances in Mitochondrial DNA Analysis for Forensic Genetics.
  46. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
  47. GPU-accelerated MitoGraph for high-throughput three-dimensional mitochondrial morphology analysis.
  48. Persistence of large mtDNA rearrangements linked to premature aging in Pol γ exonuclease-deficient mice.
  49. Circulating Cell-Free DNA in Psychiatric Disorders: Current Evidence, Inflammation-Based Stratification, and Future Perspectives.
  50. Correction to "Shenlian Extract Decreases Mitochondrial Autophagy to Regulate Mitochondrial Function in Microvascular to Alleviate Coronary Artery No-Reflow".
  51. Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
  52. AI-CURA, an automated LLM workflow for high-accuracy genetic variant classification.
  53. Mitochondria: from powerhouses of cells to hubs in antitumor immunity.
  54. Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.
  55. A large-scale human plasma metabolite atlas from over 380,000 participants.
  1. Int J Mol Sci. 2026 Jun 18. pii: 5517. [Epub ahead of print]27(12):
    Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
    Vladislav Simonov, Sergey Rastorguev.
      Mitochondrial DNA (mtDNA) mutations are associated with a diverse spectrum of diseases and pose a significant threat to human health. Despite their importance as therapeutic targets, the unique structural and electrochemical properties of mitochondria-most notably the impermeable inner mitochondrial membrane and the high membrane potential-present formidable challenges for the targeted delivery of therapeutic agents. Currently, there are no approved curative treatments for patients harboring pathogenic mtDNA mutations. In this review, we discuss recent advancements in gene therapy for mitochondrial genome-related disorders, with a particular focus on allotopic expression of mtDNA-encoded genes and mitochondrial genome editing technologies. We conclude that allotopic expression currently stands as the most promising approach for near-term clinical implementation. But we also pay great attention to programmable nucleases and base editors utilizing RNA-independent DNA recognition which are evolving with remarkable speed.
    Keywords:  DdCBE; allotopic expression; gene therapy; mitoCRISPR; mitoTALEN; mitoZFN; mitochondrial manipulation; mtDNA
    DOI:  https://doi.org/10.3390/ijms27125517
  2. Mol Neurobiol. 2026 Jun 26. pii: 728. [Epub ahead of print]63(1):
    Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
    Sanket Pramanik, Biplab Debnath, Aganta Chakraborty, Anas Islam, Shrabasti Mullick, Priya Chaudhary, Rajarshi Nath, Dinesh Kumar Chellappan, Mohini Mondal, Sumel Ashique.
      Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.
    Keywords:  DdCBE (DddA-derived Cytosine Base Editors); Heteroplasmy Correction; MitoTALENs; Mitochondria-Targeted CRISPR/Cas Systems; Mitochondrial Genome Editing; Neurodegenerative Disorders; Oxidative Stress & Mitochondrial Dysfunction; Precision Medicine
    DOI:  https://doi.org/10.1007/s12035-026-06008-2
  3. J Sex Med. 2026 Jun 05. pii: qdag187. [Epub ahead of print]23(7):
    Paradoxical hypolibido in a hyperandrogenic male with POLG-related mitochondrial disease.
    Hector Rodrigo Gonzalez-Carranza, Luis Antonio Reyes-Vallejo.
      
    Keywords:  hyperandrogenism; libido; mitochondrial diseases; testosterone
    DOI:  https://doi.org/10.1093/jsxmed/qdag187
  4. bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.
      Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.64898/2026.06.09.730804
  5. Cells. 2026 Jun 22. pii: 1129. [Epub ahead of print]15(12):
    Activity of DNA- and RNA-Guided Prokaryotic Argonautes in Human Mitochondria.
    Beatrisa Rimskaya, Ekaterina Kropocheva, Iaroslava Ponomareva, Lada Karchemkina, Lidiya Lisitskaya, Daria Gelfenbein, Egor Ulashchik, Vadim Shmanai, Andrey Kulbachinskiy, Ilya Mazunin.
      Precise manipulation of mitochondrial DNA (mtDNA) by CRISPR-Cas systems remains challenging, largely due to inefficient import of guide RNAs, motivating the exploration of alternative programmable nucleases. Here, we show that prokaryotic Argonaute nucleases (pAgos) of various classes can be efficiently targeted to human mitochondria. Using the Su9 mitochondrial targeting sequence from Neurospora crassa, we achieved robust mitochondrial import of four pAgos-DecAgo, CbuAgo, KmaAgo and RslAgo. As a functional readout of their activity in cells, we targeted the single-stranded D-loop region, which plays a central role in mtDNA replication and maintenance, reasoning that cleavage at this site was expected to potentially result in a reduction in mtDNA copy number. Of the four enzymes, only RNA-guided DecAgo induced a pronounced reduction in mtDNA levels, decreasing copy number approximately fivefold within 48 h. Unexpectedly, this effect occurred independently of exogenous guides, suggesting that DecAgo may utilize endogenous mitochondrial guide RNAs. These findings identify DecAgo as an active nuclease in human mitochondria and reveal a previously unrecognized mode of targeting, highlighting the need to further investigate the underlying mechanism and the potential role of endogenous guide molecules, as well as improving targeting specificity.
    Keywords:  D-loop; mitochondria; mtDNA copy number; prokaryotic argonautes
    DOI:  https://doi.org/10.3390/cells15121129
  6. J Pharm Sci. 2026 Jun 20. pii: S0022-3549(26)00250-9. [Epub ahead of print] 104401
    Evolving landscape of drug development for pediatric rare diseases-from successes to strategies for addressing unmet needs.
    Sydney Stern, Yifei Zhang, Michelle Pressly, Xinning Yang, Susan Abdel-Rahman, Jie Wang, Mei-Chuan Chen, Chun-Han Chen, Salvatore Pepe, Mary Doi, Gilbert J Burckart, Lynne P Yao, Robert Schuck, Jane Pf Bai.
      Over 7,000 rare diseases have been identified and 50-75% of them impact pediatrics. Pediatric rare diseases represent a critical unmet need, as nearly 95% of these conditions lack FDA-approved therapies. Progress, through scientific innovation and focused public health initiatives, has contributed to addressing the unmet needs of patients with rare diseases and promoting the development of novel therapies. However, key challenges remain, including demonstrating meaningful effects in small, heterogeneous populations, lack of validated biomarkers, designing trials that maximize patient participation, and optimizing doses often without independent dose-finding studies. In this review, we describe the landscape of FDA-approved products for rare diseases and highlight examples of pediatric drug development where approvals were informed by novel strategies. Acknowledging that rare disease drug development requires flexibility and innovations, these approaches include leveraging adult data for diseases affecting both adults and pediatric populations, extrapolating efficacy and/or safety evidence across pediatric age groups in diseases that occur only in pediatric populations, and the use of mechanistic modeling, biomarkers, innovative trial designs, and new approach methodologies to bridge gaps in knowledge for successful development of drug products for these diseases. Reviews of the ontogeny of drug metabolizing enzymes and transporters that affect drug disposition are summarized to lay the foundation for mechanistic modeling. Lastly, future perspectives illuminate the path forward to meet the unmet medical needs for treating rare pediatric diseases.
    Keywords:  Pharmacodynamic biomarkers; drug-metabolizing enzymes; mechanistic modeling; ontogeny; pediatric extrapolation; rare diseases; transporters
    DOI:  https://doi.org/10.1016/j.xphs.2026.104401
  7. Adv Exp Med Biol. 2026 ;1514 299-330
    Mammalian Respiratory Chain Complex Assemblies and Their Links to Mitochondria Stress-Induced Human Diseases.
    Runyu Guo, Maojun Yang.
      Mitochondria are considered the central organelle in cellular energy metabolism and an integral platform for signal transduction. Respiratory chain complexes are the most abundant and critical protein machines in mitochondria. Thanks to advancing technologies such as cryo-EM, molecular dynamics simulation, and FRET-based live imaging, though still under hot debate, we have now gained a much deeper insight into the organization, regulation, and functional mechanism of the respiratory chain. Accordingly, developing novel compounds targeting mitochondria is particularly appealing, for mitochondria dysfunction might be the underlying cause of many annoying human diseases, including metabolic syndromes, neurodegenerative diseases, cardiovascular diseases, and tumors.
    Keywords:  Complex I; Drug discovery; Electron transport chain; Mitochondria; Mitochondrial disorders; Respiratory chain complexes; Signaling; Structural biology; Supercomplexes
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_11
  8. Clin Ther. 2026 Jun 23. pii: S0149-2918(26)00227-4. [Epub ahead of print]
    Building Equity Into Rare Disease Research Through Biobanking: Lessons From PIK3CA-Related Overgrowth Spectrum Disorders.
    Jumi Popoola.
      Rare diseases collectively affect hundreds of millions of individuals worldwide, yet the majority remain underdiagnosed, undercharacterized, and underrepresented in biomedical research. Although individually rare, these conditions impose a significant global health burden, often associated with prolonged diagnostic delays, fragmented care pathways, and limited therapeutic options. Advances in genomic technologies have transformed the understanding of many rare diseases by enabling identification of disease-causing variants and molecular pathways that can be targeted therapeutically. However, these advances have not been distributed equitably across global populations. In many regions, particularly low- and middle-income countries (LMICs), limited access to genomic diagnostics and research infrastructure continues to impede accurate diagnosis and participation in therapeutic discovery. Biobanking represents a critical but underutilized component of the rare disease research ecosystem. Biobanks provide foundational infrastructure for translational research, biomarker discovery and clinical trial development by systematically collecting and preserving biospecimens linked to clinical and phenotypic data. When aligned with international standards and integrated with interoperable data systems, biobanks enable large-scale collaborative research even for extremely rare conditions. This opinion article argues that biobanking should be recognized as core infrastructure within rare disease strategies rather than as a secondary research activity. Using PIK3CA-Related Overgrowth Spectrum (PROS) disorders as an illustrative example, we examine how integrating biospecimen repositories with clinical and genomic data can improve diagnostic accuracy, facilitate genotype:phenotype correlations, and accelerate development of pathway-targeted therapies. We further discuss how establishing locally anchored but globally interoperable biobanks may help address persistent inequities in rare disease research by ensuring that diverse populations contribute to and benefit from advances in precision medicine. The importance of representative biobanking and inclusive rare disease datasets is particularly acute when considering how clinical presentations vary across populations. Individuals with darker skin tones frequently present with dermatologic and vascular manifestations of PROS disorders in ways that may differ from presentations documented in existing clinical atlases and training datasets. Such differences can contribute to delayed recognition, misclassification, and prolonged diagnostic odysseys. Racial and ethnically underrepresented populations with rare diseases thus face compounded disadvantages: limited genomic characterization within reference datasets, underrepresentation in biospecimen repositories, and reduced access to diagnostic tools calibrated primarily on non-diverse cohorts. Ensuring that diverse populations are systematically represented in biospecimen collections, imaging datasets, genomic repositories, and longitudinal clinical annotation is therefore not simply an equity consideration but a scientific and clinical necessity for improving diagnostic accuracy and therapeutic development across all populations.
    Keywords:  Biobanking; Genomic medicine; Global health equity; PIK3CA-related overgrowth spectrum; Precision medicine; Rare diseases
    DOI:  https://doi.org/10.1016/j.clinthera.2026.06.012
  9. Pharmacol Res. 2026 Jun 25. pii: S1043-6618(26)00237-9. [Epub ahead of print]230 108322
    Sensory decline in aging and neurodegeneration: A mitochondrial perspective.
    Oluwamayomikun Adeboye, Bianca L Gonda, Nikita Gulati, Keming Hu, Alexa R Karp, Dylan C McNally, Wesley Tsai, Jennyfer G Zarate, Madison Holmes, Lanae Johnson-Kleinpeter, Hay Young Kwok, Victory J Miranda, Julie H Nguyen, Karishma A Patel, Apurva Polagoni, Bryan Ramirez, Renata T Da Costa, Cameron R Love, Andrey Grigoriev, Maria E Solesio.
      Sensory organs (touch, sight, hearing, smell, and taste) are the primary way humans perceive the environment. Accordingly, sensory decline deleteriously affects patients' quality of life, and it is often associated with a worse prognosis of related pathologies. This decline has been broadly described in aging and in the main aging-related neurodegenerative disorders, even though it is often understudied and considered a minor symptom. The molecular pathways that drive aging-associated sensory decline are broad and diverse; however, mitochondrial dysfunction has been described at the intersection of many of these mechanisms. Mitochondria have robust mechanisms to maintain their homeostasis. These mechanisms include, for example, the unfolded protein response, the antioxidant systems, and mitophagy. During aging, these mechanisms are dysregulated, which contributes to the dysfunction of the organelle. For example, increased reactive oxygen species generation and mitochondrial DNA mutations are present in cells and tissues, the dysregulation of which is crucial for the onset of sensory decline. In this bibliographical review, we systematically and comprehensively discuss the most significant and recent findings in the field. The studies we describe here suggest that targeting mitochondrial dysfunction could be a valid, innovative, and promising pharmacological target against sensory decline in aging and aging-related neurodegenerative disorders. Moreover, targeting mitochondrial dysfunction might have positive effects on other symptoms of aging and associated pathologies, including Parkinson's and Alzheimer's Diseases. Further research in the field could significantly contribute to decreasing sensory decline, which could positively impact both lifespan and healthspan.
    Keywords:  Mitochondria; Mitochondrial dysfunction; Neurodegeneration; Sensory decline
    DOI:  https://doi.org/10.1016/j.phrs.2026.108322
  10. Nat Commun. 2026 Jun 21.
    Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
    Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.
      Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-74103-y
  11. Cardiol Res Pract. 2026 ;2026 2121810
    Bibliometric Analysis of Research Hotspots and Emerging Trends in Mitochondrial DNA and Atherosclerosis (2004-2025).
    Yun Ouyang, Gesheng Wang, Ming Zhang, Puxuan Min, Mengxiong Guo.
       Objective: To explore the research course, hotspots, and development trends of mitochondrial DNA (mtDNA) and atherosclerosis (AS) based on knowledge graph technology, providing references for clinical and basic research in this field.
    Methods: Publications themed on mtDNA and AS published between 2004 and 2025 were retrieved from the Web of Science Core Collection (WOSCC) database. CiteSpace 6.4. R1 Advanced software was used to construct and visually analyze knowledge graphs of authors, institutions, keywords, etc.
    Results: A total of 341 publications were included, with the annual publication volume showing an overall upward trend. Research methods for mtDNA and AS are diversifying, with mechanistic investigations showing a trending focus toward specific molecular pathways. A total of 241 authors and 353 publishing institutions were analyzed. Ten keyword clusters were identified, including Cluster #0 oxidative stress, Cluster #1 mitochondrial DNA, Cluster #2 degradation, Cluster #3 atherosclerosis, Cluster #4 hydrogen peroxide, Cluster #5 roles, Cluster #6 MAPK pathway, Cluster #7 epigallocatechin gallate, Cluster #8 mitochondrial DNA copy number, and Cluster #9 vascular disease.
    Conclusion: Research has evolved from foundational mechanistic studies to a focus on translational and clinical applications. Moving forward, efforts should be intensified to enhance collaboration among research teams and deepen mechanistic investigations, thereby laying a solid foundation for clinical translation.
    Keywords:  CiteSpace4; atherosclerosis1; bibliometrics5; mitochondrial DNA2; oxidative stress3
    DOI:  https://doi.org/10.1155/crp/2121810
  12. Antioxidants (Basel). 2026 Jun 18. pii: 764. [Epub ahead of print]15(6):
    Mitochondrial Dysfunction in Autism and Attention-Deficit/Hyperactivity Disorder: Evidence from Genetic, Biochemical, and Neuroimaging Approaches.
    Tina R Ram, Chunlong Mu, Sarah J MacEachern, Jane Shearer.
      Mitochondrial dysfunction has been increasingly implicated in the pathobiology of neurodevelopmental conditions, particularly autism and attention-deficit/hyperactivity disorder (ADHD). Because the developing brain is critically dependent on sustained ATP production, impairments in oxidative phosphorylation, mitochondrial dynamics, and redox balance may disrupt neuronal maturation, synaptic development, and neural circuit refinement during sensitive developmental periods. This review examines evidence from postmortem neurochemistry, genomics, magnetic resonance spectroscopy, and biomarker research to characterize mitochondrial impairment across autism and ADHD. Studies in autism report an elevated burden of heteroplasmic mitochondrial DNA (mtDNA) variants, along with alterations in mtDNA copy number, respiratory chain capacity, fission-fusion dynamics, and antioxidant defenses. Postmortem data demonstrate reduced activity of electron transport chain Complexes I, III, and V in the frontal cortex, temporal lobe, and cerebellum. These bioenergetic abnormalities are accompanied by elevated oxidative stress markers alongside mitochondria-mediated immune activation. In vivo neuroimaging corroborates these findings through elevated cerebral lactate and reduced phosphocreatine-to-ATP ratios. Evidence in ADHD is limited, but similarly implicates mitochondrial dysfunction, consistent with the frequent co-occurrence of these conditions and their partially shared architecture. The available literature supports mitochondrial dysfunction as a transdiagnostic biological feature of neurodevelopmental conditions, with relevance to mechanistic biomarker identification and targeted therapeutic development.
    Keywords:  bioenergetics; electron transport chain; energy; metabolism; mitochondria; neurodevelopment; neuroinflammation; oxidative stress; phenotype
    DOI:  https://doi.org/10.3390/antiox15060764
  13. Biomolecules. 2026 Jun 09. pii: 842. [Epub ahead of print]16(6):
    Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
    Giampaolo Morciano, Ruggiero Gorgoglione, Vito Porcelli, Amer Ahmed, Pasquale Scarcia, Angelo Vozza, Francesco Massimo Lasorsa, Giuseppe Fiermonte, Luigi Palmieri.
      Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.
    Keywords:  SLC25 carriers; metabolism; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.3390/biom16060842
  14. Clin Pract. 2026 May 27. pii: 101. [Epub ahead of print]16(6):
    Artificial Intelligence in Rare Diseases: Workflow-Integrated Precision Kidney Care.
    Charat Thongprayoon, Francesco Pesce, Wisit Cheungpasitporn.
      Rare diseases affect over 300 million individuals worldwide yet remain underdiagnosed and poorly characterized due to fragmented data, small cohorts, and phenotypic heterogeneity. Advances in artificial intelligence (AI) are enabling integration of genomics, imaging, electronic health records, and patient-generated data to support diagnosis, phenotyping, prognosis, and therapeutic discovery. In kidney care, these capabilities are reflected in tools for genomic variant prioritization, AI-assisted histopathology, and integrated risk stratification models for rare and complex kidney diseases. This review synthesizes current AI applications across the rare disease continuum and proposes a clinically grounded framework to distinguish exploratory models from systems that are methodologically robust and operationally deployable. We highlight advances that address data sparsity and heterogeneity, alongside persistent challenges in validation, generalizability, equity, and workflow integration. Finally, we outline future directions, including federated learning, digital twins, and AI-driven clinical decision agents, as pathways toward precision-guided, workflow-integrated rare disease care.
    Keywords:  artificial intelligence; clinical decision support; genomic diagnosis; nephrology; rare diseases
    DOI:  https://doi.org/10.3390/clinpract16060101
  15. Front Pharmacol. 2026 ;17 1833127
    The impact of China's drug regulatory reform on access to orphan drugs: a cross-sectional study of diseases listed in the rare disease catalog.
    Yipeng Lan, Xiaofeng Lin, Zhe Huang, Wang Zan.
       Objective: China released two batches of the Rare Disease Catalog in 2018 and 2023, respectively, listing a total of 207 diseases. This study aims to analyze the accessibility of medications for diseases included in the catalog and assess the impact of drug regulatory reforms on the supply of medications for rare diseases.
    Methods: This study compiled five categories of information on drugs for 207 rare diseases: basic information on drug availability, the number of drug approvals and production capacity, drug development trends, marketing approval efficiency, and medical insurance coverage. Descriptive statistical analysis was employed.
    Results: By the end of 2025, out of 207 rare diseases, 98 (47.3%) had drugs approved in China, with a single company being the exclusive supplier for 37 of these diseases. Between 2015 and 2025, the NMPA approved a total of 2,007 Investigational New Drug (IND) applications and 1,134 New Drug Applications (NDAs) for rare diseases, showing an overall upward trend. Following the publication of the catalog, the median review time for NDA applications for rare disease drugs was reduced by 79 days compared to pre-publication (516 vs. 595, P < 0.001); for drugs eligible for Priority Review and Approval (PRA), the median review time was reduced by 73 days compared to non-PRA drugs (493 vs. 566, P < 0.001). The time difference between the market launches of the same drug in China and the United States has been reduced by 1.52 years (5.53 vs. 4.01, P < 0.001). Of the 263 drugs used to treat 98 rare diseases, 181 were included in the medical insurance coverage, and the time to inclusion in the insurance coverage was reduced by 1.01 years following the publication of the directory (2.09 vs. 1.07, P < 0.001).
    Conclusion: With the release of the rare disease catalog and the advancement of drug regulatory reforms, access to orphan drugs in China has improved. However, more than half of all rare diseases still face the dilemma of having no available treatments. It is recommended that the coordination mechanism between drug regulation and medical insurance be maintained to better meet patients' clinical medication needs.
    Keywords:  China; accessibility of medicines; drug development; drug review and approval; orphan drug; rare disease
    DOI:  https://doi.org/10.3389/fphar.2026.1833127
  16. Int J Mol Sci. 2026 Jun 10. pii: 5275. [Epub ahead of print]27(12):
    Reduced Mitochondrial DNA Copy Number and Telomere Length in Essential Tremor Patients: Evidence from an Age- and Sex-Adjusted Cross-Sectional Case-Control Study.
    Monica Gagliardi, Alessia Felicetti, Radha Procopio, Antonio Augimeri, Costanza Maria Cristiani, Maurizio Morelli, Giuseppe Pedullà, Andrea Quattrone, Grazia Annesi, Aldo Quattrone.
      Essential tremor (ET) is a common movement disorder increasingly recognized as a complex syndrome with neurodegenerative features. While mitochondrial dysfunction and cellular aging are implicated in several neurodegenerative diseases, their role in ET remains unexplored. To investigate mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) in patients with ET and evaluate their potential as biomarkers of mitochondrial dysfunction and biological aging. In this cross-sectional case-control study, 68 ET patients (median age 66 years; 64.7% male) and 62 healthy controls (median age 70 years; 54.8% male) were enrolled. Relative mtDNA-CN and TL were quantified by quantitative PCR, measuring mitochondrial ND1 gene levels and telomere-to-single-copy gene (T/S) ratio, respectively, both normalized to β-actin. Associations with disease status were assessed using age- and sex-adjusted multivariable linear regression on log2-transformed data, with statistical significance defined as p < 0.05 after false discovery rate (FDR)-corrected Wald tests. Receiver operating characteristic (ROC) and effect size (Cohen's d) analyses were performed. ET patients showed significantly reduced mtDNA-CN (β = -2.785, 95% CI -3.700 to -1.869; pFDR = 2.53 × 10-9) and TL (β = -2.073, 95% CI -2.758 to -1.388; pFDR = 3.00 × 10-9), corresponding to ~6.9-fold and ~4.2-fold reductions, respectively. Age- and sex-stratified analyses confirmed consistent reductions, more pronounced in older individuals. Both biomarkers showed good discriminatory performance (mtDNA-CN: AUC = 0.83, 95% CI: 0.75-0.90; TL: AUC = 0.76, 95% CI: 0.68-0.85) and large effect sizes (Cohen's d = |1.192| and |1.058|), respectively. Reduced mtDNA-CN and TL support the involvement of mitochondrial impairment and accelerated cellular aging in ET and may represent accessible peripheral biomarkers and provide a basis for future longitudinal and mechanistic investigations.
    Keywords:  essential tremor; mitochondria; telomere
    DOI:  https://doi.org/10.3390/ijms27125275
  17. Oxid Med Cell Longev. 2026 ;2026(1): e8685788
    Interplay of Mitochondrial Dynamics, Nutrition, and Vitamins: Evidence From Experimental and Human Studies With Implications for Women's Health.
    Kunjal Kiran Pai, Shambhavi Shetye, Rakshith Patil, Shravya Acharya, Kishan S Kulal, Ajeetkumar Patil, Saritha U Kamath.
       BACKGROUND: Nutrition is a key modifiable factor supporting mitochondrial health and is essential for ovarian function and women's health across the life course. From menarche to menopause, mitochondrial efficiency underpins physiological balance. The menopausal transition is particularly critical, as hormonal and neuroendocrine changes are associated with impaired mitochondrial function and increased risk of age-related disorders.
    AIM: This review aimed to systematically review and synthesize the available evidence on mitochondrial function across in vitro, animal, and human studies and to evaluate the potential protective role of vitamins and nutrients in maintaining mitochondrial health, with attention to sex-specific findings.
    METHODS: A systematic search was conducted across multiple electronic databases. Forty-six eligible studies were identified and critically reviewed for evidence on mitochondrial function, sex-based differences, and nutritional influences.
    RESULTS: Mitochondrial dysfunction may contribute to the pathophysiology of age-related disorders, including osteoporosis, cardiovascular disease, neurodegenerative conditions, and cancer. Nutritional factors are crucial for preserving mitochondrial integrity. Vitamins C, E, and D, NAD + precursors such as nicotinamide riboside, coenzyme Q10, MitoQ, fucoxanthin, and cabergoline reduce oxidative stress, enhance mitochondrial biogenesis, support electron transport chain activity and ATP production, and maintain redox balance. These actions promote mitochondrial resilience and cellular energy metabolism. Evidence further indicates that women, particularly during the menopausal transition, exhibit heightened vulnerability to mitochondrial dysfunction, highlighting the relevance of nutrition-based interventions.
    CONCLUSION: Optimizing dietary intake of vitamins, antioxidants, and mitochondrial cofactors is a cost-effective, accessible strategy to support mitochondrial health and reduce age-related disease risk in women.
    Keywords:  mitochondria; nutrition; vitamins; women’s health
    DOI:  https://doi.org/10.1155/omcl/8685788
  18. Medicine (Baltimore). 2026 Jun 19. 105(25): e49417
    Causal associations between mitochondrial DNA copy number and gastrointestinal diseases: A Mendelian randomization study.
    Zheng Wang, Zhiliang Yang, Yun Zhou.
      We conducted a Mendelian randomization (MR) study to examine the associations of mitochondrial DNA copy number (mtDNA-cn) with 27 gastrointestinal diseases (GDs). To investigate the causal relationship between mtDNA-cn and the risk of 27 GDs, a two-sample MR analytic framework was used. A series of quality-control procedures were followed in order to select eligible instrumental variables that were strongly associated with mtDNA-cn. This two-sample MR study employed 2 cohorts of European ancestry with mtDNA-cn genome-wide association study summary statistics: the UK Biobank (395,718 samples) and the combined Cohorts for Heart and Aging Research in Genomic Epidemiology and UK Biobank dataset (465,809 samples). Genetic associations with 27 GDs were obtained from FinnGen and other large consortia. We conducted MR analyses separately in the 2 cohorts, followed by a meta-analysis. The Cochran Q test and MR-Egger intercept test were used to assess heterogeneity, horizontal pleiotropy, and the stability of single-nucleotide polymorphisms in GDs. The results of the discovery cohort showed that mtDNA-cn was significantly associated with ulcerative colitis (UC) after false discovery rate correction, and a suggestive association with an increased risk of diverticular disease of the intestine was noted for genetically predicted mtDNA-cn. However, the validation cohort did not find any causal relationship between mtDNA-cn and 27 GDs. Results from 2 cohorts were combined using the fixed-effect model; in the meta-analysis, the causal associations remained the same as in the discovery cohort. Our findings summarize the role of mtDNA-cn for 27 GDs. Findings may support a causal effect of mtDNA-cn in the development of UC and diverticular disease of the intestine. These findings have implications for mtDNA-cn as a biomarker of UC and diverticular disease in clinical practice.
    Keywords:  Mendelian randomization; gastrointestinal diseases; meta-analysis; mtDNA copy number
    DOI:  https://doi.org/10.1097/MD.0000000000049417
  19. medRxiv. 2026 Jun 08. pii: 2026.06.07.26354811. [Epub ahead of print]
    Multi-ancestry analysis of POLG variants in Parkinson's disease.
    Global Parkinson’s Genetics Program (GP2)
       Introduction: Variants in the polymerase gamma ( POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson's disease (PD); yet, results remain inconclusive.
    Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.
    Methods: We leveraged multi-ancestry genetic data from the Global Parkinson's Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.
    Results: Five PD cases carried potentially biallelic rare pathogenic/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.
    Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG -related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.
    DOI:  https://doi.org/10.64898/2026.06.07.26354811
  20. Biomed Pharmacother. 2026 Jun 26. pii: S0753-3322(26)00735-3. [Epub ahead of print]201 119699
    Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
    Li-Tzu Wang, Han-Ying Jhuang.
      Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
    Keywords:  Clinical trials; Gene therapy; Leber hereditary optic neuropathy; MELAS; Primary mitochondrial disease; Translational medicine; Trial design
    DOI:  https://doi.org/10.1016/j.biopha.2026.119699
  21. Pharmaceutics. 2026 Jun 12. pii: 730. [Epub ahead of print]18(6):
    Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.
    Eva Costanzi, Luca Fontana, Francesca Giroldo, Silvia Coco.
      Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.
    Keywords:  extracellular vesicles; immunomodulation; mesenchymal stromal/stem cells; mitochondrial EVs; neurodegeneration; neuroinflammation; preconditioning
    DOI:  https://doi.org/10.3390/pharmaceutics18060730
  22. Front Public Health. 2026 ;14 1822461
    European Reference Networks as core health structures where referring genetic newborn screening positive infants: an innovative operational research framework.
    Fernanda Fortunato, Rita Selvatici, Jan Kirschner, Stefaan Sansen, Emanuele Agolini, Silvia Ottombrino, Enrico Bertini, Antonio Novelli, Moshe Einhorn, Leslie Matalonga, Sergi Beltran, Ivo G Gut, Alberto M Pereira, Olaf Hiort, Franz Schaefer, Alain Verloes, Ansgar W Lohse, Arthur A M Wilde, Christine Bodemer, Guillaume Jondeau, Hélène Dollfus, Holm Graessner, Irene M J Mathijssen, Ikram L'khssim, Jean-Yves Blay, Luca Sangiorgi, Pierre Fenaux, María Del Mar Mañú Pereira, Victoria Gutiérrez Valle, Marta Mosca, Nicoline Hoogerbrugge, Rene Wijnen, Teresinha Evangelista, Carla D'Angelo, Thomas O F Wagner, Wout F J Feitz, Ruth Ladenstein, Zoltan Dobai, Nico Wulffraat, Nicola Ruperto, Paloma Jara Vega, Cinzia Maria Bellettato, Maurizio Scarpa, Michela Onali, Sébile Tchaicha, Alexis Arzimanoglou, Jun Oh, Dominic Lenz, Birute Tumiene, Aldona Zygmunt, Alessandra Ferlini.
      Rare diseases (RDs), affecting fewer than 5 people per 10,000, present unique challenges to usual care pathways due to their unique characteristics: rarity and large number of disease entities, heterogeneous clinical manifestations and genetic causes, multisystemic involvement, and high complexity of diagnosis and treatment. This complexity often hampers the setting of appropriate pathways of care, which are not easily identifiable by patients and stakeholders. This ultimately leads to significant delays in diagnosis, lack of timely access to RD treatments and profound inequalities across countries. To overcome these difficulties, European Reference Networks (ERNs) were established in 2017 to facilitate patients' referral to expertise and excellent services, aiming to reduce disparities and expedite diagnosis, standard of care, and treatment for people living with rare diseases (PLWRDs). Since 72% of rare diseases are of genetic in origin and mostly affect children, genomic newborn screening (gNBS) offers a powerful tool to overcome diagnostic barriers by providing early and accurate genetic diagnoses for a wide range of treatable pediatric RDs. Several gNBS initiatives have been implemented across Europe and worldwide. Screen4Care (S4C) is an EU-IHI funded research project integrating gNBS with artificial intelligence (AI)-based tools to improve care for PLWRDs in the EU. The project will offer gNBS to up to 18,000 infants using a capture-based panel (TREAT-panel) targeting 245 genes associated with treatable genetic disorders [ClinicalTrials.gov NCT06549218]. Within this framework, an operational pipeline and a comprehensive step-by-step process in collaboration with ERNs were developed to refer gNBS-positive newborns to the appropriate ERN, ensuring timely access to optimal standards of care and available treatments. We suggest that this organisational and structured health model might be adopted by EU Member States (MS), as it provides a defined clinical framework for identifying newborns with RDs at birth and ensuring they receive the correct care, thereby promoting patient-centred and equitable disease management.
    Keywords:  European reference networks (ERNs); genomic newborn screening; healthcare pathways; operational workflow; rare genetic diseases; screen4care; treatable genetic disorders
    DOI:  https://doi.org/10.3389/fpubh.2026.1822461
  23. Antioxidants (Basel). 2026 May 29. pii: 689. [Epub ahead of print]15(6):
    Ginkgo Biloba Extract Ameliorates Age-Related Mitochondrial Deficits in Human iPSCs and Their Derived Neurons and Astrocytes.
    Imane Lejri, Amandine Grimm, Anne Eckert.
      Mitochondrial dysfunction is a central feature of aging, driving bioenergetic decline, increased oxidative stress, and increased vulnerability to neurodegenerative diseases. Human induced pluripotent stem cells (iPSCs) and iPSC-derived neurons provide powerful models to study these processes. Ginkgo biloba extract GBE LI1370 (GBE) has demonstrated antioxidant and mitochondria-protective properties in preclinical models, including improvements in mitochondrial membrane potential, reduction in reactive oxygen species, and enhanced neuronal survival. However, its effects on mitochondrial function in human iPSCs and their differentiated derivatives in the context of aging have not yet been investigated. This study evaluated the mitochondrial protective effects of GBE (100 µg/mL) in an established iPSC-based model of aging and in neurons and astrocytes derived from aged iPSCs. Mitochondrial parameters, including ATP production, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), superoxide levels, and mitochondrial respiration, were assessed. Aged iPSCs exhibited reduced ATP production and MMP, together with increased mtROS and superoxide levels compared to young controls. Astrocytes derived from aged iPSCs also displayed mitochondrial dysfunction. Treatment with GBE for 24 h increased ATP production and MMP, reduced oxidative stress, and improved mitochondrial respiration in both young and aged iPSCs, as well as in aged iPSC-derived neurons and astrocytes. These preliminary donor-based findings support further investigation of GBE-associated mitochondrial responses in human donor-derived cellular models of aging and warrant validation in larger donor cohorts.
    Keywords:  Ginkgo biloba extract; aging; bioenergetics; iPSC-derived astrocytes; iPSC-derived neurons; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15060689
  24. Chin Med J (Engl). 2026 Jun 24.
    Mitochondrial quality control in health and disease: Updates 2026.
    Zhengzhao Liu, Wenbao Hu, Lin Sun, Huafeng Liu.
       ABSTRACT: Mitochondria are central to cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis and life processes. Mitochondrial quality control (MQC) encompasses a complex network of mechanisms-including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial proteostasis, and mitochondrial-derived vesicles-that collectively preserve the structural and functional balance of mitochondria. Recent studies have revealed that dysregulation of MQC is closely associated with a broad spectrum of diseases, such as neurodegenerative disorders, cardiovascular diseases, kidney diseases, metabolic syndrome, and cancers, highlighting its critical role in pathological processes. Despite significant progress in elucidating the molecular regulation of MQC, many aspects of its complexity and multilayered regulatory mechanisms remain unresolved. This review provides a comprehensive overview of the major molecular pathways involved in MQC and their functional alterations under physiological and pathological conditions. It emphasizes the abnormalities of MQC in various diseases and explores potential therapeutic targets. Moreover, integrating the latest research advances, this article discusses emerging treatment strategies aimed at restoring and optimizing MQC, with the goal of offering theoretical insights and clinical translation avenues for future disease prevention and management.
    Keywords:  Cardiovascular disease; Kidney disease; Mitochondria; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Neurodegenerative disease; Therapeutic strategies
    DOI:  https://doi.org/10.1097/CM9.0000000000004169
  25. Front Genet. 2026 ;17 1809097
    Diagnostic yield of long-read sequencing for rare diseases: a systematic review.
    Amal Abdulsalam Ibrahim, Khalid A Fakhro, Atiyeh M Abdallah.
       Background: Nearly half of patients with rare genetic disorders remain undiagnosed, which may in part be due to limitations of current short-read sequencing (SRS) approaches in detecting complex genomic alterations. Long-read whole genome sequencing (lrWGS) technologies can address these limitations through enhanced detection of structural variants (SVs), repetitive regions, and epigenetic changes.
    Methods: To evaluate the diagnostic yield of lrWGS in patients with rare genetic diseases receiving inconclusive or negative results from standard testing, we searched the PubMed, Science Direct, Scopus, and ProQuest databases to July 2025 for studies applying lrWGS to unresolved rare disease cases and reporting diagnostic outcomes. Risk of bias was assessed using the QUADAS-2 tool.
    Results: Nine studies involving 646 previously unresolved cases that underwent lrWGS met the inclusion criteria. Of these, 29 individuals (24 unique diagnoses involving 25 genes) received a definitive diagnosis through lrWGS, a diagnostic yield of 4.5%. SVs accounted for the majority of identified variants (41.67%), followed by combined SV/single-nucleotide variants (20.83%), methylation changes (16.67%), and other variant types (copy number variations, indels, and tandem repeats). Most detected variants were in regions typically inaccessible to short-read whole-exome sequencing (WES). lrWGS also enabled phasing and methylation analysis in a single assay, which was valuable for compound-heterozygosity detection and diagnostic interpretation.
    Conclusion: lrWGS shows clear potential for improving diagnostic rates in previously unresolved rare disease cases, particularly when applied after WES and combined with advanced tools such as phasing and methylation profiling. As technologies evolve and become more accessible, lrWGS may increasingly become a first-tier diagnostic approach, especially in phenotypically complex conditions.
    Systematic Review Registration: https://osf.io/y5azb/overview, identifier 10.17605/OSF.IO/Y5AZB.
    Keywords:  epigenesis; genetic; genetic diseases; genetic variation; high-throughput nucleotide sequencing; inborn; whole genome sequencing
    DOI:  https://doi.org/10.3389/fgene.2026.1809097
  26. Nat Commun. 2026 Jun 23.
    Sex representation in trials relative to indication-specific disease burden in FDA-approved drugs (2015-2023).
    Sophie Zaaijer, Simon C Groen.
      Sex-based disparities in disease burden and therapeutic response motivate efforts to prioritize women's health in drug development. We analyzed 195 drugs across 98 indications approved by the United States Food and Drug Administration (FDA) between 2015 and 2023 to assess whether industry focus and clinical trial enrollment reflect disease prevalence among males and females. Here, we show that therapies for female-predominant indications receive 1.5 times more approvals than male-predominant indications. Additionally, among trials leading to approval, female participation aligns with or exceeds disease prevalence in 67% of cases. Alignment is strongest in oncology, whereas cardiovascular and autoimmune diseases most often under-enroll women, with no improvement over time. We discuss that gains in female enrollment have plateaued and that further progress will require advances in diagnostics, greater use of objective endpoints, and improved tools to assess risks for women of reproductive potential.
    DOI:  https://doi.org/10.1038/s41467-026-74469-z
  27. Adv Kidney Dis Health. 2026 Jan;pii: S2949-8139(26)00028-5. [Epub ahead of print]33(1): 9-14
    After the Diagnosis.
    Anthony J Bleyer, Stanislav Kmoch.
      The diagnosis of a rare genetic disease begins an odyssey toward treatment and cure for patients, clinicians, and researchers. Even though a treatment may not have been identified, there are many ways in which the clinician can help the patient. Information available to patients and their participation in research is dependent on how many individuals have previously been diagnosed with the condition and how much prior research has been conducted. When only a few cases have been reported, information will be limited to case reports, and each newly diagnosed patient is critical to learning about the disease. As more information becomes available, patient foundations form and researchers develop a long-term interest in the condition. In addition to informing the patient about diagnosis, prognosis, and the genetics of the underlying condition, clinicians should also help to guide the patient toward patient foundations and provide information about research participation to help better characterize the condition and find treatments. In rare disease research, each patient is important in providing clinical information as well as genetic and other biological samples for study. Researchers take this information provided by patients, analyze the data, and provide patients information about their condition. As patients and researchers work together, progress in research occurs, eventually leading to a treatment. The clinician, patient, clinical researcher, and basic scientist are all critical to success toward a potential therapy.
    Keywords:  Autosomal dominant tubulointerstitial kidney disease; Kidney; Patient foundations; Rare disease; Rare disease research
    DOI:  https://doi.org/10.1053/j.akdh.2026.02.004
  28. Pediatr Investig. 2026 Jun;10(3): 258-268
    Large-language-models for pediatric diagnosis: Performance evaluation using real-world clinical notes from common and rare cases.
    Cristian Launes, Paula Esteller-Cucala, Marina Alvarez-Estape, Ivan Cano, Rosa Pino, Carla González-Grado, Andrea Aldemira-Liz, Javier Logroño, Carlos Mascías, Juanjo do-Olmo, Julián Isla, Yolima Cossio, Francesc Garcia-Cuyas.
       Importance: Rigorous evaluation of large language models (LLMs) in pediatric diagnosis using authentic clinical presentations remains limited, particularly regarding response consistency and rare disease recognition.
    Objective: To evaluate the diagnostic accuracy, consistency, and clinical usability of LLMs as diagnostic support tools in pediatric medicine compared with human clinicians using real-world cases.
    Methods: This cross-sectional study at Sant Joan de Déu Barcelona Children's Hospital evaluated four LLMs [DxGPT/GPT-4 (0613), Claude-3.5 Sonnet, GPT-4o (0513), and o1-preview] against 78 pediatric clinicians using 50 real clinical cases (25 rare diseases, 25 common conditions) from a single tertiary pediatric center. All cases were presented using Spanish intake-style clinical summaries. Each case was queried three times per LLM and evaluated by clinicians with different experience levels. Performance was assessed using the Top-1 and Top-5 diagnostic accuracy, response consistency (intraclass correlation coefficient), and qualitative evaluation. Extended clinical information was provided for 20 cases to assess the diagnostic efficiency.
    Results: Advanced LLMs significantly outperformed the clinicians in terms of diagnostic accuracy. o1-preview and Claude-3.5 Sonnet achieved mean Top-1 accuracies of 60.0% and 59.0%, respectively, compared to clinicians' 48.2% (odds ratios [ORs]: 2.99 and 2.75, both P < 0.001). Performance advantages were most pronounced for rare diseases, where o1-preview demonstrated 6-fold higher Top-5 diagnostic odds compared to clinicians (ORs: 6.00, P < 0.001). Extended clinical information improved the accuracy of both groups, particularly for rare diseases. Human-Artificial intelligence complementarity analysis revealed 94.3% union accuracy with o1-preview, representing a 10-percentage-point uplift over clinicians alone. Clinicians rated DxGPT favorably (mean, 3.9/5), particularly for rare case support (4.1/5).
    Interpretation: In this proof-of-concept study of a reference care center, newer LLMs outperformed previous models and human clinicians in complex pediatric diagnostics, particularly for rare diseases. These findings support further evaluation as augmentative diagnostic tools in similar settings, with appropriate legal, ethical, and clinical oversight frameworks.
    Keywords:  Artificial intelligence; Diagnostic; Large language models; Pediatric medicine; Rare diseases
    DOI:  https://doi.org/10.1002/ped4.70053
  29. Biomolecules. 2026 May 29. pii: 804. [Epub ahead of print]16(6):
    Mitochondria-Targeting microRNAs (mitomiRs): Potential Mediators of Environmental Mitoepigenetics in Mammalian Spermatogenesis.
    Vanessa Zak, Jonathan LaMarre.
      The field of mitoepigenetics involves the investigation of modifications in mitochondrial DNA (mtDNA), genomic DNA that encodes mitochondrial proteins, and the expression of RNAs that regulate mitochondrial gene expression but do not alter the DNA sequence. This area of research is growing rapidly and has substantial relevance to male mammalian fertility. Among the known mitoepigenetic mechanisms, mitochondrial microRNAs (mitomiRs) have attracted substantial attention due to their potential roles in modulating mitochondrial gene expression in response to environmental stressors. Since many problems with male fertility are known to result from environmental factors, there has been increasing interest in studying epigenetic mechanisms that contribute to male reproductive function. This review explores the current literature regarding different mitoepigenetic mechanisms and their implications for male mammalian fertility, focusing primarily on the known and potential involvement of mitomiRs in model species and humans. Understanding mitoepigenetics may contribute to the development of non-invasive diagnostic biomarkers and individualized therapeutic approaches to male infertility due to their stability in body fluids, tissue specificity, and sensitivity to disease states.
    Keywords:  environmental stress; epigenetics; male fertility; microRNA; mitochondria; mitoepigenetics; spermatogenesis
    DOI:  https://doi.org/10.3390/biom16060804
  30. Adv Exp Med Biol. 2026 ;1514 85-111
    The TOM Complex in the Outer Membrane of Mitochondria: A Supramolecular Assembly for Protein Import.
    Stephan Nussberger, Robin Ghosh, Shuo Wang.
      Currently, there is no comprehensive physical model explaining how unfolded polypeptide chains with diverse characteristics are transported into the mitochondria. On a molecular scale, the kinetics of how transit polypeptides approach, are captured by the protein translocation machinery at the outer mitochondrial membrane, and cross the protein translocation pore to enter the intermembrane space remain unclear. This knowledge gap is primarily due to the lack of dynamic single-molecule data on the "protein-conducting channels" involved in mitochondrial protein translocation. In this chapter, we explore the recently resolved sub-nanometer cryo-EM structures, which are a prerequisite for a fundamental understanding of the translocation mechanism, and our existing knowledge of the mitochondrial two-pore outer membrane protein translocation machinery (TOM complex). Particularly intriguing are recent findings from single-molecule TIRF microscopy indicating that the TOM core complex can function as a mechanosensor, with the pores closing upon interaction with nearby membrane structures. We emphasize novel and unexpected correlations between the structural components of the TOM complexes and their dynamic behavior within the membrane environment.
    Keywords:  Droplet interface bilayer membranes; Electron cryo-microscopy; Mechanosensitivity; Mitochondria; Native mass spectrometry; Protein import; Single-molecule fluorescence microscopy; TOM complex
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_5
  31. Sci Rep. 2026 Jun 20.
    Capsule-enhanced hierarchical vision transformers for rare disease classification from medical images.
    E S Phalguna Krishna, Gowtham Mamidisetti, Sai Srinivas Vellela, Kranthi Kumar Lella, Veeraiah Duggineni, N Balakrishna.
      Automated medical image analysis plays a vital role in rare disease detection, yet existing deep learning models often struggle with severe class imbalance, limited labeled data, and subtle morphological variations. To address these challenges, this paper proposes Swin-CapsuleNet, a hybrid architecture that integrates a hierarchical Swin Transformer with capsule-based representations, tailored for rare disease classification. The framework integrates a Swin Transformer backbone for multi-scale contextual feature extraction with a capsule-based classification head that preserves part-whole spatial relationships through dynamic routing. A class-balanced capsule loss is introduced to improve sensitivity toward under-represented disease categories. Extensive experiments conducted on a multi-center rare disease dataset demonstrate that Swin-CapsuleNet consistently outperforms state-of-the-art CNN, transformer, and capsule-based baselines. The proposed model achieves 94.1% accuracy, a 93.2% F1-score, and an AUC of 0.972, while attaining a macro-F1 of 0.899 for rare disease classes. Ablation studies validate the complementary contributions of hierarchical attention, capsule representations, and the proposed loss function. Furthermore, computational analysis shows that Swin-CapsuleNet offers a favorable balance between performance and efficiency, supporting its applicability in real-world clinical decision-support systems.
    Keywords:  Capsule-enhanced hierarchical vision transformer; Class imbalance; Convolutional neural networks; Medical image analysis; Vector-valued disease prototypes
    DOI:  https://doi.org/10.1038/s41598-026-58326-z
  32. Biochem J. 2026 Jul 08. 483(7): 1253-1280
    Proteolytic coordination of the OXPHOS Life Cycle.
    Nataliia Nechytailo, Karolina Szczepanowska.
      The mitochondrial oxidative phosphorylation (OXPHOS) system consists of multimeric, highly ordered protein complexes critical for energy production and metabolic wiring in the cell. Recent discoveries in mitochondrial proteolysis, facilitated by advances in proteomic approaches, have transformed the view of mitochondrial proteases from a simple quality-control system into a dynamically coordinated network of enzymes that actively shape the status of the OXPHOS machinery. Mapping OXPHOS-associated proteolytic circuits has uncovered specialized functions of individual proteases and identified key interaction sites. The present review outlines how mitochondrial proteases regulate the OXPHOS life cycle: expression, delivery, assembly, long-term maintenance, and disposal of mitochondrial respiratory complexes. We summarize past findings and highlight emerging concepts, including asynchronous OXPHOS turnover, cofactor-driven proteolysis, and bioenergetics-coupled degradation. Progress in these areas will deepen our understanding of how proteases coordinate the OXPHOS life cycle.
    Keywords:  mitochondria; mitochondrial proteases; mitochondrial respiratory complexes; oxidative phosphorylation; regulatory proteolysis; turnover
    DOI:  https://doi.org/10.1042/BCJ20250120
  33. Aging (Albany NY). 2026 Jun 22. 18(1): 719-732
    The multifaceted inducers of cellular senescence.
    Hilah Gal, Valery Krizhanovsky.
      Cellular senescence is a stable form of cell-cycle arrest induced by diverse intrinsic and extrinsic stimuli. While senescence contributes to tumor suppression, wound repair, and placental and embryonic development, the chronic accumulation of senescent cells promotes tissue dysfunction, chronic inflammation, tumorigenesis, and age-related diseases. This review provides a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarizes the molecular mechanisms through which they trigger the senescence program. Although these stimuli differ widely, many converge to core effector pathways, resulting in a stable growth arrest. Understanding the varied stimuli and their underlying mechanisms of senescence induction is crucial for revealing the heterogeneity of senescent cells and developing interventions that modulate senescence during aging and disease.
    Keywords:  aging; cell senescence
    DOI:  https://doi.org/10.18632/aging.206391
  34. Curr Issues Mol Biol. 2026 Jun 11. pii: 612. [Epub ahead of print]48(6):
    Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.
    Feliciana Menna, Stefano Lupo, Laura De Luca, Antonio Baldascino, Enzo Maria Vingolo, Alessandro Meduri.
      Mitochondrial dysfunction and oxidative stress are increasingly recognized as key contributors to the development and progression of retinal degenerative diseases, including age-related macular degeneration and inherited retinal dystrophies. Growing evidence suggests that alterations in mitochondrial function, excessive production of reactive oxygen species, defective mitophagy, and chronic inflammatory responses are closely interconnected processes that contribute to retinal cell damage and degeneration. This review provides an overview of the current understanding of the molecular mechanisms linking mitochondrial dysfunction to retinal degeneration, with particular emphasis on the impact of oxidative stress, mitochondrial quality-control pathways, and inflammatory signaling. Available evidence indicates that mitochondrial DNA damage, impaired bioenergetics, and dysregulated mitochondrial dynamics play a crucial role in the degeneration of photoreceptors and retinal pigment epithelium cells. In turn, oxidative stress further exacerbates mitochondrial impairment, creating a self-sustaining cycle that promotes disease progression. Recent advances have also highlighted the therapeutic potential of targeting mitochondrial pathways. Although several mitochondria-directed strategies have shown encouraging results in experimental models, their translation into clinical practice remains at an early stage. Overall, the available data identify mitochondria as a promising therapeutic target and support the development of precision medicine approaches aimed at preserving retinal function and slowing disease progression in patients with retinal degenerative disorders.
    Keywords:  biomarkers; mitochondrial dysfunction; mitochondrial therapy; mitophagy; oxidative stress; reactive oxygen species; retinal degeneration; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/cimb48060612
  35. Int J Biol Sci. 2026 ;22(11): 6035-6063
    Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.
    Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Kristina Xiao Liang.
      Astrocyte dysfunction plays a pivotal role in the pathogenesis of POLG-related mitochondrial diseases, yet the underlying mechanisms remain poorly understood. Here, we employed human iPSC-derived astrocytes, cortical organoids and astrocyte-neuron co-culture systems to model POLG mutations and investigate astrocyte-mediated neurotoxicity. Single-cell transcriptomic profiling revealed a marked expansion of A1 neurotoxic astrocytes, depletion of A2 neuroprotective astrocytes, and reduction of neuronal populations in POLG organoids. A1 astrocytes exhibited transcriptional signatures of mitochondrial dysfunction, inflammatory signaling (TGF-β, JAK-STAT), impaired neuro-supportive functions, and activation of senescence, autophagy, and proteostasis stress pathways. Co-cultured dopaminergic neurons displayed impaired morphology and widespread transcriptional downregulation of mitotic, cytoskeletal, and synaptic genes, along with activation of inflammatory and ion transport pathways. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) attenuated astrocyte reactivity, reduced IL-6 and CXCL1 secretion, improved neuronal structure and synaptic marker expression, and increased mtDNA copy number and ATP production in POLG astrocytes. Our study identifies NAD⁺ augmentation as a promising strategy to mitigate astrocyte-driven pathology in mitochondrial encephalopathies.
    DOI:  https://doi.org/10.7150/ijbs.119262
  36. Mol Cell Pediatr. 2026 Jun 22. pii: 34. [Epub ahead of print]13(1):
    Cardiomyopathy and mitochondrial encephalomyopathy in a female child associated with a heterozygous X-linked AIFM1 variant.
    Christoph Sandmann, Swathi Gudapati, Johannes A Mayr, Rami Abou Jamra, Alexander Kovacevic, Steffen Syrbe.
       BACKGROUND: AIFM1 encodes the X-linked oxidoreductase 'apoptosis-inducing factor 1, mitochondrial' that mediates caspase-independent programmed cell death and is involved in redox metabolism. To date, cardiac involvement has been reported in four patients with AIFM1 variants, primarily presenting as ventricular hypertrophy, but its clinical course and prognosis remain not well understood.
    METHODS: We report the first affected female with a heterozygous AIFM1 variant who developed infantile-onset mitochondrial encephalomyopathy and cardiomyopathy with initial ventricular hypertrophy, that progressed to left ventricular dilation and chronic heart failure. In addition, we review the available literature on AIFM1-associated cardiomyopathy to contextualize clinical findings.
    RESULTS: Genetic testing identified a heterozygous AIFM1 variant, c.506C > T (p.Pro169Leu), with extremely skewed X-inactivation (98:2) in a female. The patient presented with infantile-onset mitochondrial encephalomyopathy. Echocardiography at 8 months revealed marked left ventricular hypertrophy with preserved systolic function. During follow-up, the cardiac phenotype progressively evolved into dilated cardiomyopathy with systolic dysfunction by 2.5 years of age, necessitating initiation of heart failure therapy.
    CONCLUSIONS: A heterozygous AIFM1 variant can result in disease manifestation in females. The phenotypic spectrum of AIFM1-related disease includes cardiomyopathy, typically characterized by early-onset cardiac hypertrophy that may progress to ventricular dilatation and heart failure. This case highlights the importance of early recognition and careful cardiac monitoring in affected individuals, including female variant carriers.
    Keywords:  Cardiomyopathy; Genetic diseases; Inborn; Mitochondrial Encephalomyopathies; Mitochondrial diseases; Pediatrics; Rare diseases
    DOI:  https://doi.org/10.1186/s40348-026-00246-z
  37. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607
    Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
    Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.
      Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.
    Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2026.117607
  38. Mol Genet Metab. 2026 Jun 18. pii: S1096-7192(26)00473-7. [Epub ahead of print]148(4): 110190
    Ketogenic diet therapy in pyruvate dehydrogenase deficiency: Global clinical practice from literature and survey data.
    Ketogenic Dietitians Research Network
       BACKGROUND: Pyruvate dehydrogenase deficiency (PDHD) is a rare mitochondrial disorder characterized by impaired carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. Ketogenic diet therapy (KDT) is commonly used to bypass defective glucose metabolism; however, evidence guiding clinical practice remains limited.
    OBJECTIVE: To evaluate global clinical practice and published evidence regarding the use of KDT in children and young people with PDHD.
    METHODS: A combined literature review and international clinician survey were conducted. A systematic search identified studies reporting KDT use in PDHD. Two international surveys targeting registered dietitians and medical doctors collected data on clinical practice, diet initiation, monitoring, outcomes, and adverse effects.
    RESULTS: Forty studies describing 129 patients were identified, predominantly case reports or series. Survey responses were obtained from 41 dietitians (142 patients) and 14 physicians (64 patients) across multiple regions. All physician respondents supported referral for KDT at diagnosis regardless of genotype. Classical ketogenic diets were most commonly prescribed, though modified approaches were frequently used in clinical practice to improve feasibility and palatability. Target β-hydroxybutyrate levels typically ranged between 2 and 4 mmol/L, although treatment was frequently individualized. Findings demonstrated improvements in seizure control, motor function, cognition, and quality of life. Adverse effects were primarily gastrointestinal.
    CONCLUSIONS: KDT is a widely used and generally well tolerated therapeutic strategy for PDHD across genotypes and age groups, with reported clinical benefits extending beyond seizure control. Clinical practice demonstrates variability, reflecting the limited high-quality evidence base. Development of standardized but flexible clinical guidelines and further longitudinal studies are needed to optimize patient outcomes.
    Keywords:  Ketogenic diet therapy; Pyruvate dehydrogenase deficiency
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110190
  39. Genome Med. 2026 Jun 26.
    Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases.
    Brian M Schilder, Kitty B Murphy, Hiranyamaya Dash, Yichun Zhang, Robert Gordon-Smith, Jai Chapman, Momoko Otani, Nathan G Skene.
       BACKGROUND: Rare diseases (RDs) are a highly heterogeneous and underserved group of conditions. Most RDs have a strong genetic basis but their causal pathophysiological mechanisms remain poorly understood, limiting the development of targeted therapies.
    METHODS: We systematically characterised the cell type-specific mechanisms underlying all genetically defined RD phenotypes by integrating the Human Phenotype Ontology (HPO) with whole-body single-cell transcriptomic atlases from embryonic, foetal, and adult samples. Associations were validated against orthogonal biomedical knowledge graphs and then prioritised by strength of supporting evidence, clinical severity, and gene-therapy compatibility.
    RESULTS: We identified significant associations between 201 cell types and 9,575/11,028 (86.7%) phenotypes across 8,628 RDs, substantially expanding knowledge of phenotype-cell type links. Prioritisation by severity (e.g. lethality, motor or mental impairment) and gene-therapy compatibility (e.g. cell type specificity, postnatal treatability) identified candidate phenotypes and cell types for therapeutic targeting.
    CONCLUSIONS: We present a scalable, reproducible framework for phenome-wide, cell type-specific mechanism prediction in rare diseases, providing a major step toward systematic therapeutic development for patients across a broad spectrum of serious RDs.
    SOFTWARE AND DATA AVAILABILITY: Interactive web portal: https://neurogenomics-ukdri.dsi.ic.ac.uk/. R packages introduced in this study: KGExplorer (https://github.com/neurogenomics/KGExplorer), HPOExplorer (https://github.com/neurogenomics/HPOExplorer), and MSTExplorer (https://github.com/neurogenomics/MSTExplorer). Manuscript analyses and reproducibility code: https://github.com/neurogenomics/rare_disease_celltyping.
    Keywords:  Cell type specificity; Gene therapy; Human phenotype ontology; Phenotype-cell type associations; Rare disease; Single-cell transcriptomics; Therapeutic target identification
    DOI:  https://doi.org/10.1186/s13073-026-01692-0
  40. Int J Mol Sci. 2026 Jun 08. pii: 5190. [Epub ahead of print]27(12):
    Metabolic Brain Disorders: Prodromes, Symptoms, and Syndromes.
    Janusz Wiesław Błaszczyk.
      Life is a self-organizing and self-sustaining process that involves energy transformation, primarily regulated by the brain. The brain's main structure consists of terminally differentiated, postmitotic, non-replaceable cells, whose proper functioning and longevity depend solely on glucose-based energy metabolism. Glucose serves as the primary substrate for cellular respiration and anaerobic processes, which are essential for maintaining proper neuronal function, homeostasis, and cell repair. Research indicates that brain aging and neurodegenerative changes result from an age-related decline in glucose metabolism, largely due to a deficiency in nicotinamide adenine dinucleotide (NAD). This deficiency is particularly harmful to brain structures that contain neurons with the highest energy demands. The first signs of brain aging typically appear in the hypothalamus, as well as in the GABAergic and glutamatergic structures of the cerebral cortex and subcortical nuclei. Early symptoms of senile brain changes often manifest as systemic metabolic disorders like insulin resistance and type 2 diabetes. These are accompanied by alterations in brain energy metabolism, leading to neurological and psychiatric disorders that correspond to the affected brain regions. Over time, these changes gradually impact the brain's regions with the highest energy consumption. Current clinical studies suggest that early supplementation with NAD precursors may help slow the aging and neurodegeneration processes. However, this protective therapy appears to be less effective once the disease is fully developed.
    Keywords:  aging; brain; energy metabolism; information metabolism; neurodegenerative disorders
    DOI:  https://doi.org/10.3390/ijms27125190
  41. Biosci Trends. 2026 Jun 20.
    Stem cell-derived extracellular vesicles for rare diseases: A clinical‑bottleneck‑to‑mechanism framework for translation.
    Yue Han, Nuo Chen, Peipei Song, Yanling Chen, Wei Tang.
      Rare diseases impose a disproportionate clinical burden, and yet therapeutic progress is hindered by small cohorts, biological heterogeneity, and limited disease-specific options. Stem cell-derived extracellular vesicles (EVs), and especially exosome-enriched products, are emerging as adaptable cell-free therapeutics that preserve key paracrine activities of parent cells while offering improved controllability, engineering flexibility, and potentially lower acute immunogenicity than living-cell products. This review proposes a clinically driven bottleneck-to-mechanism framework for rare-disease translation, matching each disease class to its dominant pathological barrier, mechanism-relevant EV function, route-aware delivery strategy, and measurable potency endpoint. Using this framework, EVs may enable immune circuit rewiring in autoimmune disorders, neuroprotection and toxic-protein clearance in neurodegeneration, osteogenic and matrix-supportive repair in skeletal/connective tissue diseases, and metabolic rescue in lysosomal or mitochondrial disorders. We further highlight a key conceptual distinction between EVs as active biologics and EVs as engineered delivery vehicles. Successful translation will depend on integrating cargo design, surface targeting, biodistribution-aware administration, scalable manufacturing, and quality-by-design control, while anticipating repeat-dose pharmacokinetics/pharmacodynamics (PK/PD), immunogenicity, complement activation, procoagulant risk, impurity control, and off-target organ-accumulation challenges. Multi-omics and artificial intelligence may further refine target selection and precision engineering. Overall, stem cell-derived EVs constitute a versatile platform for treating rare diseases, but clinical success requires closer alignment among mechanism, disease specificity, product definition, and translational endpoints.
    Keywords:  artificial intelligence; cargo engineering; exosomes; extracellular vesicles; mesenchymal stem cells; rare diseases; surface targeting
    DOI:  https://doi.org/10.5582/bst.2026.01150
  42. Clin Nutr ESPEN. 2026 Jun 25. pii: S2405-4577(26)00527-9. [Epub ahead of print] 103430
    A Fat Chance at Neuroprotection: Ketogenic Diet and Parkinson's Disease.
    Gazala Hitawala, Lisa M Shulman.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms that significantly impair patients' quality of life. While pharmacological therapies provide symptomatic relief, no disease-modifying treatments have been conclusively established. In recent years, there has been increasing interest in non-pharmacological interventions, including dietary strategies, for their potential role in symptom management and disease modification. This literature review aims to examine the emerging role of the ketogenic diet (KD) in the management of PD, exploring its potential to alleviate symptoms and impact disease progression. Preliminary evidence suggests that KD may offer symptomatic benefits in PD through mechanisms such as mitochondrial support, anti-inflammatory effects, neuroinflammation, and impacting gut dysbiosis. Studies have shown promising results, particularly for non-motor symptoms such as urinary function, fatigue and cognition, however consistent improvement in motor outcomes has yet to be demonstrated. It should be noted that existing clinical data are derived from small pilot trials (generally n<20) with heterogenous dietary protocols and variable ketone targets, limiting definitive conclusions. While the mechanistic rational and early clinical signals are encouraging, larger and longer duration randomized controlled trials with standardized ketogenic protocols are needed to fully characterize KD's potential in PD management.
    Keywords:  Dietary therapy for Parkinson’s; Ketogenic Diet; Neuroprotection; Nutrition and Parkinson’s; Parkinson Disease
    DOI:  https://doi.org/10.1016/j.clnesp.2026.103430
  43. medRxiv. 2026 Jun 09. pii: 2026.06.07.26355109. [Epub ahead of print]
    STELLAR: A flexible ensemble learning framework integrating rare variants to enhance polygenic risk prediction.
    Tony Chen, Xihao Li, Haoyu Zhang, Rahul Mazumder, Xihong Lin.
      Whole-exome and whole-genome sequencing technology has enabled the discovery of rare genetic variants associated with human health and diseases. However, existing statistical methods used for rare variant association testing are not well-suited for building genetic risk prediction models that jointly incorporate rare and common variants. We propose STELLAR, a flexible ensemble learning-based approach to compute rare variant polygenic risk scores (PRS) using association summary statistics to enhance conventional common variant PRS. Our method combines burden-based and penalty-based rare variant analysis and leverages functional annotation information to prioritize potentially causal variants within the prediction models. In simulation studies, PRS using STELLAR consistently showed the highest prediction accuracy compared to models using common variants alone or rare variant burdens. Applied to UK Biobank whole-exome sequencing data (n=310,831) across eight continuous and five binary traits, STELLAR significantly improved prediction accuracy, refined stratification of individuals at the highest genetic risk beyond common variants, and prioritized biologically relevant genes. STELLAR provides a scalable strategy to incorporate rare variants into PRS in addition to common variants, advancing precision risk prediction and enabling more comprehensive assessment of genetic contributions to complex diseases.
    DOI:  https://doi.org/10.64898/2026.06.07.26355109
  44. Inflammopharmacology. 2026 Jun 22.
    Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.
    Basith Rehman Sathick Batcha, Deevan Paul Amarnath, Devasena Srinivasan, Prakash Ramakrishnan.
      Major neurodegenerative disorders, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are pathologically driven by mitochondrial failure and persistent neuroinflammation. Defects in oxidative phosphorylation, excess Reactive Oxygen Species (ROS), and impaired mitophagy cause an imbalance in neuronal energy and promote the release of mitochondrial Damage-Associated Molecular Patterns (DAMPs) that activate microglial inflammasomes and enhance inflammatory signalling. Current therapeutic strategies have largely targeted individual pathways and have been unable to effectively modulate this interrelated mitochondrial immune axis or achieve efficient delivery to the Central Nervous System (CNS). This review addresses the dual promise of berberine therapy, a biologically active plant alkaloid that enhances mitochondrial production via AMPK/PGC-1α and SIRT1, restores membrane potential, promotes mitophagy, and inhibits NF-κB and NLRP3-mediated inflammation. Nevertheless, this compound's weak solubility, limited bioavailability, and extremely poor Blood-Brain Barrier (BBB) penetration limit its therapeutic application. Encapsulation of berberine in polymeric nanoparticles, including Polyethylene glycol (PEG)-based polymeric nanoparticle systems, offers improved stability, bioavailability, and targeted mitochondrial delivery. An effective method for reducing neuroinflammation and mitochondrial dysfunction is this comprehensive phytochemical nanotechnology technique.
    Keywords:  Berberine; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Phytochemicals; Polymeric nanoparticles
    DOI:  https://doi.org/10.1007/s10787-026-02276-5
  45. Genes (Basel). 2026 May 28. pii: 609. [Epub ahead of print]17(6):
    Methodological Advances in Mitochondrial DNA Analysis for Forensic Genetics.
    Víctor Daniel Carrillo-Rodríguez, Carina Amalinalli Ruiz-Villavicencio, María Teresa Navarro-Romero, Héctor Rangel-Villalobos, Cecilia Martínez-Campos.
      Mitochondrial DNA (mtDNA) analysis is a fundamental tool in forensic genetics, particularly when biological samples exhibit severe degradation or low nuclear DNA content. Its unique biological characteristics, such as a high copy number per cell, strict matrilineal inheritance, and lack of recombination, enable human identification and reconstruction of maternal lineages in complex contexts, including disaster victim identification, historical cases, and missing persons investigations. This narrative review examines contemporary methodological approaches for investigating the human mitogenome. We discuss recent advancements in extraction and enrichment techniques, emphasizing their efficacy in reducing the interference of nuclear mitochondrial DNA sequences (NUMTs) and enhancing the recovery of informative fragments. Moreover, the shift from traditional Sanger sequencing to Massive Parallel Sequencing (MPS) is examined, as MPS has markedly enhanced the sensitivity and capability of contemporary methods to detect low-frequency heteroplasmies. Additionally, the advent of Third-Generation Sequencing (TGS), exemplified by nanopore platforms, is evaluated, which facilitates the reading of full-length native molecules without the biases introduced by PCR amplification. Despite the interpretive challenges posed by heteroplasmy, contamination, and limitations in population databases, ongoing methodological advances in mitochondrial DNA analysis continue to strengthen its reliability and expand its potential in forensic genetics.
    Keywords:  forensic genetics; human identification; massive parallel sequencing; mitochondrial DNA; third-generation sequencing (TGS)
    DOI:  https://doi.org/10.3390/genes17060609
  46. Nat Neurosci. 2026 Jun 26.
    The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
    Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.
      Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02320-1
  47. BMC Bioinformatics. 2026 Jun 20.
    GPU-accelerated MitoGraph for high-throughput three-dimensional mitochondrial morphology analysis.
    Siddharth Nahar, Zichen Wang, Eric Arkfeld, Gillian McMahon, Hiroyuki Hakozaki, Johannes Schöneberg.
      MitoGraph is a widely used tool for the automated segmentation of mitochondrial networks in three-dimensional (3D) fluorescence microscopy. However, the emergence of advanced live-cell microscopes such as lattice light-sheet microscopy (LLSM) has produced massive four-dimensional (4D, 3D+time) datasets that highlight a critical bottleneck: current CPU-based implementations are computationally prohibitive, often requiring days or weeks to process. To address this limitation, we developed MitoGraph-GPU, a Python-based GPU implementation that accelerates the dominant filtering steps by vectorizing Hessian/eigenvalue and vesselness computations using CuPy, and streamlines network processing with faster skeletonization and topology analysis. Tested across budding yeast and human lung organoid datasets, MitoGraph-GPU achieves up to 11× speedup in yeast cells and 30× speedup in per-frame segmentation of lung cells. Segmentation fidelity is preserved, with  ~99.9% agreement in maximum intensity projections of segmented images, and minimal differences in downstream measurements. Critically, this throughput enables practical analysis of large 4D datasets : in an LLSM organoid use case (10 movies, 60 frames, ~ 50 cells per movie), total processing time decreases from ~ 500 h on CPU to ~ 20 h on GPU (25× faster). By producing accurate mitochondrial surfaces and skeletons, MitoGraph-GPU can serve as an efficient segmentation module for downstream mitochondrial tracking and analyses, enabling scalable high-throughput 4D mitochondrial phenotyping.
    Keywords:  Fluorescence microscopy; GPU acceleration; Image processing; Image segmentation; Mitochondria; Network analysis
    DOI:  https://doi.org/10.1186/s12859-026-06441-z
  48. Nucleic Acids Res. 2026 Jun 22. pii: gkag648. [Epub ahead of print]54(12):
    Persistence of large mtDNA rearrangements linked to premature aging in Pol γ exonuclease-deficient mice.
    Shilan Wu, Scott A Lujan, Adam B Burkholder, Nadee Nissanka, Matthew J Longley, Piotr Mieczkowski, Thomas A Kunkel, Carlos T Moraes, William C Copeland.
      Mitochondrial DNA (mtDNA) mutations are hallmarks of aging. mtDNA in all opisthokonts is replicated exclusively by DNA Polymerase γ (Pol γ; encoded by POLG). PolgD257A/D257A mice, lacking Pol γ exonuclease proofreading (exo-), exhibit premature aging and higher mtDNA mutation rates than Polgwt/wt (exo+) mice. Using short-read sequencing and the ultra-sensitive LostArc indel-junction detection pipeline, we analyzed mtDNA from exo- and exo+ mice across 10 tissues. Indel-junction frequency, endpoint sequence context, and inferred indel size varied systematically by tissue and exonuclease state. Exo- tissues, especially post-mitotic tissues, evidenced exceptionally high burdens of mtDNA large indels (mtDNALIs). These create covalently closed, circular, double-stranded mtDNA that persists despite often lacking replication origins. This suggests limited removal of aberrant circular double-stranded DNA, particularly in post-mitotic tissues. mtDNALI endpoint sequence contexts in exo+ and exo- tissues mimic those in young and elderly human muscle and are dominated by sequence-dependent and -independent indel mechanisms, respectively. Long-read sequencing recapitulated short-read junction patterns, including endpoint concentration near the 7S DNA 3' end, but also revealed mtDNA circles with multiple mtDNALIs, including deletions and duplications. Together, these results implicate accumulation of mtDNALIs, compounded by insufficient mechanisms for eliminating closed circular aberrant mtDNA, as contributing to the premature aging phenotype.
    DOI:  https://doi.org/10.1093/nar/gkag648
  49. Int J Mol Sci. 2026 Jun 11. pii: 5285. [Epub ahead of print]27(12):
    Circulating Cell-Free DNA in Psychiatric Disorders: Current Evidence, Inflammation-Based Stratification, and Future Perspectives.
    Chiara Galbiati, Erika Vitali, Cristian Bonvicini, Roberta Ghidoni, Annamaria Cattaneo.
      Psychiatric disorders represent a leading cause of disability worldwide and are characterized by substantial biological and therapeutic heterogeneity. Despite significant research efforts, peripheral biomarkers capable of guiding diagnosis, patient stratification, and personalized treatment selection are still lacking. Circulating cell-free DNA (cfDNA) has recently emerged as a promising candidate biomarker, as it may integrate signals of cellular damage, apoptotic activity, and immune activation across multiple tissues. Beyond its role as a marker, cfDNA may also actively contribute to disease processes by functioning as a damage-associated molecular pattern (DAMP), thereby perpetuating inflammatory signaling. The mitochondrial component of cfDNA (cf-mtDNA), which also possesses strong immunostimulatory properties, represents a particularly sensitive indicator of mitochondrial vulnerability to stress. In this context, the present review aims to synthesize the most recent evidence on cfDNA and cf-mtDNA in major psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). Specifically, we examine their association with psychological stress exposure and childhood trauma, as well as their involvement in inflammation-related pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Available evidence suggests that alterations in cfDNA may be present in subgroups of patients with MDD, BD, and SCZ. However, findings remain heterogeneous and sometimes contradictory, partly due to methodological limitations, including the lack of standardized analytical protocols and insufficient control for potential confounders. Nevertheless, cfDNA holds promise as a tool for inflammation-based patient stratification and for informing personalized therapeutic strategies. Future research directions include the integration of cfDNA within multi-omics frameworks, the analysis of cfDNA methylation profiles to infer tissue of origin, and the exploration of pharmacological strategies aimed at modulating cfDNA as a potential therapeutic target.
    Keywords:  cell-free DNAs; inflammation; mitochondrial cell-free DNAs; psychiatric disorders; stress
    DOI:  https://doi.org/10.3390/ijms27125285
  50. Phytother Res. 2026 Jun 25.
    Correction to "Shenlian Extract Decreases Mitochondrial Autophagy to Regulate Mitochondrial Function in Microvascular to Alleviate Coronary Artery No-Reflow".
      
    DOI:  https://doi.org/10.1002/ptr.70399
  51. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731205. [Epub ahead of print]
    Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
    Austin K Murchison, Julia C Heiby, Hansen Tao, Matthew J Matrongolo, Alessandro Ori, Monther Abu-Remaileh.
      Zinc is an essential structural and enzymatic cofactor for roughly 10% of proteins, including transcription factors, metabolic enzymes, and cytoskeletal components. It also supports critical functions across organelles such as gene regulation in the nucleus, protein folding in the endoplasmic reticulum, and energy production and antioxidant defense in mitochondria. Despite these indispensable roles, the cellular mechanism that recycles zinc to maintain homeostasis during zinc deficiency remains poorly understood. Here, we identify a biphasic response to zinc limitation, which involves the rapid degradation of the zinc-storing metallothionein followed by the degradation, in an autophagy-dependent manner, of other zinc-binding proteins. We show that metallothionein is rapidly imported into the mitochondria to be degraded by the mitoprotease LONP1. Zinc starvation leads to severe mitochondrial dysfunction and metallothionein degradation allows local zinc release to alleviate nutrient stress. Our results reveal a non-canonical, mitochondria-mediated degradation pathway for a nutrient-storing protein that mobilizes zinc locally to maintain metabolic homeostasis and establish mitochondria as active hubs for nutrient recycling.
    DOI:  https://doi.org/10.64898/2026.06.09.731205
  52. Sci Transl Med. 2026 Jun 24. 18(855): eadz4172
    AI-CURA, an automated LLM workflow for high-accuracy genetic variant classification.
    Wei Ma, Grace Fong, Joe Lai, Heidi Wu, Shirley Pik Ying Hue, Dingge Ying, Lijuan Chen, Wenshu Tang, Christopher Preusch, Annie Tsz Wai Chu, Brian Hon Yin Chung.
      Large language models (LLMs) have been extensively tested for incorporation into medical applications in recent years; however, their potential in clinical genetics, particularly in diagnosing rare diseases, remains underexplored. Recent advancements in LLMs have improved their reasoning capabilities and transparency, facilitating enhancements in clinical workflow designs. In this study, we developed AI-CURA, a framework that nearly fully automates genetic variant classification according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines and Clinical Genome Resource (ClinGen) recommendations. The framework integrates evidence assessment for non-literature-based criteria, which can be automated using standard bioinformatic tools, with a separate LLM-supported assessment of literature-based evidence. Two state-of-the-art LLMs, DeepSeek-R1 and o3-mini-high, were tested for their performance in summarizing literature-derived evidence relevant to variant classification. We demonstrated that through careful prompt engineering and creation of ACMG-rule-specific knowledgebases, DeepSeek-R1 outperformed o3-mini-high and achieved high sensitivity and 100% specificity in interpreting ACMG rules that require understanding literature-based evidence. In further testing with 150 variants curated by ClinGen experts, DeepSeek-R1 showed high concordance with human curators in final diagnosis. Last, we showed that AI-CURA can also be used for classification reanalysis using 150 ClinVar variants with conflicting interpretations. Our study provides an LLM framework capable of automated variant classification in the diagnosis of genetic diseases and variant reanalysis.
    DOI:  https://doi.org/10.1126/scitranslmed.adz4172
  53. Front Immunol. 2026 ;17 1852236
    Mitochondria: from powerhouses of cells to hubs in antitumor immunity.
    Xiaofeng Li, Yanfeng Shi, Yan Zhao, Gengjun Zhu, Lifang Jin.
      While immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies constitute the cornerstone of current immunotherapy, their efficacy is often limited by, most notably, the immunosuppressive tumor microenvironment. Recently, mitochondria are recognized as pivotal metabolic-immune hubs that critically support tumor progression, metastasis, and immune evasion. However, this insight has not yet translated into a clear understanding of the underlying mechanisms or their therapeutic potential. This review summarizes the role of mitochondria in cellular metabolic regulation, with a focus on mitochondrial-mediated metabolic reprogramming in cancer and immune cells within the tumor microenvironment. We then discuss therapeutic opportunities to potentiate antitumor immunity by targeting mitochondrial reprogramming in cancer and CAR-T cells. Finally, we offer a forward-looking perspective on emerging mitochondria-targeted strategies, such as mitochondrial vaccines, precise mtDNA editing, and engineered mitochondrial transplantation.
    Keywords:  CAR-T; antitumor immunity; metabolic reprogramming; mitochondria; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1852236
  54. Int J Biol Sci. 2026 ;22(11): 5706-5734
    Copper-Iron Cell Death Axis: Mechanistic Crosstalk, Disease Implications and an Integrated Metallo-Redox-Metabolic Framework.
    HaoQi Huang, YuLu Chen, Yi Lu, ZiLong Yuan, Ahmed Zahoor, LiPing Ren, YuanYuan Luo, BaoCai Zhong, Jian Huang, Hui Chen, Lin Ning.
      Cuproptosis and ferroptosis are two major forms of metal-dependent cell death, characterized by mitochondrial proteotoxicity and lipid peroxidation, respectively, and are broadly implicated in diverse disease contexts. Here, by integrating mechanistic, biological, and disease-associated evidence, we propose the metal-metabolism-redox vulnerability axis, which describes cellular states under metal stress as a continuous space defined by metal homeostasis, mitochondrial metabolism, and redox balance. Within this space, cuproptosis and ferroptosis correspond to distinct execution regions rather than independent processes. Building on this concept, we further establish a metallo-redox-metabolic framework to explain how key state variables and their coupling relationships determine execution bias and drive dynamic transitions between death modalities. This framework reframes metal-dependent cell death as a state-driven system rather than a collection of discrete pathways and provides a unified perspective for understanding its roles in complex diseases. In addition, we outline predictive and testable hypotheses and highlight the importance of multi-omics integration and artificial intelligence based modeling in capturing cellular state and enabling dynamic prediction. Collectively, this work provides a conceptual foundation for understanding metal-driven cell fate decisions and for developing state-oriented therapeutic strategies.
    Keywords:  bioinformatics; cuproptosis; ferroptosis; metal-dependent programmed cell death; metallo-redox-metabolic framework
    DOI:  https://doi.org/10.7150/ijbs.132221
  55. Commun Biol. 2026 Jun 23.
    A large-scale human plasma metabolite atlas from over 380,000 participants.
    Zhirong Li, Yating Miao, Lina Jin, Yanan Ma, Xinyao Zhang.
      Large-scale metabolomics enables systematic profiling of circulating small-molecule metabolites and provides an integrative view of genetic, environmental, lifestyle, and microbial influences on human health, yet comprehensive evidence linking metabolites to diverse traits, diseases, comorbidity, prediction, and causality remains limited. Here, we analyze 251 Nuclear magnetic resonance (NMR)-derived plasma metabolites in 212,751 UK Biobank participants, with independent validation in 177,013 individuals from a newly released data wave. Testing across 884 health-related traits, 722 prevalent diseases, and 1137 incident diseases using multivariable regression and stringent Bonferroni correction, we identified 67,505 metabolite-trait, 21,982 metabolite-prevalent disease, and 41,214 metabolite-incident disease associations, with replication rates of 76.1%, 83.3%, and 74.0%, respectively. Associations were most concentrated in endocrine, metabolic, and circulatory diseases. Unsupervised clustering of disease-metabolite profiles revealed 10 and 12 disease clusters (for prevalent and incident diseases, respectively) that span International Classification of Diseases (ICD)-10 chapters yet share convergent metabolomic signatures, providing a metabolic basis for clinical comorbidity. Metabolite-based predictive models showed stronger performance for short-term than long-term outcomes, with creatinine as the most frequently selected predictor across prevalent disease models. Bidirectional Mendelian randomisation (MR) identified 61 putative metabolite-to-disease causal effects and 558 disease-driven metabolic alterations. This study provides a systematically validated plasma metabolomic atlas (https://net-matebolic.vercel.app/) linking metabolites with human traits and diseases, offering insights into comorbidity, risk prediction, and potential causal pathways.
    DOI:  https://doi.org/10.1038/s42003-026-10505-4
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