bims-polgdi Biomed News
on POLG disease
Issue of 2026–08–16
fifty papers selected by
Luca Bolliger, lxBio
  1. Structural and single-molecule insights into the core human mitochondrial DNA replisome.
  2. A Mechanism-Centered Text-Mining Landscape of Mitochondrial Bioenergetics and Signaling in Disease Research.
  3. The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
  4. Tunnel traffic: Import stress induces bidirectional mitochondrial transfer between cells.
  5. Oxidative Damage Induced Disruption of Mitochondrial Quality Control Underlying Abnormal Energy Metabolism in Peripheral Leukocytes of Schizophrenia Patients.
  6. Exploring Heteroplasmic Variants in mtDNA: Insights from Single-Cell Transcriptomics.
  7. A call for principle-based acceptance of synthetic patients: establishing the AI-driven foundation for regulatory submissions.
  8. Rebalancing innovation, affordability, and access for orphan drugs in the European Union.
  9. Mitochondrial metabolic reprogramming at the interface of chemoresistance and immune-cold tumor states.
  10. Redox Molecules in Aging and Neurodegenerative Disorders.
  11. Alterations of actin in aging.
  12. Shifting the Balance: Mitochondrial Heteroplasmy as a Driver of Cardiac Disease.
  13. Investigating POLG-driven modulation of cancer stemness: a pilot study in breast cancer cells.
  14. Cardiolipin as a Signaling Hub: Evolutionary Conservation and Programmable Platforms Coupling Mitochondrial Stress to Cell Fate.
  15. Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
  16. Self-reported perspective in rare genetic diseases: a systematic review of patient-reported outcome measures classified using the international classification of functioning, disability and health framework.
  17. Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.
  18. Awareness and perceptions of patient and public involvement in rare disease research in Japan: the role of patient advocacy groups and family members.
  19. Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.
  20. Mitochondria-Targeted Natural-Derived Compounds in Cellular Senescence: Mechanisms, Therapeutic Potential, and Future Directions.
  21. Umbilical cord-derived mitochondrial transplantation restores tendon structure and function in a preclinical model of achilles tendinopathy.
  22. Altered Mitochondrial Base Excision Repair and Mitochondrial DNA Instability in Peripheral Leukocytes of Patients with MASLD.
  23. Gene Editing, Peroxisomal Disorders, and Treatments for Rare Disease.
  24. Childhood-onset neurodegeneration and brain atrophy: defining UBTF-related developmental regression and progressive ataxia.
  25. A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization.
  26. Succinate drives macrophage inflammation by promoting GPR91 mitochondrial signaling in rheumatoid arthritis.
  27. Simulated Microgravity Induced Mesenchymal Stem Cell Senescence via the Activation of Cytosolic mtDNA-cGAS-STING Axis.
  28. Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.
  29. Extracellular Vesicles in Cardiovascular Disease: Intercellular Signaling, Liquid Biopsy Biomarkers, and Therapeutic Translation.
  30. Activation of a TFAM-Dependent Mitochondrial Translational Axis Drives Oxidative Metabolism in Grade 2 Meningiomas.
  31. Mitochondrial hOGG1-2a overexpression sensitizes HeLaS3 cells to oxidative stress, accompanied by mitochondrial dysfunction and reduced mtDNA integrity.
  32. Clinical and Economic Burden of Diseases with Accelerated Approval Therapies: Evidence of Unmet Patient Need.
  33. Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
  34. Five-year Incidence Trends and the Status of Major Rare Diseases in 2023 in the 「Annual Report on the Rare Disease Patients in Korea」.
  35. Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.
  36. Methionine tuning for health without frailty.
  37. Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.
  38. Measuring treatment satisfaction in rare diseases: challenges and opportunities for hospital pharmacy.
  39. Mitochondrial tRNA-derived fragments as candidate metastasis-modifying RNA.
  40. Rare AFG3L2 and POLG Variants Suggest a Role for Mitochondrial Dysfunction in Enteric Neuronal Vulnerability in Idiopathic Achalasia.
  41. Mapping artificial intelligence in problem-based and case-based medical education: a bibliometric analysis (2019-2026).
  42. Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia.
  43. Mitochondrial RNA polyadenylation: Defining RNA fate through 3' end regulation.
  44. Decentralized rare disease studies in Germany: first results and hurdles of secondary use of patient data.
  45. Regression, Ataxia, and Nystagmus in a Toddler: Unraveling a Rare Neurodegenerative Disorder.
  46. Regulatory Research Priorities for AI Use in the Medicine Lifecycle: A European Perspective with Global Relevance.
  47. Burden of fatigue or pruritus in patients with primary biliary cholangitis: a United States matched case-control study.
  48. Circadian Disruption Is Associated with Elevated Whole-Semen mtDNA Copy Number and Implicates CRY1 as a Candidate Regulator in Humans and Mice.
  49. Editorial: Psychiatric comorbidities of neurogenetic and neurodegenerative diseases.
  50. Targeting Mitochondria for Postoperative Cognitive Dysfunction: From Mechanisms to Therapeutics.
  1. Biochem J. 2026 Sep 02. 483(9): 1635-1651
    Structural and single-molecule insights into the core human mitochondrial DNA replisome.
    Ismael Plaza-G A, Samuel Miguez-Amil, Allison M Hayes, Grzegorz L Ciesielski, Rafael Fernandez-Leiro, Borja Ibarra.
      Replication of human mitochondrial DNA (mtDNA) is essential for the maintenance of oxidative phosphorylation and cellular energy homeostasis. Impairment of this process leads to mtDNA deletions, depletion, and point mutations that underlie a broad spectrum of mitochondrial diseases, as well as contributing to neurodegeneration, aging, and cancer. The core human mitochondrial replisome, composed of DNA polymerase γ (Polγ), the replicative helicase Twinkle, and the mitochondrial single-stranded DNA-binding protein (mtSSB), is the main complex responsible for replicating the mitochondrial genome through a highly coordinated yet still incompletely understood mechanism. Mutations in the nuclear genes encoding these proteins represent the most common cause of inherited disorders affecting mtDNA maintenance, underscoring the importance of understanding their coordinated molecular function. Recent advances in cryo-electron microscopy and single-molecule approaches have provided unprecedented insight into the structural organization and dynamic operation of the core components of the mitochondrial replisome. These complementary methods are establishing a quantitative mechanistic framework for understanding how the mitochondrial replisome initiates, progresses, and regulates the replication of the light and heavy strands of mtDNA. In the present review, we integrate recent structural and single-molecule findings to describe the mechanisms governing the activity of Polγ, Twinkle, and mtSSB at the mitochondrial replication fork, and discuss remaining challenges toward reconstructing a complete mechanistic model of human mtDNA replication.
    Keywords:  DNA replication; mitochondria; protein structure; single-molecule
    DOI:  https://doi.org/10.1042/BCJ20260373
  2. Int J Mol Sci. 2026 Jul 23. pii: 6577. [Epub ahead of print]27(15):
    A Mechanism-Centered Text-Mining Landscape of Mitochondrial Bioenergetics and Signaling in Disease Research.
    Harun Yonar, Furkan Çağrı Beşoluk, Tuğba Melike Parlak.
      Mitochondria are increasingly recognized as integrated bioenergetic and signaling hubs across disease contexts, but the rapidly expanding literature remains fragmented across mechanisms, diseases, and analytical vocabularies. This study mapped the disease-oriented literature on mitochondrial bioenergetics and signaling from 2014 to 2025 using a mechanism-centered text-mining framework integrating dictionary-based annotation and topic modeling. Records retrieved from Web of Science, Scopus, and PubMed were harmonized into a final corpus of 166,462 title-abstract records. Dictionary-based annotation was used to identify disease and mitochondrial mechanism signals, followed by disease-mechanism co-occurrence, lift-based enrichment, exploratory drug/compound annotation, non-negative matrix factorization (NMF), and structural topic modeling (STM). Publication output increased approximately 2.6-fold over the study period. The literature was organized around a central mechanistic backbone involving ROS/redox biology, cell death pathways, bioenergetics/OXPHOS, mitochondrial dysfunction/homeostasis, and quality-control processes. Cancer, cardiometabolic/metabolic disease, and neurodegeneration/neurological injury were the dominant disease contexts. Enrichment analysis revealed disease-characteristic mitochondrial signatures, while NMF identified a 20-topic thematic structure and STM showed increasing emphasis on mitochondrial dysfunction, immune-inflammatory signaling, omics-based prognostic signatures, therapeutic delivery systems, and cancer progression/resistance. Overall, mitochondrial disease research is shifting toward an integrated, application-oriented framework in which mitochondria are positioned as bioenergetic, signaling, immune-regulatory, and therapeutic-response hubs.
    Keywords:  disease–mechanism co-occurrence; mitochondrial bioenergetics; mitochondrial dysfunction; mitochondrial therapeutics; non-negative matrix factorization; oxidative stress; structural topic modeling; text mining
    DOI:  https://doi.org/10.3390/ijms27156577
  3. Cells. 2026 Jul 29. pii: 1371. [Epub ahead of print]15(15):
    The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
    Elena D Avdonina, Sergey I Kutsev, Aleksandr V Shestopalov.
      Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
    Keywords:  autophagy; fatty acid oxidation disorders; mitochondrial diseases; mitophagy; selective autophagy
    DOI:  https://doi.org/10.3390/cells15151371
  4. J Cell Biol. 2026 Sep 07. pii: e202607143. [Epub ahead of print]225(9):
    Tunnel traffic: Import stress induces bidirectional mitochondrial transfer between cells.
    Konstanze F Winklhofer, Johannes M Herrmann.
      Stressed cells can exchange mitochondria through intercellular tunneling nanotubes. In this issue of the JCB, Glover et al. (https://doi.org/10.1083/jcb.202511211) describe two functionally different tunnels: one for exporting dysfunctional mitochondria and another for retrieving respiration-active healthy mitochondria.
    DOI:  https://doi.org/10.1083/jcb.202607143
  5. Schizophr Bull Open. 2026 ;7(1): sgag029
    Oxidative Damage Induced Disruption of Mitochondrial Quality Control Underlying Abnormal Energy Metabolism in Peripheral Leukocytes of Schizophrenia Patients.
    Shuhui Li, Wenli Zhu, Jie Jiang, Yangying Bu, Qian Wang, Minghui Li, Dandan Wang, Yan Gao, Jinfeng Wang, Tianqi Wang, Xiaowen Hu, Chunling Wan.
       Background and Hypothesis: Mitochondrial dysfunction is increasingly implicated in schizophrenia (SZ) pathogenesis. To maintain mitochondrial homeostasis under cellular stress, a sophisticated mitochondrial quality control (MQC) mechanism has developed, encompassing mitochondrial biogenesis, dynamics, and mitophagy.
    Study Design: This study systematically evaluated MQC in peripheral leukocytes of 42 SZ patients and 43 healthy controls through morphological analysis, MQC gene expressions, mitochondrial DNA (mtDNA) maintenance, and oxidative damage. Besides, we validated the regulatory effects of oxidative stress on MQC in vitro using a neuronal model treated with hydrogen peroxide.
    Study Results: We observed mitochondrial fragmentation in SZ, characterized by increased organelle numbers with reduced sizes. This was supported by imbalanced MQC, with expression of biogenesis-related genes SIRT1 and TFAM upregulated (P = .008 and 0.027, respectively), and mitophagy receptor gene PHB2 suppressed (P = .041), indicating enhanced biogenesis but impaired mitophagy. Despite enhanced biogenesis, mtDNA copy number was lower (P < .001) with more oxidative damage (P = .037). Furthermore, we discovered deficits in antioxidant capacity, including reduced coenzyme Q10 levels and superoxide dismutase (SOD) activity, with SOD decline correlating with mtDNA depletion. This suggests redox imbalance contributes to MQC dysregulation, supported by findings from an oxidation-damaged neuronal model. Moreover, disrupted MQC functionally impaired energy metabolism, reflected by downregulated NDUFV1 expression (P = .031) and increased lactate-to-pyruvate ratios (P < .001).
    Conclusions: Our findings demonstrated MQC imbalance in SZ, manifested as mitochondrial fragmentation and mtDNA depletion, probably resulted from oxidative damage. These disruptions may underlie the energy metabolism abnormalities in SZ.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitophagy; mtDNA copy number; oxidative stress
    DOI:  https://doi.org/10.1093/schizbullopen/sgag029
  6. Cells. 2026 Aug 03. pii: 1403. [Epub ahead of print]15(15):
    Exploring Heteroplasmic Variants in mtDNA: Insights from Single-Cell Transcriptomics.
    Marco Barresi, Ivano Di Meo, Alessia Nasca, Eleonora Lamantea, Andrea Legati, Daniele Ghezzi.
      Mitochondrial DNA (mtDNA) heteroplasmy, which is the coexistence of wild-type and mutant mtDNA variants within the same cell, plays a critical role in modulating cellular phenotypes, disease severity, and penetrance. Bulk RNA sequencing cannot detect cell-to-cell heteroplasmy variability, limiting our understanding of the pathological mechanisms of mtDNA variants. In this study, we leveraged single-cell RNA sequencing (scRNA-seq) combined with a robust bioinformatics pipeline to characterize mtDNA heteroplasmy. We employed four fibroblast lines from patients harboring heteroplasmic mtDNA pathogenic variants in genes encoding respiratory complex I subunits. While RNA heteroplasmy corresponded to DNA-based measurements at the bulk level, single-cell analysis uncovered a diverged distribution in three out of four lines: most cells had near-homoplasmic (wild-type or mutant) mtDNA, with few cells showing intermediate levels. Furthermore, we found that high mutation levels correlate with transcriptional profile changes, although these responses were highly sample-specific, suggesting that the nuclear background and cellular context critically influence mitochondrial dysfunction and compensatory mechanisms. Our findings highlight the potential of single-cell technologies to better understand the complex link between mtDNA genetic diversity and mitochondrial phenotypic variability and to study crucial aspects of mitochondrial biology and pathology, such as clonal dynamics, at single-cell resolution.
    Keywords:  heteroplasmy; mitochondrial DNA; mtDNA variant; single-cell transcriptomics
    DOI:  https://doi.org/10.3390/cells15151403
  7. Front Digit Health. 2026 ;8 1833779
    A call for principle-based acceptance of synthetic patients: establishing the AI-driven foundation for regulatory submissions.
    Jordi Guitart.
      The pharmaceutical industry stands at the precipice of an AI-driven data revolution, with synthetic patients emerging as a transformative tool to accelerate drug discovery and development while enhancing patient privacy. However, a critical regulatory gap persists: the absence of a standardized basis from leading regulatory bodies for accepting AI-generated patient populations as evidence in regulatory submissions. This manuscript addresses this void by proposing five foundational principles-Representativeness, Utility, Robustness, Privacy Preservation, and Transparency-anchored by the "Fit for Purpose" philosophy. We introduce the operational concept of a "Technical Validation Playbook" to facilitate the first wave of regulatory acceptances for synthetic patient data. We further outline actionable recommendations for regulatory agencies and pharmaceutical sponsors to advance the acceptance of synthetic patient populations through existing qualification and scientific advice mechanisms. By establishing a proactive, principle-based approach, this framework aims to catalyze regulatory-industry alignment and unlock the transformative potential of synthetic patients, particularly for populations with unmet medical needs such as rare diseases where traditional placebo-controlled trials face insurmountable ethical and recruitment challenges.
    Keywords:  GANs; VAEs; clinical trials; drug development; generative AI; rare diseases; regulatory framework; synthetic patient data
    DOI:  https://doi.org/10.3389/fdgth.2026.1833779
  8. Lancet Reg Health Eur. 2026 Sep;68 101778
    Rebalancing innovation, affordability, and access for orphan drugs in the European Union.
    Hilde Stevens, Georges Siotis, Micael Castanheira, Mathias Dewatripont, Sanae Akodad, Sam Daems, Alain Fischer, Michel Goldman.
      Orphan drug policy in the European Union faces a double price-and-innovation gap: a small fraction of rare diseases receive important resources while the overwhelming majority are under- or un-researched, leaving most rare disease patients facing high unmet medical needs. The European Commission's reform proposals, notably the Pharma Package and the European Biotech Act, seek to rebalance incentives by adjusting market exclusivity. We argue that, while these reforms move in the right direction, they are insufficient to foster meaningful innovation while safeguarding affordability, and that a broader, more structural approach is needed. We show how proposals from the Draghi Report could complement the reforms through an EU-level HTA Coordination Office, a US-style EU ARPA-H, and expanded regulatory sandboxing. We then propose two additional instruments: public-private Special Purpose Vehicles to de-risk high-need innovation, and EU-level joint procurement to strengthen affordability and create predictable demand. Ultimately, only a coherent, well-calibrated framework can align industrial policy with the EU's ambition of leaving no rare-disease patient behind.
    Keywords:  Access; Affordability; Draghi Report; Drug pricing; EU Biotech Act; EU Pharma Package reform; Innovation incentives; Market exclusivity; Orphan medicinal products (OMPs); Policy; Rare diseases; Regulation
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101778
  9. Front Immunol. 2026 ;17 1872804
    Mitochondrial metabolic reprogramming at the interface of chemoresistance and immune-cold tumor states.
    Yanfang Liu.
      Chemoresistance and the immune-cold tumor microenvironment are major barriers to durable cancer control, yet they frequently emerge from overlapping mitochondrial adaptations selected by cytotoxic stress. In resistant tumors, mitochondria regulate oxidative phosphorylation (OXPHOS), redox buffering, apoptosis thresholds, organelle quality control, and metabolite overflow, while also shaping how antitumor immune cells experience nutrient deprivation, hypoxia, acidosis, and chronic danger signaling. Rather than assuming a single causal chain, this review distinguishes three non-equivalent relationships: direct suppression by mitochondria-derived signals, parallel emergence under shared selective pressures, and reverse causation in which immune exclusion itself facilitates mitochondrial adaptation. Within this framework, we synthesize evidence that mitochondrial adaptations support residual disease through OXPHOS dependence, mitochondrial dynamics, mitophagy, redox control, and metabolite-driven epigenetic remodeling, while concurrently reshaping T-cell, macrophage, and dendritic-cell function through lactate and acid stress, succinate, fumarate, 2-hydroxyglutarate (2-HG), adenosine, and mitochondrial DNA (mtDNA)-dependent innate immune signaling. We further highlight key determinants that influence whether mtDNA-STING signaling becomes immunogenic or suppressive, including timing, cell source, subcellular localization, and the dominant responding immune compartment. Finally, we discuss translational strategies to disrupt this mitochondria-immune interface, with emphasis on host and tumor heterogeneity, biomarker-guided selection, and treatment timing when combining with chemotherapy, mitochondrial targeting, and immunotherapy.
    Keywords:  chemoresistance; immune-cold tumor; immunometabolism; mitochondrial metabolism; oxidative phosphorylation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1872804
  10. Int J Mol Sci. 2026 Jul 23. pii: 6567. [Epub ahead of print]27(15):
    Redox Molecules in Aging and Neurodegenerative Disorders.
    Igor Y Iskusnykh, Evgenii D Kryl'skii, Tatyana N Popova, Anastasia A Zakharova.
      Oxidative stress is a key player in the pathogenesis of aging and various neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS), among others. Coupled molecules involved in chemical reduction-oxidation (redox) reactions regulate central signaling pathways and ensure the activation of cytoprotective mechanisms as needed. Such redox couples include oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH), nicotinamide adenine dinucleotide phosphate (NADP+/NADPH), and glutathione (GSSG/GSH), respectively. Under pathological conditions, concentrations of NAD+, NADPH, and GSH decrease, and an imbalance between the oxidized and reduced forms of these molecules develops. The current review focuses on the mechanisms that underlie these changes and their potential consequences for neurodegenerative processes and aging. The review also evaluates experimental studies on metabolic and genetic abnormalities associated with alterations in NAD+, NADPH, and GSH concentrations and highlights current research on strategies to regulate these compounds for neuroprotective purposes. Special attention is paid to understanding the interconnection between disturbed redox homeostasis and mitochondrial dysfunction, as this crosstalk is increasingly recognized as a crucial step in neurodegeneration. Integration of biochemical, genetic, and therapeutic perspectives provides a comprehensive understanding of redox imbalance in the pathogenesis of aging and neurodegenerative disorders. Therefore, these insights may contribute to the development of innovative interventions that target redox homeostasis, with the potential of increasing the human lifespan.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; ROS; antioxidant; brain; glutathione; mitochondria; neurodegeneration; neuron; oxidative stress
    DOI:  https://doi.org/10.3390/ijms27156567
  11. J Cell Sci. 2026 Aug 01. pii: jcs264775. [Epub ahead of print]139(15):
    Alterations of actin in aging.
    Maxim Averbukh, Tiffany Wang, Gilberto Garcia, Ryo Higuchi-Sanabria.
      The actin cytoskeleton is a highly dynamic and evolutionarily conserved multi-protein complex that regulates cellular architecture, mechanics and intracellular organization. Although actin dynamics and organization have been extensively studied in development and some disease contexts, the role of the actin cytoskeleton in aging has only recently begun to be considered. Accumulating evidence across model organisms indicates that aging is accompanied by progressive actin disorganization, which can manifest as filament disassembly, aggregation and mislocalization, impacting cellular homeostasis. In this Review, we synthesize the current understanding of how actin integrity is maintained through chaperone networks, actin-binding proteins, transcriptional programs and post-translational modifications, and how these regulatory layers change during the aging process. We then describe how these changes emerge as links between cytoskeletal decline and core aging hallmarks, including loss of proteostasis, mitochondrial dysfunction and cellular senescence. We further examine how this actin-related cellular dysregulation contributes to age-associated diseases, including neurodegeneration, cancer and muscle degeneration. Finally, we highlight recent studies suggesting that targeted modulation of actin regulatory pathways might preserve cellular resilience and healthspan, while emphasizing the challenges and opportunities in therapeutically targeting such a fundamental cellular system.
    Keywords:  Actin; Aging; Cancer; Neurodegeneration
    DOI:  https://doi.org/10.1242/jcs.264775
  12. Circ Res. 2026 Aug 14. 139(5): e328769
    Shifting the Balance: Mitochondrial Heteroplasmy as a Driver of Cardiac Disease.
    Andriana Papadaki, Itamar Braga Dias, Christoph Maack, Peter van der Meer, Nils Bomer.
      Mitochondrial heteroplasmy represents a fundamental determinant of mitochondrial function and disease, yet its consequences vary across different tissues. Although mitotic tissues possess mechanisms, such as cell division and mitochondrial turnover, to dilute or remove deleterious variants, postmitotic tissues lack this renewal capacity and are disproportionately vulnerable. Neuromuscular and neurodegenerative disorders have illustrated the impact of heteroplasmic mutations, but the (postmitotic) heart remains underexplored. Current reliance on blood-derived samples provides only an indirect view of cardiac heteroplasmy, highlighting the need for alternative approaches, such as endomyocardial biopsies and human induced pluripotent stem cell-derived cardiomyocytes. Expanding cardiac-focused research is essential for identification, clarifying pathogenesis, improving risk stratification, and guiding patient monitoring. Emerging therapies, including mitochondrial transplantation and mitochondrial-targeted DNA editing, demonstrate potential to modulate heteroplasmy and restore equilibrium. Integrating these strategies with precision medicine will be vital for addressing tissue-specific vulnerabilities. Ultimately, bridging the gap in cardiac heteroplasmy research will be critical for translating basic mitochondrial biology into meaningful clinical advances.
    Keywords:  DNA, mitochondrial; biopsy; cardiomyopathies; heart failure; heteroplasmy
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.328769
  13. Aging (Albany NY). 2026 Aug 08. 18(1): 940-969
    Investigating POLG-driven modulation of cancer stemness: a pilot study in breast cancer cells.
    Chiara Chinigò, Conor J Sugden, Marco Fiorillo, Anna Rita Cappello, Federica Sotgia, Michael P Lisanti.
      Mitochondria have emerged as key regulators of breast cancer stem cell (CSC) biology. Mitochondrial metabolic pathways, including oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis, are frequently altered during tumorigenesis, highlighting their role in breast cancer pathogenesis. Since breast CSCs are highly dependent on mitochondrial metabolism, targeting mitochondrial DNA (mtDNA) replication may represent a strategy to impair CSC maintenance. Mitochondrial DNA polymerase-γ (POLG), composed of a catalytic subunit encoded by POLG1 and an accessory subunit encoded by POLG2, is essential for mtDNA replication and repair. In this pilot study, we investigated whether targeting POLG could modulate breast CSC activity. Genetic knockdown of POLG1 and POLG2 in MCF-7 cells resulted in mtDNA depletion, reduced mitochondrial protein expression, impaired energy production, and loss of stemness-related features. To pharmacologically target POLG, we tested Alovudine, a nucleoside reverse transcriptase inhibitor known to act as an off-target POLG inhibitor. In MCF-7 cells, Alovudine reduced clonogenic potential, decreased mitochondrial DNA-encoded protein levels, and lowered oxygen consumption. To further validate these findings, we employed the independent POLG inhibitor Zalcitabine (ddC) in additional breast cancer models. ddC impaired mitochondrial respiration, reduced mammosphere formation, and modulated SOX2 and NANOG expression. Preliminary Kaplan-Meier analyses in a cohort of 458 breast cancer patients showed that high POLG1 expression correlates with worse clinical outcomes, including relapse-free and overall survival. Taken together, these findings suggest that POLG supports mitochondrial function and CSC maintenance, highlighting its potential as a therapeutic target and prognostic biomarker in breast cancer.
    Keywords:  POLG; breast cancer; cancer metabolism; cancer stem cells; mitochondrial DNA
    DOI:  https://doi.org/10.18632/aging.206406
  14. Int J Mol Sci. 2026 Jul 31. pii: 6868. [Epub ahead of print]27(15):
    Cardiolipin as a Signaling Hub: Evolutionary Conservation and Programmable Platforms Coupling Mitochondrial Stress to Cell Fate.
    Patrice X Petit.
      Cardiolipin (CL), a dimeric phospholipid with four acyl chains and a small polar head group, is one of the most striking examples of evolutionary continuity in cell biology. Present in the plasma membrane of α-proteobacteria and retained without fundamental modification in the inner mitochondrial membrane (IMM) of every eukaryote examined, CL has persisted across roughly two billion years of evolution, a period over which the mitochondrion shed the great majority of its ancestral genes. This review develops, as an organizing hypothesis rather than an established fact, the proposal that CL acts as a programmable signaling hub: a lipid whose physical chemistry and membrane address allow it to nucleate distinct supramolecular platforms in response to discrete stress signals, each platform coupling a specific mitochondrial state to a defined cell fate outcome. Three CL-dependent platforms are examined, together with a fourth, emerging axis, and the evidence supporting each is explicitly graded. Platform 1, the catalytic peroxidase platform, converts the constitutive CL-cytochrome c (cyt c) structural complex into an enzymatic reaction under oxidative stress, generating oxidized CL (oxCL) species that contribute to cyt c release from the IMM; this platform is the best supported of the four. Platform 2, the receptor-like mitophagy platform, exploits NME4-dependent CL scramblase activity to translocate CL from the IMM to the outer mitochondrial membrane (OMM) surface upon membrane potential dissipation, creating an externalized "eat-me" signal recognized by LC3-II; the evidence here is moderate and largely cell-based. Platform 3, the caspase-8/BID activation platform, is proposed to assemble a CL microdomain scaffold at the OMM that recruits caspase-8, markedly accelerates BID cleavage, and couple extrinsic apoptotic signals to mitochondrial outer membrane permeabilization (MOMP); this model rests substantially on reconstituted systems and requires further validation in intact cells and in vivo. A fourth, still-debated axis links CL externalization to innate immune activation through NLRP3 recruitment, for which alternative membrane-recruitment models exist. The argument advanced here is that the conservation of CL is unlikely to be explained by its structural roles alone, although those roles are themselves sufficient to impose strong selection; disentangling structural from signaling contributions remains an open problem, and the comparative genomic work needed to do so has not yet been performed.
    Keywords:  Barth syndrome; Bid; NLRP3; apoptosis; cardiolipin; caspase-8; evolutionary conservation; mitochondria; mitophagy; signaling hub
    DOI:  https://doi.org/10.3390/ijms27156868
  15. Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00935-6. [Epub ahead of print]45(8): 117857
    Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
    Koyeli Das, Rituparna Samanta, Tamar Ziv, Johannes M Herrmann, Bella Kalderon, Ophry Pines.
      Tim23 is an essential component of the mitochondrial inner membrane translocase and Sfc1 is a carrier that exchanges succinate for fumarate across that membrane. Sfc1 and succinic acid availability regulate dual targeting of fumarase and aconitase by facilitating mitochondrial import of their newly synthesized precursors, as shown by pulse-chase experiments. Here, we show that Sfc1 associates with Tim23 in vivo, and succinate modulates this association, which in turn affects mitochondrial protein import. Physical interaction between Tim23 and Sfc1 was proven by co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) and biotin-based proximity labeling (TurboID). Proximity labeling and structural modeling-informed mutagenesis allowed us to dissect the carrier activity of Sfc1 from its function as a TIM23 regulator. We performed Rosetta-MP docking of Sfc1 and Tim23 to envisage the interface. Thus, our findings show that metabolites can regulate mitochondrial import and adjust the segregation of key metabolic enzymes between the cytosol and mitochondria.
    Keywords:  CP: cell biology; CP: metabolism; Tim23; aconitase; dual targeting; fumarase; glyoxylate shunt; metabolic signaling; metabolites; mitochondrial protein import; succinate-fumarate carrier; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117857
  16. J Patient Rep Outcomes. 2026 Jul 25. pii: 141. [Epub ahead of print]10(1):
    Self-reported perspective in rare genetic diseases: a systematic review of patient-reported outcome measures classified using the international classification of functioning, disability and health framework.
    Rachele Simeon, Marina Usai, Alice Tramonti, Renata Canova, Daniela Frigerio, Anna Berardi, Elisa Pelosin, Carola Cosentino.
       BACKGROUND: Rare and ultra-rare genetic diseases (GDs) involve complex, multidimensional burdens not fully captured by clinical endpoints, highlighting uncertainties in the availability, scope, and quality of Health-Related Quality-of-life patient-reported outcome measures (HRQoL-PROMs).
    OBJECTIVES: To identify PROMs developed or validated to assess HRQoL in rare and ultra-rare GDs, map their content using the International Classification of Functioning, Disability and Health (ICF), and evaluate their measurement properties according to COSMIN methodology.
    METHODS: Original studies reporting PROM development or measurement properties in rare or ultra-rare GDs were included. PubMed, Embase, PsycINFO, Web of Science, registries, outcome-measure repositories, reference lists, and citation tracking were searched from inception to March 26, 2026, without language restrictions. Study selection, data extraction, and risk-of-bias (RoB) assessment were performed independently. Methodological quality was evaluated using the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) RoB checklist. Measurement properties were rated as sufficient, insufficient, indeterminate, or inconsistent, and certainty of evidence was assessed using a modified GRADE approach. PROM content was mapped to ICF components and synthesized narratively; no meta-analysis was conducted due to heterogeneity.
    RESULTS: Fifty-nine studies were included, covering 45 PROMs across 29 rare or ultra-rare GDs. Instruments were predominantly disease-specific, although generic and adapted measures were also identified. PROMs mainly addressed body functions and activities/participation, while environmental factors, social participation, stigma, and access-to-care domains were consistently underrepresented. Internal consistency and construct validity were most frequently assessed, whereas responsiveness, measurement error, and cross-cultural validity were rarely evaluated. Only three PROMs (HAE-QoL, NF1-AdQoL, EPP-QoL) were classified as COSMIN category A and recommended; most were category B, and five were category C.
    DISCUSSION: The evidence is limited and methodologically weak, and many QoL-PROMs fail to capture key multidimensional aspects of QoL; more rigorous, patient-centered, disease-specific development and validation are needed. This review examined questionnaires used to assess health related quality of life in people with rare and ultra-rare genetic diseases. Although 45 PROMs were identified, only three had enough evidence to be recommended. Many questionnaires focused mainly on symptoms and physical functioning, while important aspects such as social participation, stigma, care access, and environmental support were often missing. Future PROMs should be developed with strong patient involvement and validated across age groups, languages, and disease contexts.
    Keywords:  Genetic rare disease; Health-related quality of life; International classification of functioning; Measurement properties; PROM; Patient-reported outcome
    DOI:  https://doi.org/10.1186/s41687-026-01155-5
  17. Cells. 2026 Aug 03. pii: 1404. [Epub ahead of print]15(15):
    Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.
    Md Riad Chowdhury, Gui-Hwa Jeong, In-Kyu Lee.
      Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD+ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS-STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan.
    Keywords:  NLRP3; PDK4; SASP; aging; inflammaging; meta-inflammation; mitochondrial dysfunction; mitophagy; mtROS; pyruvate dehydrogenase
    DOI:  https://doi.org/10.3390/cells15151404
  18. Res Involv Engagem. 2026 Aug 13. pii: 125. [Epub ahead of print]12(1):
    Awareness and perceptions of patient and public involvement in rare disease research in Japan: the role of patient advocacy groups and family members.
    Saori Watanabe, Kaori Muto, Akiko Nagai, Hideki Yui, Yukitaka Kiya.
       BACKGROUND: Patient and public involvement (PPI) in medical research has increasingly been incorporated into research policies and funding frameworks in Japan, but empirical evidence on how patients and family members perceive PPI remains limited. This is particularly important in rare disease research, where patient populations are small and involvement may depend on organised patient communities. This study explored awareness, experience, perceived benefits and barriers, and support needs regarding PPI among rare disease patients and family members in Japan.
    METHODS: A cross-sectional online survey was conducted between December 2021 and April 2022 through two national rare disease patient network organisations. Adults with a rare disease or family members of such individuals were eligible. Of 218 responses, 212 met the eligibility criteria and were analysed. Subgroup comparisons used Pearson's chi-squared test, with Fisher's exact test when expected cell counts were below 5.
    RESULTS: The sample comprised 101 patients (47.6%) and 111 family members (52.4%); 172 of 209 respondents (82.3%) reported prior participation in a patient advocacy group (PAG). Prior awareness of PPI was reported by 29.7% and prior experience by 20.8%. PAG participation was the only respondent characteristic examined that was associated with awareness (33.1% vs. 13.5%; p = 0.018). Nearly all respondents identified at least one perceived benefit of PPI, most commonly advancement of disease research (84.9%). Response patterns differed between PPI-aware and PPI-unaware respondents, and between patients and family members. Compared with patients, family members more often identified advancement of disease research and incorporation of patient and public perspectives as benefits, lack of knowledge about medical research as a barrier, and educational opportunities for patients and families as a needed form of support.
    CONCLUSIONS: Prior PPI awareness was limited, and PAG participation was the only respondent characteristic examined that was associated with awareness. Patients and family members showed somewhat different perceptions, with family members more often emphasising both the value of PPI and the need for educational support. Meaningful PPI in rare disease research requires not only formal promotion but also practical infrastructure, including public information, education, and support for PAGs, to make involvement feasible and sustainable.
    Keywords:  Japan; Patient advocacy groups; Patient and family perspectives; Patient and public involvement; Rare disease research
    DOI:  https://doi.org/10.1186/s40900-026-00955-9
  19. Front Pharmacol. 2026 ;17 1852905
    Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.
    Xinyu Xue, Xihan Liao, Xing Ji, Kailin Huang, Huanlin Wu, Wei Li.
      Doxorubicin (DOX) is a broad-spectrum anthracycline chemotherapeutic agent, and its clinical application is severely limited by dose-dependent cardiotoxicity (DIC), for which there are currently no effective clinical interventions. Mitochondria are the central organelles regulating myocardial energy metabolism and cell survival, and mitochondrial dysfunction is considered the initiating and core mechanism underlying DIC. DOX disrupts the mitochondrial quality control (MQC) system and induces mitochondrial metabolic reprogramming, thereby leading to mitochondrial dysfunction. This results in excessive production of mitochondrial reactive oxygen species (mROS) and leakage of mitochondrial DNA (mtDNA), ultimately inducing PANoptosis. PANoptosis is a newly defined inflammatory programmed cell death pathway that integrates key features of apoptosis, pyroptosis, and necroptosis. This review delves into the molecular mechanisms by which mitochondrial dysfunction triggers PANoptosis in DIC, focusing on key aspects such as impaired mitochondrial protein homeostasis, mitochondrial dynamics imbalance, suppressed mitochondrial biogenesis, inhibited mitophagy, and mitochondrial metabolic reprogramming. It systematically discusses DIC-targeted intervention strategies against mitochondrial homeostasis and PANoptosis, including mitochondrial-targeted antioxidants, mitochondrial dynamics regulators, mitophagy activators, mitochondrial biogenesis promoters, mitochondrial transplantation, PANoptosis inhibitors, nanomedicine delivery systems, and gene/cell therapy. The aim is to balance the antitumor efficacy of DOX and reduce its cardiac adverse effects, thereby providing a new theoretical basis and potential therapeutic targets for the clinical prevention and treatment of DIC.
    Keywords:  PANoptosis; doxorubicin; doxorubicin-induced cardiotoxicity; mitochondrial dysfunction; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fphar.2026.1852905
  20. Biology (Basel). 2026 Aug 06. pii: 1328. [Epub ahead of print]15(15):
    Mitochondria-Targeted Natural-Derived Compounds in Cellular Senescence: Mechanisms, Therapeutic Potential, and Future Directions.
    Jirapat Namkaew, Pornparn Kongpracha, Thiranut Jaroonwitchawan.
      Cellular senescence is a root cause of aging and age-related disease. Senescent cells persist in tissues, secreting inflammatory factors that fuel inflammaging and immune decline. At the subcellular level, mitochondrial dysfunction has become recognized as a central driver of the senescent state: metabolism shifts toward glycolysis, mitophagy stalls while reactive oxygen species production escalates, mitochondrial dynamics tip toward hyperfusion or fragmentation, and damaged mitochondrial DNA leaks into the cytosol to activate the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, amplifying the senescence-associated secretory phenotype. Conventional drugs have struggled to address these layered defects, steering interest toward natural bioactive compounds-polyphenols, flavonoids, saponins-that can simultaneously restore mitophagic flux, boost antioxidant defenses, rebalance fission-fusion, and intercept mitochondrial DNA-driven inflammation. However, the key issue is delivery: these molecules rarely reach mitochondria in meaningful concentrations in vivo due to their poor bioavailability, rapid metabolism, and off-target distribution. Platforms using triphenylphosphonium, mitochondria-penetrating peptides, or biomimetic shells have successfully funneled therapeutic payloads into mitochondria in several models of disease. We contend that the proposed systematic integration of these delivery systems with natural senotherapeutic compounds offers a promising direction for future research.
    Keywords:  cellular senescence; mitochondria-targeted delivery; mitochondrial dysfunction; natural bioactive compounds
    DOI:  https://doi.org/10.3390/biology15151328
  21. J Transl Med. 2026 Aug 07. pii: 1036. [Epub ahead of print]24(1):
    Umbilical cord-derived mitochondrial transplantation restores tendon structure and function in a preclinical model of achilles tendinopathy.
    Da-Yoon Kim, Mi Jin Kim, Min-Jeong Park, Mina Lim, Eun-Seo Back, Chang-Koo Yun, Seong Hun Kim, Hyuk Nam Kwon, Chaeyoung Lee, Kyunghoon Min, Yong-Soo Choi.
       BACKGROUND: Achilles tendinopathy is a degenerative musculoskeletal disorder for which disease-modifying therapies remain limited, largely due to the inability of current interventions to directly restore cellular bioenergetic function. Emerging evidence has identified mitochondrial dysfunction as a central contributor to tendon degeneration, highlighting mitochondria as a potential therapeutic target. Here, we evaluated umbilical cord-derived mitochondria (UC-MT) as a dose-defined, cell-free therapeutic strategy for tendinopathy.
    METHODS: UC-MT were isolated from human umbilical cord-derived mesenchymal stem cells and characterized for mitochondrial integrity and bioenergetic activity. Therapeutic efficacy was evaluated in vitro using TNF-α-induced human tenocyte injury models and in vivo in a collagenase-induced rat model of Achilles tendinopathy. Dose-response effects were systematically assessed (5, 10, and 20 µg), and mitochondrial function, metabolic profiles, extracellular matrix remodeling, and functional recovery were analyzed using integrated molecular, histological, and functional assays, including transcriptomic and metabolomic profiling.
    RESULTS: UC-MT treatment significantly restored mitochondrial membrane potential, ATP production, and respiratory complex activity in injured tenocytes, accompanied by attenuation of inflammatory signalling. Among the tested doses, 10 µg UC-MT consistently produced the most robust therapeutic effects across mitochondrial, metabolic, and structural outcome measures. In vivo, UC-MT administration improved tendon histoarchitecture, collagen organization, and functional performance, while integrated multi-omics analyses revealed coordinated metabolic reprogramming, including restoration of mitochondrial complex I-linked bioenergetic pathways.
    CONCLUSIONS: Taken together, these findings position UC-MT as a dose-defined, cell-free therapeutic modality with translational potential for tendon regeneration. By directly targeting mitochondrial dysfunction, UC-MT restores mitochondrial bioenergetics and supports tendon regeneration in preclinical models of tendinopathy.
    Keywords:  Achilles tendinopathy; Cell-free regenerative therapy; Mitochondrial bioenergetics; Mitochondrial transplantation; Umbilical cord-derived mitochondria
    DOI:  https://doi.org/10.1186/s12967-026-08768-w
  22. Cells. 2026 Aug 05. pii: 1415. [Epub ahead of print]15(15):
    Altered Mitochondrial Base Excision Repair and Mitochondrial DNA Instability in Peripheral Leukocytes of Patients with MASLD.
    Sylwia Ziółkowska, Marcin Kosmalski, Bianka Świderska, Agnieszka Szczypiorowska, Kinga Jarmusz, Magdalena Ejsmont, Adam Marek Wróblewski, Janusz Szemraj, Tadeusz Pietras, Aleksandra Jabłkowska, Piotr Czarny.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder that is strongly associated with mitochondrial dysfunction and oxidative stress, which may potentially compromise the integrity of mitochondrial DNA (mtDNA). However, the role of the base excision repair (BER) pathway-the main mechanism responsible for repairing oxidative lesions in mitochondria-and maintaining mtDNA stability in MASLD remains poorly understood. Here, we analyzed total mRNA expression levels of key BER components in whole-blood samples, along with mitochondrial protein levels of the selected components. Additionally, we assessed the mtDNA copy number and the damage of mtDNA and nuclear DNA in peripheral leukocytes from MASLD patients and healthy controls. We found that MASLD patients differed from controls in mtDNA and nuclear DNA damage, mtDNA copy number, and selected BER-related markers. However, because the MASLD and control groups also differed substantially in age and BMI, these molecular differences should be interpreted as potentially being associated with age- and BMI-related metabolic status rather than attributable to MASLD alone. While several BER-related genes were downregulated at the mRNA level, the corresponding mitochondrial protein levels were not consistently decreased in MASLD (ProteomeXchange: PXD075974), indicating a discordance between transcriptional and protein-level regulation. These results suggest that altered mitochondrial BER and mtDNA instability in peripheral leukocytes may reflect the combined influence of MASLD, aging, obesity, and broader metabolic dysfunction.
    Keywords:  DNA repair; MASLD; base excision repair; mitochondrial DNA; steatosis
    DOI:  https://doi.org/10.3390/cells15151415
  23. N Engl J Med. 2026 Aug 13. 395(7): 711-714
    Gene Editing, Peroxisomal Disorders, and Treatments for Rare Disease.
    Rebecca C Ahrens-Nicklas.
      
    DOI:  https://doi.org/10.1056/NEJMcibr2606991
  24. J Med Genet. 2026 Aug 14. pii: jmg-2025-111356. [Epub ahead of print]
    Childhood-onset neurodegeneration and brain atrophy: defining UBTF-related developmental regression and progressive ataxia.
    Amanda Nagy, Anna Luddy, Francine Molay, Haley McLaughlin, Lizbeth De La Rosa Abreu, Catherine Becker, Markus Terrey, Cathleen M Lutz, Anoopum Gupta, Florian S Eichler.
       BACKGROUND: The heterozygous variant c.628G>A (p.Glu210Lys) in UBTF (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed development followed by regression, with individuals frequently experiencing movement disorders. This study defines the natural history of this rare disorder and explores potential biomarkers in humans and mice.
    METHODS: Caregivers of individuals with CONDBA completed cross-sectional surveys detailing genetic, developmental and clinical features. Patients evaluated in a neurogenetics clinic underwent Brief Ataxia Rating Scale (BARS) assessments compared with remotely collected wrist and ankle accelerometry data. Neurofilament light chain (NFL) levels were assessed in the clinic cohort and in a Ubtf E210K knock-in mouse model.
    RESULTS: All 11 caregiver surveys reported onset of neurodevelopmental regression (median 3.5 years, range 0.5-5 years), at times following anaesthesia or illness and 82% developed ataxia. Motor activity data from five participants (median 11.8 years, range 8.1-12.5 years) had high test-retest reliability, correlated with ataxia severity as measured by the BARS, and showed declines across multiple measures over the study period. NFL was abnormally elevated in both humans and the mouse model.
    CONCLUSION: UBTF-related CONDBA presents with early normal or mildly delayed development followed by regression and progressive ataxia. Wearable accelerometers provide a reliable measure of disease severity, and elevated NFL may serve as a biomarker of neuronal injury in both humans and animal models.
    Keywords:  Central Nervous System Diseases; Cerebellar Diseases; Movement Disorders; Neurodegenerative Diseases; Pediatrics
    DOI:  https://doi.org/10.1136/jmg-2025-111356
  25. Int J Mol Sci. 2026 Aug 03. pii: 6978. [Epub ahead of print]27(15):
    A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization.
    Mazhor Aldosary, Hanan AlQudairy, Nourah Alshalan, Mohammad A Al-Muhaizea, Eman Alobeid, Albandary AlBakheet, Ebtissal Khouj, Aljoharah M Alharbi, Walaa Alenazi, Hanin R Omar, Monther Alhamdoosh, Abdullah Alsuwaidan, Hindi Alhindi, Ahmed Alfares, Anas M Alazami, Stefan T Arold, Dilek Colak, Robert W Taylor, Namik Kaya.
      SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient's cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.
    Keywords:  ANT1; ATP production; SLC25A4; cardiomyopathy; mitochondrial oxygen consumption; myopathy
    DOI:  https://doi.org/10.3390/ijms27156978
  26. Sci Transl Med. 2026 Aug 12. 18(862): eaea8468
    Succinate drives macrophage inflammation by promoting GPR91 mitochondrial signaling in rheumatoid arthritis.
    Wankang Zhang, Luping Wang, Yingjie Zhao, Yao Mu, Lei Qiu, Xinyu Feng, Yueye Wang, Jiemin Zhao, Yan Chang, Wei Wei, Xuezhi Yang.
      High succinate concentrations are implicated in rheumatoid arthritis (RA) and other inflammatory diseases through G protein-coupled receptor 91 (GPR91)-mediated signaling. Despite the therapeutic potential of targeting GPR91, conflicting reports on the receptor's inflammatory roles have hindered treatment development. Here, we report that the effects of succinate on GPR91 signaling are biphasic and concentration dependent. At physiological succinate concentration, membrane-localized GPR91 promotes M2 polarization through Gq-mediated activation of phospholipase C and intracellular calcium mobilization. In RA, elevated succinate induces GPR91 internalization and mitochondrial translocation, thereby disrupting Gq signaling. Mechanistically, mitochondrial GPR91 recruits Gs proteins and, together with intracellular succinate, activates the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway. PKA then phosphorylates cytidine/uridine monophosphate kinase 2 at serine-404, stabilizing it to enhance mitochondrial DNA (mtDNA) synthesis. Newly synthesized mtDNA is oxidized (forming ox-mtDNA) and released into the cytosol, activating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to drive macrophage inflammation. Myeloid-specific GPR91 deletion or inhibition of intracellular succinate accumulation alleviates arthritis in mice. This study reveals that GPR91 reprograms signaling by subcellular relocation, providing a promising therapeutic strategy for autoimmune diseases.
    DOI:  https://doi.org/10.1126/scitranslmed.aea8468
  27. J Cell Physiol. 2026 Aug;241(8): e70220
    Simulated Microgravity Induced Mesenchymal Stem Cell Senescence via the Activation of Cytosolic mtDNA-cGAS-STING Axis.
    Lei Huang, Rui Huang, Wenjun Lv, Zimeng Li, Yun Tu, Guanbin Song, Qing Luo.
      Microgravity brings various pathological changes to astronauts, which may be related to the senescence of adult stem cells. However, how microgravity affects the senescence of stem cells remains barely known. In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence. Rotating culture also promoted the cytosolic leakage of mitochondrial DNA (mtDNA), while the depletion of mtDNA inhibited cGAS-STING activation and reversed MSC senescence. Knockdown of either BAK or BAX, proteins forming pores on the mitochondrial outer membrane, suppressed mtDNA leakage, cGAS-STING activation, and MSC senescence, suggesting that BAK/BAX mediates the activation of mtDNA-cGAS-STING axis and the associated MSC senescence. Recovering mitochondrial function by Mito TEMPO inhibited the activation of mtDNA-cGAS-STING axis and reversed MSC senescence. In vivo, using rat hindlimb unloading (HU) model to simulate microgravity, it was found that inhibition of STING ameliorated MSC senescence induced by HU. Together, our study demonstrated that simulated microgravity induces MSC senescence by the activation of cytosolic mtDNA-cGAS-STING axis and indicated cGAS-STING pathway as a therapeutic target of MSC senescence under microgravity.
    Keywords:  cell senescence; mesenchymal stem cells; mitochondrial dysfunction; mtDNA‐cGAS‐STING axis; simulated microgravity
    DOI:  https://doi.org/10.1002/jcp.70220
  28. Burns Trauma. 2026 ;14 tkag037
    Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.
    Yanmin Xin, Yiting He, Xingguo Liu.
      The mitochondrial unfolded protein response (UPRmt) is a conserved mitochondrial stress response that is activated by mitochondrial dysfunction to maintain proteostasis. Although UPRmt has been extensively studied in aging and cancer, its role in trauma and critical illness remains poorly understood. Here, we propose a unifying conceptual framework in which UPRmt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPRmt activation triggered by diverse insults and highlight how UPRmt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPRmt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPRmt in trauma and critical illness. Moderate activation promotes mitochondrial recovery, limits reactive oxygen species accumulation, and supports immune cell function, thereby enhancing tissue resilience and repair. In contrast, sustained or dysregulated UPRmt contributes to mitochondrial failure, sterile inflammation, and the progression to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Furthermore, we discuss emerging evidence linking UPRmt to immune regulation and inflammatory responses, and propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for a broad spectrum of human diseases. Crucially, we synthesize how UPRmt mechanisms contribute to post-traumatic mitochondrial damage, sterile inflammation, SIRS, and MODS. We propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for trauma, burns, and critical illness.
    Keywords:  Immunity; MODS; SIRS; Trauma; UPRmtproteostasis
    DOI:  https://doi.org/10.1093/burnst/tkag037
  29. Circ Res. 2026 Aug 14. 139(5): e327198
    Extracellular Vesicles in Cardiovascular Disease: Intercellular Signaling, Liquid Biopsy Biomarkers, and Therapeutic Translation.
    Michail Spanos, Priyanka Gokulnath, Gaurav Behera, Christopher Azzam, Saumya Das.
      Cardiovascular diseases remain the leading global cause of mortality, highlighting the need for improved early detection and targeted interventions. Extracellular vesicles (EVs) are nano-sized, bilipid-layered particles released by all cell types that carry RNAs, proteins, lipids, and metabolites reflective of their parent cells. They mediate intercellular communication by transferring cargo that alters recipient cell transcriptomic and proteomic states, and this property may be leveraged for therapeutic delivery. This review provides a comprehensive, cardiovascular disease-focused synthesis of EV biology with emphasis on what is clinically actionable and mechanistically novel. The review describes EV biogenesis and their multiomic cargo composition, followed by tissue-resolved and cell type-resolved EV signaling across cell types relevant to cardiovascular disease. A dedicated section addresses EV-mediated interorgan crosstalk across the heart-kidney, heart-liver, brain-heart, and adipose-heart axes as a systems-level framework for cardiometabolic disease. We next turn to translational applications, describing EV cargo composition under pathological conditions with implications for disease-related signaling and the potential for biomarker development. For liquid biopsy applications, the review introduces a 3-tier evidence framework classifying circulating EV biomarkers by clinical validation status, supported by a practical preanalytical checklist for cardiovascular plasma studies. Engineered, stem cell-derived, and RNA-loaded EV therapeutic modalities are evaluated, and active clinical trials are catalogued along with key challenges in cargo loading, biodistribution, immunogenicity, and regulatory standardization. We conclude with a structured future directions and perspectives section identifying the most tractable open questions required to advance EVs from discovery to cardiovascular clinical practice.
    Keywords:  biomarkers; cardiovascular diseases; cell communication; drug delivery systems; extracellular vesicles; liquid biopsy; microRNAs
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.327198
  30. Cell Biochem Funct. 2026 Aug;44(8): e70277
    Activation of a TFAM-Dependent Mitochondrial Translational Axis Drives Oxidative Metabolism in Grade 2 Meningiomas.
    Stella G Cavalcante, Benedito Jamilson Araújo Pereira, Antonio M Lerario, Paula R Sola, Sueli M Oba-Shinjo, Suely K N Marie.
      Meningiomas exhibit marked biological heterogeneity that is not fully captured by current histopathological grading. Increasing evidence suggests that mitochondrial metabolism contributes to tumor aggressiveness; however, the molecular mechanisms regulating mitochondrial function in meningiomas remain poorly defined. Here, we investigated the role of mitochondrial transcription factor A (TFAM)-driven mitochondrial biogenesis and translation in meningioma progression. We performed integrative transcriptomic, immunohistochemical, and mitochondrial DNA analyses in a well-characterized cohort of 91 meningiomas, comprising World Health Organization grade 1 (G1) and grade 2 (G2) tumors with long-term clinical follow-up. RNA sequencing identified enrichment for mitochondrial metabolic pathways, including oxidative phosphorylation and ATP metabolism, that was preferentially activated in G2 meningiomas. TFAM and its upstream regulator PGC1α were significantly upregulated at both mRNA and protein levels in G2 tumors and exhibited a positive correlation, consistent with enhanced mitochondrial biogenesis. Although mitochondrial DNA copy number did not differ significantly between grades, G2 meningiomas showed a trend toward increased mitochondrial mass. Notably, G2 meningiomas demonstrated marked enrichment of mitoribosomal genes, including MRPL15, MRPL35, MRPL42 and MRPS22, whose expression correlated positively with TFAM and PGC1α expression levels. Network analysis identified TFAM as a central hub linking mitochondrial biogenesis, translation, and metabolic pathway activation. These findings were independently validated using a publicly available meningioma transcriptomic dataset. Together, our results reveal a TFAM-centered mitochondrial regulatory program that integrates mitochondrial biogenesis, translational capacity, and oxidative metabolism in higher-grade meningiomas. This mitochondrial translational axis represents a previously unrecognized mechanism underlying meningioma progression and highlights potential metabolic vulnerabilities for therapeutic intervention.
    DOI:  https://doi.org/10.1002/cbf.70277
  31. Free Radic Res. 2026 Aug 14. 1-29
    Mitochondrial hOGG1-2a overexpression sensitizes HeLaS3 cells to oxidative stress, accompanied by mitochondrial dysfunction and reduced mtDNA integrity.
    Weizhi Wang, Lanyun Yan, Fengxian Wu, Qiu-Mei Zhang-Akiyama.
      Mitochondria are essential organelles responsible for cellular ATP production and contain their own mitochondrial DNA (mtDNA), which encodes key components of oxidative phosphorylation. Because mitochondria continuously generate reactive oxygen species (ROS), mtDNA is particularly susceptible to oxidative damage. Although DNA repair enzymes are present in mitochondria, the regulation of mtDNA repair and its impact on cellular responses to oxidative stress remain incompletely understood. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme in the base excision repair (BER) pathway, and the mitochondrial isoform hOGG1-2a contributes to the maintenance of mtDNA integrity.In this study, HeLaS3 cell lines stably overexpressing hOGG1-2a were established to examine responses to oxidative stress. hOGG1-2a overexpression was associated with reduced survival following H2O2 treatment, γ-ray exposure, heat shock, and ultraviolet C (UVC) irradiation. Apoptotic cell death increased after oxidative stress. Mitochondrial membrane potential assessed by JC-1 staining was significantly reduced in hOGG1-2a-overexpressing cells. Long-range PCR analysis revealed reduced mtDNA amplification efficiency, and oxidative stress was accompanied by a greater reduction of the mitochondrial enzyme Aconitase 2. These cells exhibited elevated basal ATP levels and altered ATP responses under oxidative stress conditions. In addition, mitochondrial superoxide-associated fluorescence detected by MitoSOX™ was significantly increased.Combined long-range PCR and Sanger sequencing indicated reduced mtDNA amplification after H2O2 exposure without a marked increase in point mutations.Collectively, these findings suggest that hOGG1-2a overexpression sensitizes cells to oxidative stress and is associated with mitochondrial redox dysregulation, reduced mitochondrial membrane potential, altered ATP responses, and reduced mtDNA amplifiability during prolonged stress.
    Keywords:  base excision repair; hOGG1-2a; mitochondrial DNA; mitochondrial alterations; mtDNA integrity; oxidative stress
    DOI:  https://doi.org/10.1080/10715762.2026.2716701
  32. Ther Innov Regul Sci. 2026 Aug 08.
    Clinical and Economic Burden of Diseases with Accelerated Approval Therapies: Evidence of Unmet Patient Need.
    Hanke Zheng, Shanshan Wang, Jason Shafrin, Shravani Bheema, Kathryn Spurrier, Jonathan D Campbell.
       BACKGROUND: Some US payers delay coverage for non-oncology treatments approved via the Food and Drug Administration (FDA)'s accelerated approval (AA) pathway.
    OBJECTIVES: To estimate the economic burden and characteristics of diseases with therapies approved via the AA pathway compared to diseases with no AA therapies.
    METHODS: The study identified the initial FDA-approved AA indications for all non-oncology therapies from January 2015 to February 2025. For comparison, 100 non-oncology diseases with the most recent FDA-approved non-AA therapies were identified. Annual economic burden and disease characteristics were extracted from peer-reviewed literature, with costs inflated to 2025 USD. Economic burden studies that used a societal perspective were prioritized. Comparative analyses were conducted using the Mann-Whitney U Test.
    RESULTS: Thirty-two non-oncology AA treatments were identified representing 16 unique diseases. Average annual incremental societal costs for AA diseases were 1.4 times higher than for non-AA diseases ($91,857 vs. $65,468, p = 0.012). Additionally, the annual average productivity loss and caregiver burden were 1.8 times ($17,635 vs. $9,620, p = 0.092) and 2.4 times ($20,268 vs. $8,294, p = 0.055) greater in the AA diseases, respectively. Diseases with newly-approved AA treatments were characterized by shorter life expectancy (59.3 vs 65.1 years), lower average quality of life (0.64 vs 0.69), and more likely to be rare diseases (68.8% vs 53.1%) compared to non-AA diseases.
    CONCLUSION: Non-oncology diseases with treatments approved via the AA pathway imposed a higher economic burden and had more severe disease characteristics compared to non-AA diseases. These findings should be considered alongside AA coverage policy decision-making.
    Keywords:  Accelerated approval; Economic burden; Economic evaluation; Productivity loss; Rare disease
    DOI:  https://doi.org/10.1007/s43441-026-01030-x
  33. Sci Adv. 2026 Aug 14. 12(33): eaeh0657
    Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
    Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li.
      Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.
    DOI:  https://doi.org/10.1126/sciadv.aeh0657
  34. Public Health Wkly Rep. 2026 ;19(31): 1301-1323
    Five-year Incidence Trends and the Status of Major Rare Diseases in 2023 in the 「Annual Report on the Rare Disease Patients in Korea」.
    Il-Su Park, Kyounga Lee, Jeongwook Lee, Jae-Hoon Ji, Eun-Ji Choi, Jee-Young Kim, Do-Hyeon Park, Kyoung-Hwa Choi.
       Objectives: This study analyzed 5-year trends in rare disease incidence, deaths, and medical expenditures in the Republic of Korea using the 「Annual Report on the Rare Disease Patients in Korea」 (the Annual Report), with particular attention to the 2023 incidence figures by age, province, and frequently occurring diseases.
    Methods: This retrospective descriptive study used data from the Annual Report from 2019 to 2023. The annual numbers of newly registered rare disease cases and of deaths and the figures for healthcare utilization were analyzed, with particular attention to the incidence status in 2023.
    Results: Newly registered rare disease cases remained at around 50,000 annually before rising to 62,420 in 2023, with deaths and medical expenditures also increasing. In 2023, the incidence was highest among individuals in their 60s and those in the Gyeonggi-do region. Idiopathic pulmonary fibrosis and systemic lupus erythematosus with organ or system involvement were the most common rare diseases among males and females, respectively. Crohn's disease of the small and large intestine was the most frequent among those in their 10s and 20s, autosomal dominant polycystic kidney disease among those in their 30s to 50s, and idiopathic pulmonary fibrosis among those aged 60 and older, which last also incurred the highest total annual medical expenditure.
    Conclusions: The Annual Report has enhanced analytical accuracy and comprehensiveness through data refinement and statistical expansion. Future efforts should be directed to a transition from incidence-centered statistics to the establishment of a longitudinal data infrastructure that records incidence rates, survival rates, and the overall prevalence of rare diseases.
    Keywords:  Incidence; Public health surveillance; Rare disease statistics; Rare diseases
    DOI:  https://doi.org/10.56786/PHWR.2026.19.31.2
  35. Redox Biol. 2026 Aug 06. pii: S2213-2317(26)00336-8. [Epub ahead of print]96 104337
    Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.
    Xiaohan Chen, Shunpeng Xing, Xufeng Cen, Jikai Shen, Jiwei Zhu, Xu Lin, Le Xu, Fengqi Wang, Yanan Tian, Xuan Lai, Yuejia Luo, Hongguang Xia, Jian Hu, Luming Wang.
      Acute lung injury (ALI) is driven by excessive inflammation and mitochondrial dysfunction, but how mitochondrial DNA (mtDNA) release engages inflammatory signaling remains incompletely understood. Here, we demonstrate that TJ0113, a novel mitophagy activator, confers protection against LPS-induced ALI by promoting mitochondrial quality control and limiting cytosolic mtDNA accumulation. Transcriptomic and ultrastructural analyses showed that TJ0113 restored mitophagy and reduced oxidative stress. Single-cell transcriptomic profiling identified ZBP1 as the most prominently induced cytosolic nucleic acid sensor in injured lungs, revealing inflammatory alveolar macrophages as a major ZBP1-enriched population. Mechanistically, cytosolic mtDNA accumulation triggered ZBP1 activation, leading to necroptotic (MLKL) and pyroptotic (GSDMD) signaling. TJ0113 suppressed ZBP1 activation by enhancing mitophagy and reducing mtDNA release, and inhibition of mitophagy abolished its protective effects. Consistently, ZBP1 knockdown recapitulated the anti-inflammatory effects of TJ0113, as evidenced by reduced downstream inflammatory signaling and decreased cytosolic Z-NA puncta, and pharmacological mitochondrial depletion (EB) similarly attenuated the inflammatory phenotype. Our findings identify the mtDNA-ZBP1 axis as a critical link between mitochondrial dysfunction and inflammation in ALI, and position TJ0113 as a promising therapeutic candidate targeting this axis.
    Keywords:  Acute lung injury; Alveolar macrophages; Mitochondrial DNA; Mitophagy; ZBP1
    DOI:  https://doi.org/10.1016/j.redox.2026.104337
  36. Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00239-1. [Epub ahead of print]38(8): 1518-1520
    Methionine tuning for health without frailty.
    Amanda Garrido, Nathan L Price, Rafael de Cabo.
      Dietary protein quality, not merely quantity, shapes metabolic health and aging trajectories. Fanti et al. show that moderate methionine supplementation to a low-protein, Mediterranean-inspired diet activates a GH-GLP-1-FGF21 axis that reduces adiposity and frailty without caloric restriction; their findings provide a mechanism for why traditional plant-rich diets may promote longevity while sometimes compromising physical robustness.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.013
  37. Ther Deliv. 2026 Aug 11. 1-40
    Exosome-based nanomedicine for neurological disorders: mechanisms, engineering, and therapeutic potential.
    Nidhi Singh, Lahanya Guha, Alka Kumari.
      Exosomes are naturally occurring extracellular vesicles that have emerged as promising bio-inspired nanocarriers for the treatment of neurological disorders owing to their intrinsic biocompatibility, low immunogenicity, and ability to cross the blood-brain barrier. This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system. Particular emphasis is placed on the application of engineered exosomes in neurodegenerative diseases, stroke, spinal cord injury, neuropathic pain, and neuroinflammatory disorders. In addition, we discuss how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation, including heterogeneity, scalability, reproducibility, purity, and regulatory standardization. By integrating mechanistic insights with translational perspectives, this review provides a framework for the rational design and future clinical implementation of exosome-based nanomedicines for neurological disorders. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. Publications available from database inception through [Month Year] were screened using combinations of keywords including "exosomes," "extracellular vesicles," "neurological disorders," "brain-targeted delivery," "exosome engineering," "drug delivery," and "clinical trials." Additional relevant articles were identified through manual searches of reference lists from selected studies and recent reviews.
    Keywords:  Exosomes; blood-brain barrier; drug delivery systems; exosomal engineering; neurological disorders
    DOI:  https://doi.org/10.1080/20415990.2026.2715878
  38. Eur J Hosp Pharm. 2026 Aug 12. pii: ejhpharm-2026-005284. [Epub ahead of print]
    Measuring treatment satisfaction in rare diseases: challenges and opportunities for hospital pharmacy.
    Sandra Caíña López, Silvia Vázquez-Gómez, Andrea Portela Sotelo, Carmen Dávila Pousa.
      
    Keywords:  EDUCATION, PHARMACY; PATIENT SAFETY; PHARMACEUTICAL PREPARATIONS; PHARMACISTS; PHARMACY SERVICE, HOSPITAL
    DOI:  https://doi.org/10.1136/ejhpharm-2026-005284
  39. Cancer Res Commun. 2026 Aug 11.
    Mitochondrial tRNA-derived fragments as candidate metastasis-modifying RNA.
    Katy L Swancutt, R McKinnon Walsh, Sydney Quijano, Emily Schueddig, Devin C Koestler, Adam D Scheid, Tony Vanden Bush, Yi Jing, Isidore Rigoutsos, Danny R Welch.
      How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using Mitochondrial-Nuclear eXchange (MNX) mice, we previously showed that mtDNA single nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences. The only mtDNA SNP correlating with these phenotypes resides in the gene encoding mitochondrial tRNA-Arginine (mt-tRNAArg (UCG), mt-TR), suggesting a role for non-protein-coding loci. Here we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TR. Northern blotting revealed distinct tRF that are differentially expressed among mtDNA SNP, between lung and liver, and between sexes. Surprisingly, small RNA sequencing untreated RNA did not detect the same tRF in high abundance. However, demethylating and restoring 5'-OH and 3'-PO4 termini allowed detection of sequences consistent with the northern blot bands. Enforcing exact matching to the mitochondrial genome and normalizing to their parental molecule revealed putative tRF sequences with shared cleavage sites. Based on connections among mtDNA SNP, the resulting SNP-dependent tRF, and SNP-metastasis correlation, we propose that these tRF may function as metastasis modifiers. These data also expand the functional output of the mitochondrial genome that can contribute to phenotype modification.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-26-0360
  40. Int J Mol Sci. 2026 Jul 28. pii: 6756. [Epub ahead of print]27(15):
    Rare AFG3L2 and POLG Variants Suggest a Role for Mitochondrial Dysfunction in Enteric Neuronal Vulnerability in Idiopathic Achalasia.
    Anna Latiano, Francesca Tavano, Lucia Micale, Luigi Bisceglia, Tommaso Biagini, Giulia Mantini, Marco Gentile, Antonio Merla, Fabrizio Bossa, Giuseppe Biscaglia, Tiziana Latiano, Alessandra Pia Bisceglia, Vito Annese, Marco Castori, Tommaso Mazza, Orazio Palmieri.
      Idiopathic achalasia is a rare esophageal motility disorder characterized by the selective degeneration of inhibitory myenteric neurons. Its genetic basis remains poorly defined. We investigated whether rare coding variants may contribute to disease susceptibility. Exome sequencing was performed in 31 individuals with idiopathic achalasia and seven unaffected relatives. Candidate variants were prioritized using phenotype-driven filtering and assessed through in silico and structural analysis of publicly available gene expression and single-cell transcriptomic datasets. No pathogenic or likely pathogenic variants were identified in achalasia-associated genes. A gene-agnostic analysis identified two rare heterozygous missense variants in unrelated patients: AFG3L2 c.2105G>A (p.Arg702Gln) and POLG c.1760C>T (p.Pro587Leu). Both genes encode mitochondrial proteins involved in neuronal homeostasis. The variants affected conserved residues, mapped to functionally relevant protein regions, and were predicted by multiple computational approaches to affect protein stability and function. Both genes were highly expressed in esophageal tissue, with AFG3L2 showing enrichment in enteric neuronal populations. These exploratory findings support a potential link between mitochondrial dysfunction, enteric neurodegeneration, and idiopathic achalasia. Rare mitochondrial-related variants may contribute to disease susceptibility in selected individuals by increasing vulnerability of inhibitory enteric neurons, although functional validation and larger studies are required. Accordingly, our findings should be considered hypothesis-generating rather than evidence of causality.
    Keywords:  achalasia; exome sequencing; in silico analysis; inhibitory neurons; mitochondrial dysfunction; rare variants
    DOI:  https://doi.org/10.3390/ijms27156756
  41. Front Med (Lausanne). 2026 ;13 1901004
    Mapping artificial intelligence in problem-based and case-based medical education: a bibliometric analysis (2019-2026).
    Qingyuan Tan, Yukui Ma, Jichun Zhao, Huanrui Hu.
       Introduction: Problem-based learning (PBL) has been a cornerstone of medical education since its introduction at McMaster University in the 1960s. Since the public release of ChatGPT in November 2022, artificial intelligence (AI) tools have increasingly been applied to PBL and case-based learning (CBL) contexts, yet the research landscape at this intersection remains poorly characterized. This study aimed to map the growth trajectory, thematic structure, and collaboration networks of AI-PBL/CBL research from 2019 to 2026.
    Methods: A comprehensive search of Scopus and Web of Science was conducted on June 2, 2026, combining AI-related terms with PBL/CBL frameworks and medical education contexts. Using a PRISMA-guided bibliometric review workflow, 1,616 records were identified; after deduplication and eligibility screening, 735 unique publications (2019-2026, original articles, reviews, conference papers, and other eligible indexed document types) were included. Bibliometric analyses employed VOSviewer for network visualization (keyword co-occurrence, co-authorship, co-citation), CiteSpace for citation burst detection, and Bibliometrix for thematic mapping, three-field plot, and factorial analysis.
    Results: Publication output grew from 25 papers in 2022 to 254 in 2025, with 206 papers indexed by June 2, 2026. The United States (n = 70) and China (n = 64) led publication volume. Keyword co-occurrence analysis identified four thematic clusters: a central AI-focused cluster, a medical education and clinical reasoning cluster, a nursing and simulation-oriented cluster, and an educational technology cluster. Kung et al.'s 2023 study evaluating ChatGPT's performance on the USMLE was the most frequently co-cited reference (62 co-citations, betweenness centrality = 0.11). Thematic mapping positioned machine learning as a motor theme, while clinical reasoning, medical education, and self-directed learning appeared in the basic themes quadrant. The country/region collaboration network comprised 33 countries/regions and was led by the United States and China, although collaboration patterns remained uneven across regions.
    Conclusion: To our knowledge, this is the first bibliometric study specifically focused on the intersection of AI technologies with PBL/CBL in health professions education. The findings reveal rapid growth after 2023, four distinct but interconnected research clusters, and a collaboration network led by the United States and China, with uneven regional participation. These results may inform curriculum design and research priorities in AI-enhanced medical education.
    Keywords:  ChatGPT; PBL (problem based learning) model; artificial intelligence - AI; bibliometric analysis; case-based learning (CBL); clinical reasoning; large language models (LLM); medical education - graduate
    DOI:  https://doi.org/10.3389/fmed.2026.1901004
  42. Hum Gene Ther. 2026 Aug 09. 10430342261474315
    Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia.
    Federica Pilotto, Laure Dall'Agnol, Laurence Reutenauer, Marie Paschaki, Hélène Puccio.
      Friedreich ataxia (FA) is a progressive neurodegenerative disorder caused by reduced expression of frataxin (FXN), a mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis. Although gene therapy strategies aimed at restoring FXN have shown promise, excessive expression can lead to mitochondrial dysfunction, emphasizing the importance of maintaining FXN within a physiological range. Here, we evaluated a gene therapy approach based on a human mini-frataxin construct (miniFXN7) incorporating an endogenous regulatory element to enable controlled FXN expression. The construct was delivered systemically using an AAV-PHP.eB vector in the Pvalb-cKO mouse model of FA. MiniFXN7 treatment resulted in widespread neuronal transduction and restoration of FXN expression toward a near-physiological range in the neuronal populations examined. Treated mice exhibited sustained improvements in motor coordination and proprioceptive function, including normalization of H-reflex responses. At the cellular level, miniFXN7 restored succinate dehydrogenase activity, a mitochondrial Fe-S enzyme, and was associated with partial normalization of mitochondrial morphology. In parallel, neuronal integrity was preserved and astrogliosis reduced across the cerebellum. These findings demonstrate that physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue in FA, supporting a gene therapy strategy based on a transgene expression driven by endogenous regulatory elements.
    Keywords:  Friedreich ataxia; Pvalb-cKO mouse; gene therapy; miniFXN7
    DOI:  https://doi.org/10.1177/10430342261474315
  43. Biochim Biophys Acta Mol Cell Res. 2026 Aug 12. pii: S0167-4889(26)00106-0. [Epub ahead of print] 120207
    Mitochondrial RNA polyadenylation: Defining RNA fate through 3' end regulation.
    Linden Muellner-Wong, William Carter, Christoph Freyer, Anna Wredenberg.
      Polyadenylation is a conserved post-transcriptional RNA modification with fundamentally different consequences for RNA fate across biological systems. In bacteria, chloroplasts, and plant mitochondria, adenylation is generally associated with RNA turnover and degradation, whereas its role in metazoan mitochondria remains incompletely understood. In metazoa, polyadenylation is best known for generating complete UAA stop codons in a subset of mitochondrial mRNAs. However, this explanation does not fully account for the evolutionary conservation of the modification, its diverse RNA substrates, or the broad phenotypic consequences of disrupted polyadenylation. In this review, we re-examine RNA adenylation and propose that, in metazoan mitochondria, polyadenylation primarily establishes a permissive 3' end state that governs RNA maturation, stability, translational competence, and decay. This perspective provides a unifying explanation for the diverse functions attributed to mitochondrial polyadenylation.
    Keywords:  Gene expression; Mitochondria; Polyadenylation; RNA homeostasis; mtPAP
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120207
  44. BMC Med Inform Decis Mak. 2026 Aug 12. pii: 313. [Epub ahead of print]26(1):
    Decentralized rare disease studies in Germany: first results and hurdles of secondary use of patient data.
    Michele Zoch, Christian Gierschner, Jens Weidner, Martin Sedlmayr, Gabriele Müller, Daniela Choukair, Georg F Hoffmann, Nicole Toepfner, Reinhard Berner, Fabian Prasser, Josef Schepers, Helge Hebestreit.
       BACKGROUND: The research challenges associated with rare diseases is characterized by a scarcity of information as well as reliable data due to their low prevalence. The problem of the "underpowered studies" is stemmed from a small research community, limited study participants and scarce data. The German project "Collaboration on Rare Diseases - Medical Informatics" (CORD-MI), tackles these problems by improving research opportunities and patient care by employing innovative IT solutions for collaborative data use across 20 German university hospitals. One possibility was to conduct decentralized studies based on secondary data. Three studies based on four rare diseases served as examples: (1) Cystic Fibrosis (CF), (2) Phenylketonuria (PKU), and (3) Kawasaki Disease and Multisystem Inflammatory Syndrome in Children (MIS-C).
    METHODS: All three decentralized studies were conducted using routine inpatient data from German university hospitals. For each use case, an interdisciplinary team defined research questions, created analysis scripts based on the Core Data Set of the Medical Informatics Initiative (MII), executed these locally at participating sites, and aggregated anonymized results for descriptive statistical analysis. A frequency threshold rule was applied to protect patient privacy. Study protocols and analysis scripts for data extraction and evaluation are publicly available, and the studies were reported in detail in accordance with the Reporting of Studies Conducted Using Observational Routinely-Collected Health Data (RECORD) Statement.
    RESULTS: Results from up to 17 German university hospitals were achieved for all three decentralized studies. The challenges in the areas of health care process bias, inaccurate coding of rare diseases, difficult verification of study results, and loss of information due to masking of small study case numbers as well as imprecise definition of the cohorts are discussed.
    CONCLUSIONS: Naming the hurdles enables the identification of areas for improvements, which will be the base for the development of new approaches or adaptations of existing tools and methodologies for the future. Although adaptation would make an impact, the initial results already show that decentralized analyses based on secondary use of patient data can improve research and thus also the care for people with rare diseases.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Decentralized study; Health care process bias; Interoperability; Rare diseases; Secondary data analysis
    DOI:  https://doi.org/10.1186/s12911-026-03688-7
  45. Clin Case Rep. 2026 Aug;14(8): e73294
    Regression, Ataxia, and Nystagmus in a Toddler: Unraveling a Rare Neurodegenerative Disorder.
    K Venkataramana Reddy, Agasthya Daggu, Sumanth Reddy Mudiyala, Siddartha Reddy Gangapuram, M Geethika, Lakshya Nehal Samineni.
      Infantile neuroaxonal dystrophy (INAD) should be considered in any toddler presenting with psychomotor regression and cerebellar atrophy, even when basal ganglia iron deposition is absent on initial MRI. Molecular genetic testing of PLA2G6 is essential for definitive diagnosis, enabling accurate genetic counseling and timely multidisciplinary supportive care.
    Keywords:  PLA2G6 ProteinHuman; cerebellar atrophy; genetic; infantile neuroaxonal dystrophy; neurodegeneration with brain Iron accumulation; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/ccr3.73294
  46. Clin Pharmacol Ther. 2026 Aug 13.
    Regulatory Research Priorities for AI Use in the Medicine Lifecycle: A European Perspective with Global Relevance.
    Luis C Pinheiro, Amanda C Langston, Marie Orre, Joerg Zinserling, Konstantina Boumaki, Bastian V H Hornung, Siobhan O'Sullivan, Gabriel Westman, Karl Broich, Peter Arlett.
      Regulatory bodies play a central role in providing guidance that enables safe and effective use of artificial intelligence tools in medicine development and evaluation. Regulators can also act as catalysts for regulatory science research. To inform these efforts, a European-wide survey was conducted to solicit stakeholder perspectives on the priority areas for regulatory science research related to the use of artificial intelligence in the medicine lifecycle. Twenty-eight regulatory science research questions were developed covering seven thematic domains: (1) research integrity and intellectual property; (2) accuracy and reliability of AI tools; (3) data governance, confidentiality, and consent; (4) regulation and oversight; (5) ethics, fairness, and bias prevention; (6) resources and support for AI use; and (7) impact on jobs and skills. Within each domain, stakeholders ranked four research challenges. A total of 273 responses were collected from regulators, pharmaceutical industry professionals, patients and consumers, academics, and healthcare professionals. Rankings of research challenges frequently converged across stakeholder groups and levels of AI experience. The top-ranked research questions within each domain were weighted according to the overall importance ranking of each domain to identify a list of 10 priority areas of research. The majority of the 10 priority areas fell within the domains of "Accuracy and reliability of AI tools," "Data governance, confidentiality, and consent," and "Ethics, fairness, and bias prevention." This list aims to support researchers and research funding bodies in addressing knowledge gaps on artificial intelligence in the medicines lifecycle.
    DOI:  https://doi.org/10.1002/cpt.70400
  47. J Comp Eff Res. 2026 Aug 12. e250179
    Burden of fatigue or pruritus in patients with primary biliary cholangitis: a United States matched case-control study.
    Sonal Kumar, Nisreen Shamseddine, Hongbo Yang, Su Zhang, Jingyi Chen, Kris V Kowdley.
      Aim: Primary biliary cholangitis (PBC) is a rare liver disease associated with high morbidity. This study assessed the burden of fatigue and/or pruritus among patients with PBC in the US. Materials & methods: This retrospective study used IQVIA PharMetrics® Plus data (2016-2022). Patients with PBC and fatigue and/or pruritus were selected as cases. Controls were patients with PBC (no fatigue nor pruritus), matched 1:1 to cases by key characteristics. The index date for cases was a random symptom diagnosis date post-initial PBC diagnosis and for controls, a random medical visit date matching the time distribution from initial PBC diagnosis to index. Cumulative incidence of PBC comorbidities was described using Kaplan-Meier analysis and compared via Cox Proportional hazard models. Generalized estimating equations compared healthcare resource use (HRU) and costs per-patient-per-year. Results: A total of 1839 fatigue cases/controls (mean age [years]: 56.5; 88.7% female) and 760 pruritus cases/controls were included (mean age [years]: 55.8; 90.8% female). Comorbidities at 1, 3 and 5-years post-index were higher for cases than controls (fatigue: 1.7 vs 0.7, 2.2 vs 0.9 and 2.5 vs 1.0; pruritus: 1.9 vs 0.8, 2.3 vs 1.0 and 2.7 vs 1.0; all p < 0.001). Common comorbidities were anxiety, urinary tract infection, depression and sleep disorders (hazard ratios in cases vs controls: fatigue, 1.3-4.0; pruritus, 1.5-2.8; all p < 0.01). One-year post-index, cases had higher rates of healthcare visits (incidence rate ratios: fatigue, 1.8-5.8; pruritus 1.6-6.1) and total healthcare costs (mean cost difference: fatigue, $42,515; pruritus $40,536). Conclusion: Patients with PBC who experience fatigue and/or pruritus faced a greater clinical and economic burden compared with those without these symptoms, highlighting the need for effective treatments to alleviate PBC symptoms.
    Keywords:  comorbidity burden; fatigue; primary biliary cholangitis; pruritus; rare disease; real-world data
    DOI:  https://doi.org/10.57264/cer-2025-0179
  48. Int J Mol Sci. 2026 Jul 23. pii: 6569. [Epub ahead of print]27(15):
    Circadian Disruption Is Associated with Elevated Whole-Semen mtDNA Copy Number and Implicates CRY1 as a Candidate Regulator in Humans and Mice.
    Mengchao He, Chuanyu Chen, Jing Gu, Yimeng Wang, Yingzhong Dai, Siwen Luo, Xiaolu Zhao, Baojian Wu, Jia Cao, Qing Chen.
      Circadian disruption has been linked to impaired male fecundity, but its association with semen molecular phenotypes and circadian genes remains unclear. We analyzed 441 men from the Male Reproductive Health in Chongqing College Students cohort to assess whether social jetlag, an indicator of circadian disruption, was associated with whole-semen mitochondrial DNA copy number (mtDNAcn), an emerging biomarker of male fecundity. Core circadian genes related to mtDNAcn were screened using genetic polymorphism data. A light-cycle phase-shifting mouse model, Cry1-knockout mice, and testicular Cry1 re-expression models were used for experimental validation, with histology, transcriptomics, single-cell data, and proteomics analyses used to explore mechanisms. Social jetlag was associated with higher mtDNAcn in men (1.29-fold, p = 0.026), with a concordant increase in circadian-disrupted mice (1.33-fold, p = 0.010). Among core circadian genes, CRY1 showed the strongest association with mtDNAcn (p = 0.048). Cry1 knockout elevated mtDNAcn (2.18-fold, p < 0.001), whereas testicular Cry1 re-expression reduced it toward wild-type levels. Circadian disruption and Cry1 deficiency were accompanied by seminiferous epithelial disorganization, spermatogenesis-related transcriptomic changes, and altered mitochondrial pathway signatures. To our knowledge, this study is the first to identify whole-semen mtDNAcn as a circadian-disruption-associated molecular phenotype and supports CRY1 as a candidate regulator.
    Keywords:  circadian disruption; circadian genes; semen mitochondrial DNA copy number (mtDNAcn); social jetlag; spermatogenesis
    DOI:  https://doi.org/10.3390/ijms27156569
  49. Front Neurol. 2026 ;17 1930461
    Editorial: Psychiatric comorbidities of neurogenetic and neurodegenerative diseases.
    Rui Ban, Li Wang, Xiaohui Duan, Kai Dong, Anthony L Vaccarino.
      
    Keywords:  ADHD; CADASIL; Parkinson's disease; Wilson's disease; chorea-acanthocytosis; cognitive impairment; pantothenate kinase-associated neurodegeneration; primary coenzyme Q10 deficiency
    DOI:  https://doi.org/10.3389/fneur.2026.1930461
  50. Mol Neurobiol. 2026 Aug 08. pii: 822. [Epub ahead of print]63(1):
    Targeting Mitochondria for Postoperative Cognitive Dysfunction: From Mechanisms to Therapeutics.
    Ao Zhang, Ayang Zhao, Guibo Fan, Liangcan He, Sihua Qi.
      Postoperative cognitive dysfunction (POCD) is a frequent neurological complication in older surgical patients, leading to substantial declines in quality of life and placing a considerable burden on society. This review provides a comprehensive overview of how mitochondrial dysfunction contributes to POCD, including disrupted energy metabolism, excessive reactive oxygen species production, calcium imbalance, and abnormalities in mitochondrial dynamics and quality control processes. These mitochondrial impairments further trigger neuroinflammation and activate multiple cell death pathways. In addition, the review examines current mitochondria-targeted therapeutic strategies and their underlying mechanisms, highlighting the neuroprotective roles of agents such as SS-31, Mdivi-1, P110, and NLRP3 inhibitors in preclinical studies. It also explores the promise of multi-target combinational treatments, time-specific interventions, and individualized therapeutic approaches. Finally, the review discusses key barriers to clinical translation such as limited blood-brain barrier permeability, unintended drug effects, and altered pharmacokinetics in the elderly and considers emerging technologies, including nanocarrier drug-delivery systems and AI-guided personalized treatment plans, as potential tools for achieving more precise prevention and management of POCD.
    Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Neuroinflammation; Postoperative cognitive dysfunction (POCD); Targeted therapy
    DOI:  https://doi.org/10.1007/s12035-026-06120-3
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