bims-polgdi Biomed News
on POLG disease
Issue of 2025–11–16
sixty papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
  2. Alternative start codon selection shapes mitochondrial function and rare human diseases.
  3. Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
  4. Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling.
  5. Unlocking extracellular mitochondria from bench to clinical application in stroke.
  6. Calmodulinopathies: the need for a registry.
  7. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
  8. Liver Involvement in POLG Disease-a Multicentre Cohort Study of 202 Patients.
  9. Mitochondrial Genome Variants and Nuclear Mitochondrial DNA Segments in 7331 Individuals from NyuWa and 1KGP.
  10. Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.
  11. Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.
  12. Testing the mother's curse hypothesis in human mitochondrial genome evolution.
  13. From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
  14. Triphenylphosphonium-based mitochondrial targeting in cancer therapy: mechanisms, progress, and perspectives.
  15. Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies.
  16. Developmental Differences in Myocardial Mitochondrial Reticulum Networks in the Offspring Exposed to Diabetic Pregnancy.
  17. The Pedigree Study of Leber's Hereditary Optic Neuropathy in Korean Population.
  18. Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.
  19. Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.
  20. Migrasomes: Emerging players in intercellular communication and disease pathogenesis (Review).
  21. Residual Genetic Material in Mature Red Blood Cells.
  22. Gene Therapy in Rare Genetic Disorders: Current Progress and Future Perspectives.
  23. The legacy of Bruce Ames and mitochondrial DNA mutagenicity: integrating oxidative stress, aging, and modern perspectives.
  24. Therapeutic potential of natural compounds in the management of chronic diseases: Targeting PINK1-Parkin pathway.
  25. CRISPR-Based Functional Genomics in Pluripotent Stem Cells.
  26. Intranasal delivery of lipid-based nanoparticles for the treatment of neurodegenerative diseases: advances, challenges and future perspectives.
  27. Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.
  28. Mitochondrial cargo quality determines the paracrine effects of extracellular vesicles derived from vascular endothelial cells.
  29. Extracellular vesicles from mesenchymal stromal cells: an emerging therapy for intractable neonatal disorders.
  30. GREGoR: accelerating genomics for rare diseases.
  31. Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
  32. Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.
  33. Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington's Disease Neuropathology.
  34. Aging and immunity.
  35. Probiotics Ameliorate Aging-Related Cognitive Impairments and Pathological Changes through Alleviating Telomere Attrition and Enhancing Mitochondrial Function in Senescence-Accelerated Mouse Prone 8 Mice.
  36. Comprehensive clinical and genetic characterization of Bardet-Biedl Syndrome: insights from the largest Turkish cohort.
  37. Sphingolipid and methionine metabolism in aging.
  38. Induced Pluripotent Stem Cells (iPSC) and Their Use in Disease Modeling.
  39. GenTIGS: a database empowering research and clinical insights on rare genetic disorders with an Indian perspective.
  40. A Novel Digital Platform to Support Child and Family Mental Health in Australia (Child and Family eHub): Protocol for a Mixed Methods Evaluation.
  41. Rare liver diseases - Etiology, diagnosis and management: A review.
  42. Uncommon yet impactful - case-based reflections on rare neurologic disorders.
  43. Hypoxia-preconditioning human bone marrow-derived mesenchymal stem cells induce high-quality mitochondrial transfer through gap junctions to alleviate ischemia-reperfusion injury in liver graft.
  44. Acute Respiratory Distress Syndrome Caused by Varicella Pneumonia in an Immunocompetent Adult: A Case Report.
  45. A Case for Disease-Specific Biomarkers for Rare Genetic Disorders.
  46. RARE-X: A Patient-Driven Approach for Collecting Symptom and Patient-Reported Outcome Data in Rare Diseases.
  47. The drug discovery and therapeutic nano-strategies targeting cellular senescence.
  48. Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
  49. Aligning with regulatory agencies for the use of digital health technologies in drug development: a case study from Parkinson's disease.
  50. Therapists' and patients' experiences with electronic patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) before and during treatment in community mental health services: a qualitative study in Norway.
  51. Brain hacks: Engineering a microbial factory for Parkinson's disease.
  52. Knowledge and attitudes about epilepsy of neurology outpatients in Türkiye.
  53. Design and application of synthetic human gut microbial communities.
  54. Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.
  55. STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
  56. Natural compounds targeting mitochondrial metabolism in cancer therapy: a literature review.
  57. Orphan drugs: The final frontier in the fight against rare diseases.
  58. Extracellular vesicles in pulmonary diseases: roles and therapeutic potential.
  59. The molecular mechanisms of cuproptosis and its role in central nervous system diseases.
  60. M3Hep: A Multimodal Hepatotoxicity Prediction Model Combining Mitochondrial Toxicity and Masking Strategy.
  1. Int J Mol Sci. 2025 Oct 22. pii: 10275. [Epub ahead of print]26(21):
    Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
    Shruti Somai, Chioma H Aloh, Dillon E King, William C Copeland.
      Mitochondria are vital for cellular energy production, as these organelles generate most of the cellular energy required for various metabolic processes. Mitochondria contain their own circular DNA, which is present in multiple copies and is exclusively maternally inherited. Cellular energy in the form of adenosine 5'-triphosphate is produced via oxidative phosphorylation and involves the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. Mitochondrial DNA itself is replicated by a dedicated set of nuclear-encoded proteins composed of the DNA polymerase gamma, the Twinkle helicase, the mitochondrial single-stranded DNA binding protein, as well as several accessory factors. Mutations in these genes, as well as in the genes involved in nucleotide metabolism, are associated with a spectrum of mitochondrial disorders that can affect individuals from infancy to old age. Additionally, mitochondrial disease can arise as a result of point mutations, deletions, or depletion in the mitochondrial DNA or in genes involved in mitochondrial transcription, replication, maintenance, and repair. Although a cure for mitochondrial diseases is currently elusive, several treatment options have been explored. In this review, we explore the molecular insights of the core mitochondrial replisome proteins that have aided our understanding of mitochondrial diseases and influenced current therapies.
    Keywords:  DNA polymerase γ; PolG; PolG2; Twinkle; mitochondria; mitochondrial diseases; mtDNA; mtDNA replication; mtSSB
    DOI:  https://doi.org/10.3390/ijms262110275
  2. Mol Cell. 2025 Nov 07. pii: S1097-2765(25)00854-8. [Epub ahead of print]
    Alternative start codon selection shapes mitochondrial function and rare human diseases.
    Jimmy Ly, Matteo Di Bernardo, Yi Fei Tao, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.
      Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.
    Keywords:  TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.013
  3. Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):
    Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
    Margherita Zamberlan, Martina Semenzato.
      Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.
    Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes
    DOI:  https://doi.org/10.3390/ijms262110581
  4. Brain Behav. 2025 Nov;15(11): e71045
    Characterization of Novel POLG Mutations in Mitochondrial Encephalomyopathy: Pathogenic Validation and Comprehensive Genetic Profiling.
    Fanjing Zhou, Jiang Chen, Tingzheng Zhang, Fengnan Niu, Jinglong Hu, Yun Xu, Meijuan Zhang.
       INTRODUCTION/AIMS: Mitochondrial encephalomyopathies are multisystem disorders caused by defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndrome is a rare manifestation, often associated with POLG mutations. This study identifies a novel POLG mutation in a SANDO patient, validates its pathogenicity, and analyzes the molecular genetics of 61 reported POLG-SANDO cases.
    METHODS: After obtaining informed consent, the proband underwent neurological examination, electromyography, muscle/nerve biopsies (histochemical/ultrastructural analyses), and genetic testing (whole-exome sequencing, mtDNA analysis). Pathogenicity of identified POLG variants was assessed in Cas9-mediated primary neuronal models expressing mutant proteins by measuring reactive oxygen species (ROS) levels and mtDNA copy number (qRT-PCR, ND1/APP ratio). Literature searches (PubMed, CNKI, Wanfang, and ClinVar) identified reported POLG mutations and clinical features in SANDO.
    RESULTS: Clinical and biopsy findings confirmed SANDO syndrome. Genetic analysis revealed compound heterozygous POLG mutations: a novel c.3297G>C (p.W1099C) and a known c.1774C>T (p.L592F). Neurons expressing either mutant exhibited elevated ROS levels (p < 0.05) and reduced mtDNA copy number compared with controls. Literature synthesis identified over 30 SANDO-associated POLG mutations, with p.A467T (31.2%) and p.W748S (22.1%) being the most frequent. The mean age of onset was 31.6 years.
    CONCLUSIONS: We identify a novel pathogenic POLG variant (p.W1099C) causing mitochondrial dysfunction via impaired mtDNA maintenance, expanding the SANDO genetic spectrum. Functional studies confirmed both mutations induce mitochondrial dysfunction (elevated ROS and decreased mtDNA Copy Number), validating their pathogenicity. The compiled mutation profile aids diagnosis of this phenotypically heterogeneous, frequently misdiagnosed disorder.
    Keywords:  POLG mutation; SANDO; mitochondrial encephalomyopathy
    DOI:  https://doi.org/10.1002/brb3.71045
  5. Stem Cells Transl Med. 2025 Nov 14. pii: szaf060. [Epub ahead of print]14(11):
    Unlocking extracellular mitochondria from bench to clinical application in stroke.
    Gen Hamanaka, Dong-Bin Back, Ji-Hyun Park, Shin Ishikane, Kazuhide Hayakawa.
      Within the central nervous system (CNS), mitochondria serve as vital energy sources for neurons, glial cells, and vascular functions, maintaining intracellular metabolic balance. Recent studies involving cellular models, rodents, and humans reveal that metabolically active mitochondria can be released into the extracellular space, playing roles in intercellular communication within the CNS. When taken up by neurons, these extracellular mitochondria may provide neuroprotective effects. Conversely, damaged mitochondria and their released components during severe tissue injury or inflammation can contribute to neurodegenerative processes. Thus, mitochondria secreted under pathological conditions in the CNS hold promise as biomarkers indicative of recovery. Additionally, transplantation of external mitochondria shows potential as a therapeutic approach for various CNS disorders. This mini review focuses on recent advances in the transfer of mitochondria between cells, the use of extracellular mitochondria as biomarkers, and the prospects of mitochondria transplantation from experimental research to clinical application, particularly in diseases like stroke.
    Keywords:  biomarkers; central nervous system; extracellular mitochondria; mitochondria transplantation; mitochondrial modification; stroke
    DOI:  https://doi.org/10.1093/stcltm/szaf060
  6. Europace. 2025 Oct 31. pii: euaf158. [Epub ahead of print]27(11):
    Calmodulinopathies: the need for a registry.
    Peter J Schwartz, Lia Crotti.
      Calmodulinopathies are very rare genetic disorders associated with a high risk for sudden cardiac death. Disease-causing variants in 1 of the 3 identical CALM genes cause severe forms of long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, or idiopathic ventricular fibrillation, and there are many unanswered questions concerning management and underlying mechanisms. What is currently known depends largely on the initial publications from the ICamR (International Calmodulinopathy Registry). However, progress is delayed because the accrual of patients in ICamR is slow. As we did long ago for long QT syndrome, this is a call for action, requesting doctors all over the world to enroll even their isolated cases in the Registry. This is the only way to obtain, for an adequate number of patients, the data necessary to define the spectrum of clinical manifestations and the genotype-phenotype correlation essential for an improved risk stratification and best therapeutic management. If you are willing to contribute, please contact us.
    Keywords:  Calmodulinopathies; Channelopathies; Genetics; Long QT Syndrome; Registries; Sudden cardiac death
    DOI:  https://doi.org/10.1093/europace/euaf158
  7. Sci Adv. 2025 Nov 14. 11(46): eaea4660
    The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
    Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4660
  8. J Inherit Metab Dis. 2025 Nov;48(6): e70112
    Liver Involvement in POLG Disease-a Multicentre Cohort Study of 202 Patients.
    Erle Kristensen, Karin Naess, Martin Engvall, Claus Klingenberg, Magnhild Rasmussen, Eylert Brodtkorb, Elsebet Ostergaard, Irenaeus de Coo, Leticia Pias-Peleteiro, Pirjo Isohanni, Johanna Uusimaa, Kari Majamaa, Mikko Kärppä, Mika H Martikainen, Juan Dario Ortigoza-Escobar, Trine Tangeraas, Siren Berland, Carolyn M Sue, Judith Sylvia Walker, Emma Harrison, Heather Biggs, Rita Horvath, Niklas Darin, Shamima Rahman, Omar Hikmat.
      Liver involvement in POLG disease is common and associated with high morbidity and mortality. Detailed, large-scale, systematic studies of liver involvement are lacking. This study aims to describe the onset, clinical course and prognostic implications of liver involvement in POLG disease. We conducted a multinational, retrospective study including clinical, genetic and biochemical data from patients with confirmed POLG disease. Patients were stratified according to age of disease onset: early-onset (< 12 years), juvenile/adult-onset (12-40 years), and late-onset (> 40 years). Of the 202 patients, 110 (54%) had liver involvement. This could present at any time during the lifespan, but occurred more frequently in patients with early-onset disease (76/98, 78%). Median onset age for liver involvement in females was 7 years (range: 1 month to 50 years), and 21 months in males (birth to 71 years). Infection-triggered disease onset carried a significantly higher risk of liver involvement than spontaneous or other disease triggers. Eighty-five percent of those with liver involvement also had epilepsy. Liver involvement was an indicator of poor prognosis and was significantly associated with worse survival. This study provides a comprehensive description of liver involvement in a large cohort of POLG disease patients. Liver involvement is common in this disease and associated with significantly worse survival. POLG disease should be considered in children presenting with liver involvement, and rapid genetic testing may guide management decisions. Our findings emphasize the need for early vigilance in monitoring liver involvement in all patients with confirmed POLG disease, particularly those with early-onset disease and during intercurrent infection.
    Keywords:  hepatopathy; liver disease; liver transplantation; mitochondrial disorder; mitochondriopathy; valproate
    DOI:  https://doi.org/10.1002/jimd.70112
  9. Genomics Proteomics Bioinformatics. 2025 Nov 05. pii: qzaf098. [Epub ahead of print]
    Mitochondrial Genome Variants and Nuclear Mitochondrial DNA Segments in 7331 Individuals from NyuWa and 1KGP.
    Yuanxin Wang, Jiajia Wang, Yanyan Li, Peng Zhang, Zhonglong Wang, Shuai Liu, Yiwei Niu, Yirong Shi, Sijia Zhang, Tingrui Song, Tao Xu, Shunmin He.
      Dysfunctional mitochondria are implicated in various diseases, however comprehensive characterization of mitochondrial DNA (mtDNA) in the Chinese population remains limited. Here, we conducted a systematic analysis of mtDNA from 7331 samples, comprising 4129 Chinese samples (NyuWa) and 3202 samples from the 1000 Genomes Project (1KGP). We identified 7216 distinct high-quality mtDNA variants, classified them into 22 macro-haplogroups, and detected 1466 distinct nuclear mitochondrial DNA segments (NUMTs). Among these, 88 mtDNA variants and 642 NUMTs were specific to NyuWa. Genome-wide association analyses revealed significant correlations between 12 mtDNA variants and 199 nuclear DNA (nDNA) variants. Our findings demonstrated that all individuals in both NyuWa and 1KGP harbored common NUMTs, while one-fifth possessed ultra-rare NUMTs that tended to insert into nuclear gene regions. Notably, rare NUMTs in the NyuWa cohort showed significant enrichment of nuclear breakpoints in long interspersed nuclear elements (LINEs) compared to 1KGP. Overall, this study provides the first comprehensive profile of NUMTs in the Chinese population and establishes the most extensive resource of Chinese mtDNA variants and NUMTs based on high-depth whole genome sequencing (WGS) to date, providing valuable reference resources for genetic research on mtDNA-related diseases.
    Keywords:  Mitochondrial DNA; NUMTs; Whole genome sequencing; mtDNA variants; mtDNA-nDNA variant association
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf098
  10. Cell Mol Neurobiol. 2025 Nov 10. 45(1): 101
    Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.
    Li Zhang, Ying Ge, Jingjing Wu, Mei Wang, Nanqu Huang, Yong Luo.
      Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.
    Keywords:  Mesenchymal stem cells; Mitochondrial damage; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s10571-025-01624-3
  11. Cells. 2025 Nov 05. pii: 1738. [Epub ahead of print]14(21):
    Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.
    Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.
      Mitochondrial dysfunction is a key contributor to cardiac injury and heart failure, and extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their ability to deliver mitochondrial-targeted cargo. This review systematically maps the evidence on how EVs modulate mitochondrial dynamics-including fusion, fission, mitophagy, and biogenesis-in regenerative cardiology. We comprehensively searched PubMed, Scopus, and Web of Science up to September 2025 for original studies. A total of 48 studies were included, with most utilizing EVs from mesenchymal stem cells, induced pluripotent stem cells, or cardiac progenitors. The review found that EV cargo influences key pathways such as DRP1 and MFN2, restores mitochondrial membrane potential, reduces ROS accumulation, and improves cardiomyocyte survival. While engineered EVs showed enhanced specificity, a lack of standardized preparation and quantitative assessment methods remains a significant challenge. We conclude that EV-mediated mitochondrial modulation is a promising strategy for cardiac repair, but the field needs harmonized protocols, deeper mechanistic understanding, and improved translational readiness to advance beyond preclinical research. The future of this research lies in integrating systems biology and precision targeting.
    Keywords:  EV-based drug delivery; cardiac regeneration; extracellular vesicles (EVs); heart failure therapy; mitochondrial biogenesis and mitophagy; mitochondrial dynamics; mitochondrial transfer; regenerative cardiology; stem cell-derived EVs; translational cardiovascular medicine
    DOI:  https://doi.org/10.3390/cells14211738
  12. Genome Biol Evol. 2025 Nov 05. pii: evaf207. [Epub ahead of print]
    Testing the mother's curse hypothesis in human mitochondrial genome evolution.
    Ruiqi Yuan, Jianzhi Zhang.
      In species where mitochondrial DNA (mtDNA) is maternally inherited such as vertebrates, mtDNA mutations harming males only are not subject to purifying selection and thus can spread in a population, especially when these mutations benefit females. Therefore, the mother's curse hypothesis (MCH) posits a greater mtDNA mutation load in males than in females. MCH is potentially important for human health, disease, and evolution, but a systematic test that considers the vast human mtDNA variation is lacking. Analyzing the genotypic and phenotypic data of approximately 0.5 million British participants in the UK Biobank, we estimate the reproductive fitness of mtDNA variants in each sex. Contradicting MCH, a positive intersexual correlation in the number of offspring exists across mitochondrial haplogroups. While a significant variation in the number of opposite-sex sexual partners-a proxy for reproductive fitness in premodern societies-is present among mitochondrial haplogroups, no significant intersexual correlation in this quantity is detected. The frequencies of a few mtDNA variants differ significantly between males and females, suggesting that these variants differentially affect the survival in the two sexes, but the number of such variants with lower male frequencies is not significantly different from that with lower female frequencies. Analysis of disease associations also finds no enrichment of male disease-associated mtDNA variants despite the discovery of multiple sex-biased disease associations. Together, these findings provide no genomic support to MCH in humans and suggest no difference in mtDNA mutation load between the two sexes that is detectable in the UK Biobank.
    Keywords:  GWAS; disease; fitness; mtDNA; mutation load; sex
    DOI:  https://doi.org/10.1093/gbe/evaf207
  13. J Extracell Vesicles. 2025 Nov;14(11): e70192
    From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
    Rostyslav Horbay, Vasyl Syrvatka, Artem Bedzay, Mikaela van der Merwe, Dylan Burger, Shawn T Beug.
      According to the endosymbiotic theory of mitochondrial origin, an α-proteobacterium entered a prokaryotic cell and, through symbiosis, evolved into the mitochondria-the powerhouse of the cell. Like other bacteria, the α-proteobacteria generate their own extracellular vesicles (EVs), a trait that was passed onto the mitochondria, enabling them to generate mitochondria-derived vesicles (MDVs). MDVs, similar to small EVs (sEVs), are vesicles ranging from 30 to 200 nm in diameter and carry cargo for degradation by lysosomes and peroxisomes. MDVs share several features with sEVs, including targeted cargo degradation, biogenesis, packaging into multivesicular bodies, nucleic acid and protein transportation, induction of immune responses, and surface antigen presentation. MDVs may also be released from the cell in a manner similar to sEVs, potentially influencing intercellular communication and immune responses. Furthermore, the presence of MDVs presents opportunities for early disease detection, including neurodegenerative disorders and cancer. In this review, we explore the differences and similarities between MDVs and EVs, including their roles in immunity.
    Keywords:  endosomal sorting complex required for transportation (ESCRT); endosome; lysosome; mitochondria‐derived vesicles (MDVs); mitophagy; multivesicular body (MVB); peroxisome; small extracellular vesicles (sEVs)
    DOI:  https://doi.org/10.1002/jev2.70192
  14. Chem Commun (Camb). 2025 Nov 14.
    Triphenylphosphonium-based mitochondrial targeting in cancer therapy: mechanisms, progress, and perspectives.
    Min Yang, Jiaming Ou, Haibo Yan, Yun He, Linling Gan, Shao-Lin Zhang.
      Targeting mitochondria has emerged as a promising anticancer strategy, as these organelles regulate tumor metabolism, apoptosis, and drug resistance. Triphenylphosphonium (TPP)-based strategies leverage the mitochondrial membrane potential to achieve selective accumulation in cancer cells, thereby providing a versatile platform for advancing precision cancer therapy. This review summarizes recent progress in the development of TPP-based anticancer agents, their mechanisms of action, and the current challenges. We also highlight future research directions, which will focus on designing multifunctional TPP molecules, integrating TPP-based therapeutics with complementary treatment modalities, and developing tissue- or cell-specific smart delivery systems. Additional promising strategies include combining TPP-based therapies with immunotherapy to overcome tumor immune evasion, targeting mitochondrial DNA to disrupt cancer bioenergetics, and employing TPP conjugates for fluorescence imaging to monitor drug distribution and mitochondrial targeting efficiency. Collectively, these approaches are expected to accelerate the clinical translation of TPP-mediated mitochondrial therapies, opening new avenues for precision oncology.
    DOI:  https://doi.org/10.1039/d5cc05709d
  15. Int J Mol Sci. 2025 Oct 29. pii: 10497. [Epub ahead of print]26(21):
    Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies.
    Ganna Nevoit, Maksim Potyazhenko, Ozar Mintser, Gediminas Jarusevicius, Alfonsas Vainoras.
      This perspective piece extrapolates knowledge of mitochondriology to the clinical aspects of cardiovascular disease (CVDs) development. The aim was to deepen the understanding of the etiopathogenesis of CVDs by conceptualizing the systemic involvement of mitochondrial dysfunction mechanisms in their follow-up. A theoretical comparison of mitochondrial status and mitochondrial dysfunction across stages of the cardiovascular continuum was performed based on a systematic analysis of the scientific literature data using general scientific, theoretical, and logical methods and normative rules. Conceptual aspects of the involvement of mitochondrial dysfunction (MD) mechanisms at each stage of the CVDs continuum were identified. MD is a dynamic, complex, multifactorial process that is characterized by quantitative and qualitative changes in the mitochondrial pool of human body cells during the development of CVDs. MD is a fundamental participant in the pathogenesis of CVDs, predetermining the nature and features of the clinical manifestation and course of the disease in each patient. MD has distinctive features at each stage of the catamnesis of CVDs and can be classified according to this principle. The development of objective methods for assessing the degree of MD and its classification criteria is a promising task for future scientific research.
    Keywords:  cardiovascular continuum; cardiovascular diseases; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms262110497
  16. Cells. 2025 Oct 29. pii: 1698. [Epub ahead of print]14(21):
    Developmental Differences in Myocardial Mitochondrial Reticulum Networks in the Offspring Exposed to Diabetic Pregnancy.
    Prathapan Ayyappan, Tyler C T Gandy, David Sturdevant, Tricia D Larsen, Pradeeksha Mukuntharaj, Andrew Paulson, Trace A Christensen, Jeffrey L Salisbury, Michelle L Baack.
      Diabetic pregnancy increases the offspring's risk of neonatal and adult cardiovascular disease (CVD). We previously used a rat model (Sprague-Dawley) to show that diabetic pregnancy impairs mitochondrial bioenergetics, dynamics, mitophagy, and quality control in the offspring's heart, and we hypothesized that mitochondrial dysfunction during early development influences the adult myocardium structure to confer cardiometabolic disease risk with aging. Here, we used 3D serial block face-scanning electron microscopy (SBF-SEM) to analyze perinuclear (PN) and intrafibrillar (IF) mitochondrial networks in the left ventricular sections from control and pregestational diabetes-exposed newborn (NB) rats that were three-week-old and four-month-old. Diabetes-exposed myocardium had 50% fewer PN and 20% fewer IF mitochondria at birth but counts increased more rapidly, resulting in no difference at three weeks and 35% more PN and 49% more IF mitochondria by four months. Despite rising counts, mitochondria volumes remained significantly lower at every developmental timepoint. This shows that diabetic pregnancy causes maldevelopment of the myocardial mitochondrial reticulum which likely contributes to adult CVD.
    Keywords:  diabetic pregnancy; heart disease; mitochondrial dynamics; mitochondrial networks; myocardial development; myocardial reticulum
    DOI:  https://doi.org/10.3390/cells14211698
  17. Semin Ophthalmol. 2025 Nov 14. 1-5
    The Pedigree Study of Leber's Hereditary Optic Neuropathy in Korean Population.
    Dong Hee Ha, Ungsoo Samuel Kim.
       PURPOSE: To investigate the pedigree-based penetrance analysis in Korean Leber hereditary optic neuropathy (LHON).
    METHODS: The pedigrees of 32 LHON patients' families were thoroughly examined. Index patients were probands diagnosed by mitochondrial DNA (mtDNA) mutation at the position of 11,778 or 11,484, while secondary cases were affected relatives ascertained through index cases. We identified susceptible and at-risk family members of the index patients. We categorized susceptible individuals as unaffected offsprings connected within the matrilineal lineage and at-risk individual as a susceptible individual under the age of 25. The penetrance rates for family members by their relationship with the index patients were analyzed. The differences in penetrance rates by degree of relationship and sex were also investigated.
    RESULTS: Among the 32 families, 29 (90.6%) had the 11,778 mutation, while 3 (9.4%) had the 14,484 mutation. The average penetrance rates were 37.1% for male and 10.2% for female. For Koreans, one previous study reported a ratio of 1.6:1, and in the present study, the ratio was found to be 2.3:1. The total number of individuals at risk was 24 (10 males and 14 females).
    CONCLUSIONS: This study expands previous research by offering new information on the penetrance of LHON in the Korean population through pedigree analysis.
    Keywords:  Epidemiology; Koreans; Leber hereditary optic neuropathy; pedigree; penetrance
    DOI:  https://doi.org/10.1080/08820538.2025.2588702
  18. Neurochem Res. 2025 Nov 10. 50(6): 354
    Mitochondria-Mediated Mechanisms of Ferroptosis in Neurological Diseases.
    Rujie Zhong, Hailin Yang, Xiaoyu Li, Feiyu Wang, Li Zhai, Jing Gao.
      Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of various neurological disorders. Mitochondria, the powerhouses of cells, play dual roles as both initiators and mediators of ferroptosis by integrating lipid peroxidation cascades, oxidative stress responses, and iron homeostasis dysregulation. This review first comprehensively explores the multifaceted mechanisms by which mitochondria mediate ferroptosis in neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS), epilepsy, stroke, and brain injury, with a focus on mitochondrial lipid peroxidation and iron metabolism dysregulation. Building on these mechanistic insights, we further discuss emerging evidence suggesting that targeting mitochondrial pathways may represent a promising therapeutic strategy for mitigating ferroptosis-associated neuronal damage. By synthesizing these findings, our review establishes a conceptual foundation for developing innovative neuroprotective interventions through precise modulation of mitochondrial function within ferroptotic pathways.
    Keywords:  Ferroptosis; Mitochondria; Neurological diseases; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s11064-025-04605-6
  19. Mitochondrion. 2025 Nov 12. pii: S1567-7249(25)00095-9. [Epub ahead of print] 102098
    Assessment of mitochondrial viability under calcium Stress: Insights for mitochondrial transplantation.
    Melody Toosky, Arash Kheradvar.
      Mitochondrial transplantation has emerged as a promising cardioprotective strategy for ischemia-reperfusion injury, aiming to restore bioenergetic function by delivering healthy mitochondria to damaged tissue. However, conflicting reports exist regarding whether mitochondria can survive exposure to the calcium-rich extracellular environment, such as the bloodstream, prior to cellular uptake. Resolving this question is essential for advancing the therapeutic use of mitochondria in clinical settings. Isolated mitochondria from L6 rat skeletal muscle cells were incubated with physiologic (1.3  mM), sub-physiologic (0.65  mM), and supraphysiologic (2.6  mM) concentrations of calcium. Mitochondrial membrane potential was assessed using MitoTracker™ Red FM fluorescence, and structural integrity was evaluated using impedance-based Coulter counter analysis over a 12-hour time course. Mitochondria exposed to 1.3  mM calcium retained 90-95 % membrane potential by 12 h, while 2.6  mM calcium caused progressive loss of function and integrity, approaching levels seen in freeze-thawed controls. Coulter counter measurements revealed more extensive mitochondrial loss across all calcium-treated groups than fluorescence assays alone, suggesting that dye-based methods may underestimate structural damage. Nonetheless, a substantial proportion of mitochondria remained both structurally and functionally intact at physiologically relevant calcium levels. These findings demonstrate that a substantial number of mitochondria can retain membrane potential and structural integrity after exposure to extracellular calcium concentrations approximating those found in blood. This supports the feasibility of intracoronary mitochondrial transplantation and underscores the need for further in vivo studies to optimize survival and efficacy of mitochondria delivered in calcium-rich environments.
    Keywords:  Calcium overload; Cardioprotection; Extracellular mitochondria; Intracoronary Delivery; Ischemia-reperfusion injury; Mitochondrial membrane potential; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.mito.2025.102098
  20. Mol Med Rep. 2026 Jan;pii: 36. [Epub ahead of print]33(1):
    Migrasomes: Emerging players in intercellular communication and disease pathogenesis (Review).
    Yuanliang Cao, Quan Wan, Boqi Zhou, Haixin Zeng, Xiaojie Lu.
      Migrasomes are novel extracellular organelles that were first reported in 2015. The present review summarizes the discovery, structural characteristics, biological functions and relationships of this new cellular organelle with diseases. Migrasomes are annular organelles that extend from the trailing edge of cells during cell migration and are rich in proteins, lipids, nucleic acids and other biomolecules. They serve important roles at multiple levels, including roles in cell‑cell communication, tissue remodeling and immune regulation. The formation and function of migrasomes are associated with the regulation of various molecules and signaling pathways, including nucleation, expansion and maturation. Migrasomes also have important roles in organ morphogenesis, angiogenesis, mitochondrial quality control and immune regulation. In addition, migrasomes are closely associated with the development of various diseases, including kidney diseases, pneumonia after stroke, neurodegenerative diseases and cancer, providing new perspectives and potential targets for disease diagnosis and treatment. For example, in cancer, migrasomes can act as positioning signals, regulating the invasion of liver cancer cells. In neurodegenerative diseases, migrasomes may have a role in clearing damaged mitochondria, thereby helping to alleviate inflammatory responses and cellular dysfunction. Collectively, these findings suggest that migrasomes have notable potential for use in clinical disease diagnosis and treatment.
    Keywords:  biomarkers; cell migration; cell‑cell communication; migrasomes; mitochondrial quality control
    DOI:  https://doi.org/10.3892/mmr.2025.13746
  21. Int J Mol Sci. 2025 Nov 05. pii: 10774. [Epub ahead of print]26(21):
    Residual Genetic Material in Mature Red Blood Cells.
    Georgios Dryllis, Sotirios P Fortis, Aspasia Kouroupaki, Ioannis Tsamesidis, Vassilios Birtsas, Andreas G Tsantes, Serena Valsami, Konstantinos Konstantopoulos, Effie G Papageorgiou, Ilias Pessach, Anastasios G Kriebardis.
      Mature erythrocytes are traditionally regarded as anucleate cells lacking nuclear DNA. However, evidence shows they retain residual genetic material, including mitochondrial DNA (mtDNA) and RNA fragments. This review explores the role of such genetic material in cellular function, diagnostics, and erythropoiesis. A comprehensive literature review was conducted, focusing on (i) erythropoiesis, (ii) enucleation of erythroid precursors, (iii) the presence of DNA in red blood cells (RBCs), and (iv) RNA fragments such as messenger RNA (mRNA), microRNA (miRNA), and other non-coding RNAs. Mature RBCs harbor small amounts of DNA and diverse RNA species. Residual DNA can act as damage-associated molecular patterns (DAMPs), triggering immune responses when released under stress or injury. RNA fragments reflect the transcriptional activity of precursor cells and have been linked to potential diagnostic applications. Studies suggest that RBC-derived RNA signatures may serve as non-invasive biomarkers for diseases such as diabetes, cardiovascular conditions, and hematological disorders. These profiles mirror changes in erythropoiesis and provide insights into systemic pathophysiology. Residual genetic material in RBCs extends their role beyond oxygen transport. It contributes to immune modulation and may provide novel diagnostic and therapeutic opportunities, enhancing disease detection and understanding of erythropoiesis.
    Keywords:  RBC; biomarkers; erythropoiesis; lncRNAs; miRNAs; red blood cells; residual genetic material
    DOI:  https://doi.org/10.3390/ijms262110774
  22. Curr Genomics. 2025 ;26(4): 278-289
    Gene Therapy in Rare Genetic Disorders: Current Progress and Future Perspectives.
    Sundus Khawaja, Raja Hussain Ali, Ishtiaq Ahmed, Muhammad Umair.
      Rare genetic disorders collectively affect millions of individuals worldwide, presenting a significant clinical and research challenge due to the diversity and complexity of the underlying mutations. Current treatment options are often limited, focusing on symptom management rather than addressing the root genetic causes. This review article aims to provide a perspective on the evolving field of gene therapy for rare genetic disorders, emphasizing recent advancements, current challenges, and future directions. A comprehensive review of recent advancements in gene therapy for rare genetic disorders was conducted, focusing on therapeutic strategies, delivery systems, and clinical outcomes. Key examples, such as the use of viral vectors and gene-editing technologies (e.g., CRISPR), were highlighted. The challenges, including immune responses and ethical concerns, were also examined. Gene therapy has achieved significant milestones, with the successful development of therapies like Zolgensma for spinal muscular atrophy and Luxturna for retinal dystrophy. However, several hurdles, including efficient gene delivery, immune reactions, and long-term safety, remain unresolved. Gene therapy holds transformative potential for the treatment of rare genetic disorders. While recent successes mark a new era in genetic medicine, ongoing research is required to refine delivery mechanisms, overcome immune-related barriers, and ensure ethical and safe therapeutic interventions.
    Keywords:  Gene therapy; Zolgensma; ex vivo gene therapy; in vivo gene therapy; rare genetic disorders
    DOI:  https://doi.org/10.2174/0113892029361490250310041259
  23. Front Mol Biosci. 2025 ;12 1710944
    The legacy of Bruce Ames and mitochondrial DNA mutagenicity: integrating oxidative stress, aging, and modern perspectives.
    Jennifer Dang, Jia Yu Liou, Rida Mullah, Cecilia Giulivi.
      
    Keywords:  Ames bacterial mutagenicity test; aging; mitochondrial dysfunction; mtDNA mutagenesis; nutrition; oxidative stress; triage theory
    DOI:  https://doi.org/10.3389/fmolb.2025.1710944
  24. Pathol Res Pract. 2025 Nov 07. pii: S0344-0338(25)00477-7. [Epub ahead of print]277 156284
    Therapeutic potential of natural compounds in the management of chronic diseases: Targeting PINK1-Parkin pathway.
    Naglaa F Khedr, Hend M Selim, Gamal A Abourayya.
      Chronic diseases like neurodegenerative disorders, musculoskeletal issues, metabolic diseases, cancer, liver and kidney disorders are increasingly linked to mitochondrial dysfunction. PINK1-Parkin-mediated mitophagy, a vital autophagic process, plays a central role in maintaining cellular homeostasis by selectively eliminating damaged mitochondria, which is crucial for preserving mitochondrial integrity and preventing reactive oxygen species accumulation. Activation of the PINK1-Parkin signaling pathway has emerged as a promising therapeutic strategy to restore mitochondrial function and attenuate disease progression. Recent studies have demonstrated that natural PINK1-Parkin activators offer significant therapeutic potential for treating a wide range of chronic diseases by modulating mitochondrial dynamics, alleviating cellular inflammation, and preventing mitochondrial damage. This review provides an in-depth analysis of the molecular mechanisms underlying PINK1-Parkin signaling, discusses the therapeutic benefits of natural activators, and presents them as a compelling strategy for addressing mitochondrial dysfunction and mitigating the progression of chronic diseases.
    Keywords:  Chronic liver diseases; Mitophagy; Musculoskeletal Disorders; Neurodegenerative disorders; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.prp.2025.156284
  25. Stem Cell Rev Rep. 2025 Nov 14.
    CRISPR-Based Functional Genomics in Pluripotent Stem Cells.
    Setareh Zahedi.
      The integration of CRISPR-based functional genomics with pluripotent stem cell (PSC) technologies has been recognized as a transformative approach for investigating gene function, modeling human disease, and advancing regenerative medicine. The aim of this review is to provide a comprehensive evaluation of recent developments in CRISPR-Cas platforms, including gene knockouts, base and prime editing, and CRISPR activation or interference (CRISPRa/i), as applied to PSC systems. Studies employing human PSCs, including embryonic stem cells and induced pluripotent stem cells, have been examined to summarize methodologies for genome-wide screening, lineage tracing, and therapeutic engineering. Advances in editing efficiency, delivery strategies, and genomic safety have been reported, while limitations persist in the form of off-target modifications, epigenetic variability, and cell-type-specific responses. Notable applications include the generation of immune-evasive PSC lines, the development of organoid models for physiological and pathological studies, and the implementation of phenotypic screening for disease-relevant traits. Collectively, these technological and methodological advancements have established functional genomics of PSC-CRISPRSPR as a versatile and powerful framework for elucidating fundamental aspects of human biology, dissecting complex traits, and accelerating the translation of discoveries from experimental research to clinical implementation.
    Keywords:  CRISPR; CRISPR-Cas systems; Embryonic stem cells; Functional genomics; Genome editing; Induced pluripotent stem cells; Pluripotent stem cells; Regenerative medicine; organoids
    DOI:  https://doi.org/10.1007/s12015-025-11019-y
  26. Expert Opin Drug Deliv. 2025 Nov 14. 1-19
    Intranasal delivery of lipid-based nanoparticles for the treatment of neurodegenerative diseases: advances, challenges and future perspectives.
    Xavier Mulet I Piera, Rubén Del Campo-Montoya, Mar Cuadrado-Tejedor, Ana Garcia-Osta, Elisa Garbayo, María J Blanco-Prieto.
       INTRODUCTION: Neurodegenerative diseases such as Parkinson's or Alzheimer's disease urgently require new therapeutic approaches. Despite significant efforts, no disease-modifying therapies targeting specific molecular pathways have demonstrated consistent clinical efficacy. This challenge has shifted attention toward drug delivery strategies that improve bioavailability, targeting, and patient accessibility. Intranasal delivery has emerged as a promising, non-invasive approach that bypasses the blood-brain barrier, and improves patient compliance. Lipid-based systems, especially following the success of COVID-19 vaccines, have gained attention as versatile platforms for delivering RNAs. Their ability to encapsulate diverse payloads and tunable composition makes them ideal candidates for targeting neurodegenerative disorders via the intranasal route.
    AREAS COVERED: This review discusses recent advances in intranasal delivery for the treatment of neurodegenerative disorders, emphasizing on lipid-based nanoparticles. It addresses formulation challenges such as stability, targeting efficiency, and compatibility with nasal physiology, and outlines key design parameters affecting brain delivery. Future directions are explored to advance formulation development and clinical translation.
    EXPERT OPINION: Intranasal lipid-based drug delivery represents a promising strategy to bypass the blood-brain barrier in neurogenerative disorder treatment. Although regulatory gaps and the absence of long-term safety evaluation, intranasal administration offers clear advantages for CNS targeting underscoring strong potential for future clinical translation.
    Keywords:  Blood-brain barrier (BBB); drug delivery systems; intranasal delivery; lipid-based nanoparticles; neurodegenerative diseases (NDs)
    DOI:  https://doi.org/10.1080/17425247.2025.2587903
  27. Cent Nerv Syst Agents Med Chem. 2025 ;25(4): 496-512
    Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.
    Nitika Garg, Sanchit Dhankhar, Ankush Dhariya, Chander Parkash, Samrat Chauhan, Thakur Gurjeet Singh.
      The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.
    Keywords:  Alzheimer's; Liposomes; amyotrophic lateral sclerosis.; disorders; huntington; neurodegeneration; parkinson's
    DOI:  https://doi.org/10.2174/0118715249342585241230065557
  28. Biomed Pharmacother. 2025 Nov 13. pii: S0753-3322(25)00945-X. [Epub ahead of print]193 118751
    Mitochondrial cargo quality determines the paracrine effects of extracellular vesicles derived from vascular endothelial cells.
    Zahid A Manzar, Lucas J Davis, Karl F Swanson, Erik Muñoz, Hazel H Szeto, Hans Minderman, B Rita Alevriadou.
      Cell-derived extracellular vesicles (EV) are mediators of intercellular communication with increased circulating levels of endothelial cell-derived EV (EC-EV) reported in cardiovascular diseases (CVD). The EC-EV ability to elicit either detrimental or restorative effects on target EC is thought to be, in part, due to horizontal transfer of their mitochondrial cargo. To understand the role of mitochondrial cargo in EC-EV paracrine effects, large EV were collected from media of cultured human EC, and the number of mitochondria-carrying EV (mitoEV), EV mitochondrial cargo mass, and mitoEV quality/polarization were quantified. EC activation with tumor necrosis factor (TNF)-α caused an increased release rate of EV (TNF-EV), including mitoEV that carried a larger and more depolarized mitochondrial cargo, compared to EV released from control EC (C-EV). EC co-treatment with TNF-α and the mitochondria-targeted antioxidant MitoTEMPO restored both the mitochondrial cargo quality and the number of mitoEV carrying polarized mitochondria to levels similar to C-EV. TNF-EV, but not C-EV, dose-dependently upregulated inflammatory gene expression in target naïve EC. Fluorescence microscopy showed the EV mitochondrial cargo to transfer and colocalize with the target EC mitochondrial network. Mitochondrial cargo depolarization of C-EV using carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone was sufficient for those EV to trigger inflammation in target naïve EC. In conclusion, the mitochondrial redox state of donor EC regulates mitoEV mitochondrial cargo quality that, at least in part, determines their capacity to cause target EC dysfunction and promote CVD. The mitochondrial membrane potential (ΔΨm) in EC-mitoEV may be a new biomarker and therapeutic target in vascular biology and medicine.
    Keywords:  Extracellular vesicles; Inflammation; Mitochondria; Mitochondrial membrane potential; Mitochondrial transfer; Vascular endothelial cell
    DOI:  https://doi.org/10.1016/j.biopha.2025.118751
  29. Stem Cells Transl Med. 2025 Sep 28. pii: szaf050. [Epub ahead of print]14(10):
    Extracellular vesicles from mesenchymal stromal cells: an emerging therapy for intractable neonatal disorders.
    Sein Hwang, Young Eun Kim, Misun Yang, So Yoon Ahn, Se In Sung, Yun Sil Chang.
      Neonatal disorders affecting different organs are highly multifactorial and involve a complex interplay among prematurity, inflammation, oxidative stress, tissue injury, immune dysregulation, and impaired regeneration. Conditions such as hypoxic-ischemic encephalopathy, intraventricular hemorrhage, neonatal stroke, bronchopulmonary dysplasia, and necrotizing enterocolitis often result from or cause multi-organ dysfunction. This multifaceted nature presents a substantial therapeutic challenge, as current treatment plans are largely supportive and are limited to addressing the underlying immaturity and injury. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutics owing to their ability to modulate inflammation, promote repair, and support organ maturation. By delivering a rich secretome of proteins, lipids, and regulatory RNAs, MSC-EVs retain the regenerative benefits of mesenchymal stromal cells while offering improved safety and storage. This review provides a comprehensive overview of MSC-EV therapy for neonatal disorders, focusing on the mechanisms of action, preclinical evidence, and future perspectives on clinical translation. By integrating the currently available study findings, this review highlights the potential of MSC-EVs as a multifaceted therapy for preterm infants, capable of addressing both tissue injury and developmental immaturity.
    Keywords:  mesenchymal stromal cell-derived extracellular vesicles; mesenchymal stromal cells; neonatal disorders; prematurity
    DOI:  https://doi.org/10.1093/stcltm/szaf050
  30. Nature. 2025 Nov;647(8089): 331-342
    GREGoR: accelerating genomics for rare diseases.
    GREGoR Partner Members
      Rare diseases are collectively common, affecting approximately 1 in 20 individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in next-generation sequencing, development of new computational and functional genomics approaches to prioritize genes and variants and increased global sharing of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Furthermore, all data generated, currently representing over 7,500 individuals from over 3,000 families, are rapidly made available to researchers worldwide through the Analysis, Visualization and Informatics Lab-space (AnVIL) to catalyse global efforts to develop approaches for genetic diagnoses in rare diseases. Most of these families have undergone previous clinical genetic testing but remained unsolved, with most being exome-negative. Here we describe the collaborative research framework, datasets and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.
    DOI:  https://doi.org/10.1038/s41586-025-09613-8
  31. Autophagy. 2025 Nov 13.
    Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
    Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.
    Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2589909
  32. Cells. 2025 Oct 27. pii: 1678. [Epub ahead of print]14(21):
    Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.
    Patrice X Petit.
      Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players.
    Keywords:  BH3 interacting domain death agonist (also BID-FL); BID; CLOOH; Cell death; DISC; GUV; MTCH2; Mitochondria; Mitochondrial Carrier Homolog 2; OMM outer mitochondrial membrane; cardiolipin peroxidized; death inducing signalling complex; giant unilamellar-vesicles; p15); tBID (truncated BID at the n terminal end
    DOI:  https://doi.org/10.3390/cells14211678
  33. Int J Mol Sci. 2025 Nov 01. pii: 10672. [Epub ahead of print]26(21):
    Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington's Disease Neuropathology.
    Hannah K Hale, Kayla M Elias, Shawn Ho, Gunnar F Kwakye.
      There are no disease-modifying treatments available for Huntington's disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson's and Alzheimer's, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdhQ7/Q7) or mutant (STHdhQ111/Q111) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function.
    Keywords:  3-nitropropionic acid (3-NPA); Huntington’s disease; methylene blue; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/ijms262110672
  34. Immunity. 2025 Nov 11. pii: S1074-7613(25)00473-X. [Epub ahead of print]58(11): 2609-2612
    Aging and immunity.
    Christoph A Thaiss, Ye Tian, Daniel A Winer, Michelle Linterman, Adrian Liston, Corina Amor, Scott W Lowe, Guang-Hui Liu.
      Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve not only longevity but also health span.
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.019
  35. J Agric Food Chem. 2025 Nov 14.
    Probiotics Ameliorate Aging-Related Cognitive Impairments and Pathological Changes through Alleviating Telomere Attrition and Enhancing Mitochondrial Function in Senescence-Accelerated Mouse Prone 8 Mice.
    Siquan Zhou, Shufang Shan, Ruirui Li, Xiaoyu Wang, Jingyuan Xiong, Guo Cheng.
      Aging-related cognitive impairment, characterized by DNA damage and mitochondrial dysfunction, still lacks effective treatment strategies. Recent findings suggest that Lactobacillus delbrueckii (LD), Streptococcus thermophilus (ST) and Bifidobacterium longum (LB) may have the ability to ameliorate mitochondrial dysfunction and DNA damage. Therefore, to elucidate the antiaging effects of these probiotics, we administered LD, ST, LB, and their combinations to 4 month-old senescence-accelerated-mouse-prone 8 (SAMP8) mice for 24 weeks. Consequently, these probiotics and their combinations alleviated neuronal damage, enhanced synaptic plasticity, mitigated telomere attrition, improved mitochondrial function, and enhanced cognitive and memory functions in aging SAMP8 mice. In the gut microbiota and metabolites, the relative abundance of Limosilactobacillus, Ligilactobacillus, piperidine-4-carboxamide, and Leu-Ile-Glu-Glu increased and that of Paramuribaculum decreased in the probiotic-treated SAMP8 mice. In summary, the antiaging effects, attributed to alleviating telomere attrition and enhancing mitochondrial function, for probiotics were confirmed in aging mice, with the probiotic combinations exhibiting a larger effect.
    Keywords:  SAMP8 mice; aging; cognitive impairment; gut microbiota; mitochondrial function; probiotics; telomere attrition
    DOI:  https://doi.org/10.1021/acs.jafc.5c09572
  36. Eur J Pediatr. 2025 Nov 11. 184(12): 748
    Comprehensive clinical and genetic characterization of Bardet-Biedl Syndrome: insights from the largest Turkish cohort.
    Şenol Demir, Bilgen Bilge Geçkinli, Çekdar Kapazan, Ayberk Türkyılmaz, Didem Dizdar Yiğit, Özlem Şahin, Mehmet Eltan, Esra Arslan Ateş.
      Bardet-Biedl Syndrome (BBS) is a rare, pleiotropic ciliopathy involving retinal dystrophy, polydactyly, obesity, and renal abnormalities. Despite growing knowledge of its genetic basis, data from populations with high rates of consanguinity remain limited. This study presents the largest genetically confirmed BBS cohort reported from Türkiye, consisting of 25 individuals who underwent clinical exome-based multigene panel testing. Biallelic pathogenic variants were identified in all patients, including three novel variants in the ARL6/BBS3, BBS9, and BBS10 genes, observed in four patients, including two siblings. Retinal dystrophy was the most common feature (94.1%), followed by polydactyly (88.0%), obesity (68.0%), and renal anomalies (52.0%). Genotype-phenotype comparisons highlighted notable variability, particularly among individuals with BBS1 and BBS10 pathogenic variants, consistent with prior international cohorts. This cohort underscores the clinical heterogeneity of BBS and reveals potential population-specific patterns shaped by consanguinity and genetic background. Our findings support the utility of multigene panels in clinical diagnosis and provide a basis for national registries and targeted care strategies for rare inherited diseases in underrepresented populations.
    Keywords:  Bardet–Biedl syndrome; Ciliopathy; Genotype–phenotype correlation; Next-generation sequencing; Turkish cohort
    DOI:  https://doi.org/10.1007/s00431-025-06592-w
  37. J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):
    Sphingolipid and methionine metabolism in aging.
    Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.
      Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.
    Keywords:  Aging; Metabolism; Methionine; Sphingolipids
    DOI:  https://doi.org/10.1242/jcs.264026
  38. Cureus. 2025 Oct;17(10): e93999
    Induced Pluripotent Stem Cells (iPSC) and Their Use in Disease Modeling.
    Alicja Dorota, Nicole Maryniak, Anna Mariankowska, Cezary Milczarek, Michal Dorota, Wojciech Zywiec, Karol Kozlowski, Illia Koval, Bartosz Czyzewski, Joanna Czyzewska.
      This paper reviews methodologies for culturing induced pluripotent stem cells (iPSCs) and highlights their applications in disease modeling and regenerative medicine. iPSCs can be reprogrammed from multiple somatic cell sources, including keratinocytes, fibroblasts, peripheral blood mononuclear cells, and urinary epithelial cells. Their ability to differentiate into patient-specific cell types provides unique opportunities to model neurodegenerative, cardiovascular, metabolic, and autoimmune disorders in vitro. Pluripotency is typically induced by the overexpression of four canonical transcription factors-Oct4, Sox2, Klf4, and c-Myc. iPSC culture is technically demanding, as the cells display genomic and epigenetic instability and require tightly controlled microenvironmental conditions to maintain viability and pluripotency. Rigorous quality control, including PCR-based assays and genomic integrity analyses, is essential. Advances in iPSC technology have enabled personalized disease modeling, mechanistic studies of pathogenesis, drug screening, and the development of precision therapies. Despite their translational promise, iPSCs remain limited by issues of genomic instability, clinical safety, and the lack of standardized culture protocols.
    Keywords:  biomarkers; genetic editing; in vitro experiments; induced pluripotent stem cells (ipscs); regenerative therapy
    DOI:  https://doi.org/10.7759/cureus.93999
  39. NAR Genom Bioinform. 2025 Dec;7(4): lqaf143
    GenTIGS: a database empowering research and clinical insights on rare genetic disorders with an Indian perspective.
    Iliyas Rashid, Pooja S, Shivranjani C Moharir, Rakesh K Mishra.
      Rare genetic disorders (RGDs) are conditions affecting fewer than 1 in 2000 individuals. Recent advances in genetics and healthcare renewed hope for better diagnosis and treatment. RGDs are common in India due to consanguinity and limited diagnostic testing. To converge the global- and India-specific knowledge about RGDs to a single platform for researchers, clinicians, and stakeholders, we developed GenTIGS database-a "go-to platform" for information retrieval and data analysis. GenTIGS is a comprehensive database containing information about genes, pathogenic variants, and clinical symptoms, with a focus on disorders reported globally and in India. GenTIGS delivers a variety of features and data points important to researchers, academicians, and clinicians in the RGD domain, ensuring efficient information retrieval. This platform provides information on 2306 RGDs and 2772 associated genes, including 691 disorders reported in India. It also includes details on 3525 clinical symptoms and 307 340 pathogenic variants for these disorders. GenTIGS offers comprehensive information and analytical tools for in-depth analysis and exploration of genes and variants associated with RGDs, thus supporting progress in genetic medicine and research through enhanced understanding and analysis. Accessible at https://db.tigs.res.in/gentigs/.
    DOI:  https://doi.org/10.1093/nargab/lqaf143
  40. JMIR Res Protoc. 2025 Nov 13. 14 e72548
    A Novel Digital Platform to Support Child and Family Mental Health in Australia (Child and Family eHub): Protocol for a Mixed Methods Evaluation.
    Suzy Honisett, Raghu Lingam, Valsamma Eapen, Brian Oldenburg, Naomi Hackworth, Harriet Hiscock, George Charalambous, Lisa Minton, Glenn Pringle, Sue Woolfenden, Kim Dalziel, John Eastwood, Sharon Goldfeld.
       BACKGROUND: Child mental health disorders are a significant Australian public health issue with high prevalence rates compounded by inequitably higher rates for those living in families with lower income, lower levels of parental education, and higher levels of unemployment. Prevention and early intervention approaches are critical to address problems early. When caregivers seek information and services to support their child's mental health needs, they commonly use many untested online search strategies. To address this, we developed a digital Child and Family eHub (eHub) prototype through a user-centered design process involving families experiencing adversity and local service providers. The eHub provides online navigation and evidence-based information for families and aims to increase equitable access to and use of (1) information and (2) the existing primary health, mental health, and social services system to improve mental health outcomes for caregivers with children aged 0-12 years. This protocol outlines how we will evaluate the eHub.
    OBJECTIVE: This study aims to evaluate the feasibility, acceptability, appropriateness, and preliminary impact of the eHub digital platform for caregivers of children aged 0-12 years, particularly those experiencing adversity. The evaluation will assess implementation outcomes, caregiver and child mental health outcomes, and help-seeking behaviors over a 6-month period.
    METHODS: A prospective cohort of 270 caregivers of children aged 0-12 years will be recruited from 3 socioeconomically diverse Australian sites (Wyndham Vale in Victoria and Marrickville and Fairfield in New South Wales). Participants will be recruited through local community hubs, health and social service providers, and social media, and will enroll via the REDCap (Research Electronic Data Capture; Vanderbilt University) survey platform. A mixed methods type 3 implementation impact evaluation will be undertaken, which tests an implementation strategy while observing and gathering information on the intervention's impact on relevant outcomes. In this protocol, implementation will be assessed as a primary outcome using Proctor's outcomes for the implementation framework, and secondary outcomes will include caregiver access and use of the eHub and associated child and parent mental health outcomes. Data will be collected at baseline and 6 months. Quantitative data will be analyzed using descriptive statistics and regression models; repeated measures will be analyzed using generalized estimating equations. Qualitative data will be analyzed using framework analysis.
    RESULTS: The study was funded in December 2021. Participant enrollment for the study began in February 2024, with participants involved in the eHub evaluation for 6 months.
    CONCLUSIONS: The results of this study will be instrumental in refining the intervention for future scaling to other Australian sites. This study has the potential to offer an accessible, cost-effective, and scalable digital solution to improve service navigation and mental health outcomes for children and families experiencing adversity.
    TRIAL REGISTRATION: ISRCTN Registry ISRCTN49839991; https://doi.org/10.1186/ISRCTN49839991.
    INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/72548.
    Keywords:  child health services; child mental health; consumer health information; digital health technology; family supports
    DOI:  https://doi.org/10.2196/72548
  41. Biomol Biomed. 2025 Nov 12.
    Rare liver diseases - Etiology, diagnosis and management: A review.
    Qi Long, Rawaz D Tawfeeq, Yu Jiang, Huabao Liu, Meiao Tan.
      Rare liver diseases (RLDs) are diverse and often misdiagnosed conditions that impose significant clinical and public health challenges due to their variable presentations and limited treatment options. This study aims to synthesize contemporary evidence on the etiology, classification, diagnostics, and management of RLDs and to identify near-term research and implementation priorities. We conducted a systematic search of PubMed and Scopus for the years 2015 to 2025 using predefined keywords. We included peer-reviewed human studies, such as guidelines, randomized trials, and large registries, focusing on mechanisms, diagnostic strategies, and treatments. We excluded animal studies and non-peer-reviewed reports, extracting data on disease biology, diagnostic tools, outcomes, and molecular therapies. RLDs can be categorized into genetic/inherited, autoimmune cholestatic, and other vascular/metabolic entities. Care for these diseases is increasingly guided by structured pathways that integrate biochemistry and serology with magnetic resonance cholangiopancreatography (MRCP), elastography, targeted next-generation sequencing (NGS), and selective biopsy. Emerging biomarkers, such as circulating microRNAs, alongside machine learning in imaging techniques, enhance disease staging and prognostication. Key management strategies include the use of bile-acid modulators, surgical interventions, and ileal bile acid transporter (IBAT) inhibitors for progressive familial intrahepatic cholestasis (PFIC). Lifelong copper chelation is recommended for Wilson disease, with trientine preferred for neurologic phenotypes. Supportive care in alpha-1 antitrypsin deficiency (A1ATD) is complemented by the investigation of molecular chaperones. Additionally, gene-directed therapies, gene editing, RNA-based approaches, and cell therapies show early promise but raise concerns regarding durability, safety, and ethical considerations, particularly for pediatric patients. In conclusion, implementing precision medicine frameworks that rely on standardized diagnostics, multicenter registries, and equitable access is crucial for facilitating earlier detection and translating mechanism-targeted therapies into sustainable, globally accessible benefits.
    DOI:  https://doi.org/10.17305/bb.2025.13278
  42. Neurol Neurochir Pol. 2025 Nov 13.
    Uncommon yet impactful - case-based reflections on rare neurologic disorders.
    Tomasz Chmiela, Zbigniew K Wszolek.
      Rare diseases (RDs) are a heterogeneous group of disorders defined by their low prevalence - affecting fewer than 1 in 2,000 individuals in Europe and fewer than 200,000 people in the US. Although individually uncommon, rare diseases collectively impact an estimated 263 to 446 million people worldwide. Early recognition and diagnosis remain major challenges, particularly in neurology, where overlapping phenotypes and limited awareness often delay appropriate management. We present 3 illustrative case studies highlighting the diagnostic and therapeutic complexities associated with rare neurologic disorders. The first case describes a patient with CSF1R-related disorder; diagnosis was significantly delayed due to initial misattribution of symptoms to traumatic brain injury. This delay ultimately precluded timely intervention with disease-modifying therapies such as hematopoietic stem cell transplantation. The second case involves a patient with frontotemporal dementia and parkinsonism linked to chromosome 17 with a pathogenic c.837T>G, p.N279K variant in the MAPT gene, also known as pallidopontonigral degeneration. Although a strong family history facilitated early diagnosis, the case underscores the broader challenges of managing hereditary neurodegenerative diseases within affected families. The third case presents an exceptionally rare scenario of dual pathogenic mutations in ATXN3 and ATXN8OS, resulting in concurrent diagnoses of spinocerebellar ataxia types 3 and 8. This case exemplifies the clinical ambiguity and interpretive difficulty posed by co-occurring rare variants with overlapping symptomatology. Collectively, these 3 cases emphasize the importance of accurate, timely diagnosis to avoid unnecessary testing in rare neurologic diseases. Timely recognition enables access to emerging personalized therapies and support systems.
    Keywords:  CSF1R-RD; MAPT; PPND; SCA; SCA3; SCA8; rare diseases
    DOI:  https://doi.org/10.5603/pjnns.108495
  43. Cell Commun Signal. 2025 Nov 13. 23(1): 495
    Hypoxia-preconditioning human bone marrow-derived mesenchymal stem cells induce high-quality mitochondrial transfer through gap junctions to alleviate ischemia-reperfusion injury in liver graft.
    Xinling Luo, Weiqi Zeng, Erfeng Xiong, Ziming Wang, Jingsheng Huang, Meiqi Luo, Zhongxian He, Jinyu Liu, Dongdong Yuan.
       BACKGROUND: Amid the widespread scarcity of donor livers, mitigating ischemia-reperfusion injury (IRI) of liver grafts is vital for ensuring early recovery of post-transplant liver function. Human bone marrow-derived mesenchymal stem cells (hBMSCs) have shown potential in alleviating IRI damage by regulating mitochondrial function. Hypoxia-preconditioning hBMSCs (hypo-hBMSCs) have shown considerable promise in enhancing therapeutic efficacy, yet the underlying mechanism remain to be elucidated. Therefore, this study aims to explore the role of hypo-hBMSCs in alleviating hepatic IRI and uncover their potential mechanisms, with the goal of offering new strategies for the application of hBMSCs in liver protection after transplantation.
    METHODS: Initially, we investigated the impact of hypoxia preconditioning on the quality of hBMSCs mitochondria and whether hypo-hBMSCs can alleviate IRI damage in liver grafts by transferring mitochondria. Subsequently, by employing the enhancer RA and the inhibitor Gap26 to modulate the function of gap junctions (GJs) in vivo and in vitro, we confirmed their crucial role in the process of hypo-hBMSCs transferring mitochondria to hepatocytes. Ultimately, through bioinformatics analysis, Co-IP, siRNA and overexpression, we demonstrate that the up-regulated Cx43 and Cx32 in hypo-hBMSCs can form homotypic Cx43-GJs and Cx32-GJs with hepatocytes, thereby enhancing the transfer of mitochondria.
    RESULTS: The results indicate that hypoxia preconditioning diminishes superoxides accumulation and elevates the mitochondrial membrane potential by inducing mitophagy in hBMSCs, consequently improving mitochondrial quality. Upon administration via portal vein injection, hypo-hBMSCs significantly mitigate hepatic IRI. Compared with hBMSCs, hypo-hBMSCs are capable of transferring more mitochondria to hepatocytes through GJs. When the function of GJs is modulated by the enhancer RA or the inhibitor Gap26, the efficiency of mitochondrial transfer correspondingly shifts. Further investigation uncovers that hypo-hBMSCs prompts an upsurge in the expression of Cx43 and Cx32 (not Cx26). Nevertheless, these proteins are unable to form heterotypic GJs (Cx43-Cx32-GJs) with hepatocytes; instead, they form homotypic Cx43-GJs and Cx32-GJs, which facilitate the transfer of mitochondria between hypo-hBMSCs and hepatocytes.
    CONCLUSION: Hypo-hBMSCs can enhance mitochondrial quality by inducing mitophagy. Meanwhile, they can up-regulate Cx43 and Cx32 to form homotypic Cx43-GJs and Cx32-GJs with hepatocytes, thereby transferring more high-quality mitochondria to hepatocytes to exert a protective effect.
    Keywords:  Gap junctions; HBMSCs; Hepatic ischemia-reperfusion injury; Hypoxia preconditioning; Mitochondrial transfer
    DOI:  https://doi.org/10.1186/s12964-025-02497-1
  44. Cureus. 2025 Oct;17(10): e94042
    Acute Respiratory Distress Syndrome Caused by Varicella Pneumonia in an Immunocompetent Adult: A Case Report.
    Mohammed K Zubaidi, Haneen Hussein Sahib, Younus M Al-Khazaali, Moamel Jaafar Ali, Ali J Ahmed.
      Varicella infection, caused by the varicella-zoster virus (VZV), is a self-limiting disease in immunocompetent individuals. However, in patients with immunosuppression, underlying pulmonary disease, and risk factors such as aging, smoking, and pregnancy, it can lead to a potentially life-threatening disseminated disease. Lungs are the most frequently affected internal organ in disseminated VZV. Varicella pneumonia commonly presents with progressive respiratory symptoms accompanied by a cutaneous rash. Varicella pneumonia can rapidly progress to acute respiratory distress syndrome (ARDS). Timely clinical recognition, supported by radiological findings and molecular testing, along with early treatment, is key to improving prognosis. We present a case of ARDS complicating varicella pneumonia in an immunocompetent 25-year-old male who presented with skin rash and respiratory compromise, but without inflammatory nodules on chest imaging.
    Keywords:  acute respiratory distress syndrome; ards; pneumonia; pulmonology; varicella pneumonia; varicella-zoster virus; vzv
    DOI:  https://doi.org/10.7759/cureus.94042
  45. Neurology. 2025 Dec 09. 105(11): e214398
    A Case for Disease-Specific Biomarkers for Rare Genetic Disorders.
    Vera Fridman.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000214398
  46. Genet Med. 2025 Nov 12. pii: S1098-3600(25)00281-3. [Epub ahead of print] 101634
    RARE-X: A Patient-Driven Approach for Collecting Symptom and Patient-Reported Outcome Data in Rare Diseases.
    Vanessa Vogel-Farley, Karmen Trzupek, Jade Gosar, Katelyn Hobbs, Kelly Wentworth, Bridget Michaels, Geoffrey Beek, Tina Dang, Mackenzie Abramson, Megan O'Boyle, Nicole Boice, Charlene Son Rigby, Zohreh Talebizadeh.
       PURPOSE: Innovation in rare disease research is constrained by limited access to reliable and accessible patient data. Accurate characterization of many conditions requires infrastructure that captures population diversity. Existing efforts are often disease specific, investigators led, with limited data sharing. The RARE-X platform was developed to address these limitations by enabling patient-reported data collection and supporting broader data access.
    METHODS: RARE-X is a disease-agnostic platform designed to capture symptoms and patient-reported outcomes using a shared survey structure. Participants across conditions complete a core set of surveys, enabling standardized data collection and cross-disease comparisons. The platform supports global participation, enables longitudinal data capture, and provides data access to researchers through an established request process.
    RESULTS: Since its launch, and at the time of this report, RARE-X has enrolled 7,493 participants from 93 countries, including 3,857 patients and 3,636 caregivers or siblings, across 74 rare disease communities supported by over 120 Patient Advocacy Groups. Sixty-three percent are U.S.-based and 37% international. Data is used in research applications, community reporting, and computational analyses.
    CONCLUSION: RARE-X addresses limitations of traditional registries by enabling standardized, cross-disease data collection, stakeholder input and data sharing, with potential to inform therapeutic development and advance rare disease research.
    Keywords:  clinical outcome assessments; cross-disorder research; patient-driven; patient-reported outcomes; rare diseases
    DOI:  https://doi.org/10.1016/j.gim.2025.101634
  47. Mater Today Bio. 2025 Dec;35 102480
    The drug discovery and therapeutic nano-strategies targeting cellular senescence.
    Yumei Wang, Mingqi Liu, Xinzhao Chen, Song Wang, Jiatong Li, Yuman Sun, Xuting Zheng, Jianxiang Zhang, Heran Li.
      Cellular senescence is a primary driver of aging, where damaged or senescent cells (SnCs) continuously accumulate in the body, altering the local tissue environment and causing various pathologies in different organs or tissues, offering brand-new diagnostic and therapeutic possibilities for aging-related disease. This review begins by discussing the multiple molecular mechanisms of cellular senescence. We mainly focus on the therapeutic strategies and their clinical applications targeting cellular senescence, where senolytic and senomorphic drugs are currently two main categories of anti-aging therapies. Besides, nicotinamide adenine dinucleotide (NAD+) enhancers or multiple therapies for anti-inflammatory and immunomodulation also hold great promise. Crucially, we highlight the design principles and formulation strategies on engineered nanotechnology-based drug delivery system (NDDS) targeting SnCs, including combination therapies and drug loading, delivery routes and bio-distribution, targeted therapy and precision medicine as well as stimuli-responsive drug release. Subsequently, we comprehensively analyze the therapeutic nano-strategies for neurodegenerative diseases, cardiovascular diseases, bone and joint diseases, fibrosis disease, cancer, and other aging-related diseases targeting cellular senescence. Finally, we propose the strength, weakness, opportunity and threat (SWOT) analysis and summarize the future development directions of the therapeutic nano-strategies targeting manipulating SnCs and treating aging related diseases, thereby paving the way for innovative and effective approaches for aging-related disease management.
    Keywords:  Aging-related disease; Nanotechnology-based drug delivery system; SWOT analysis; Senescent cells; Senotherapy
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102480
  48. Cells. 2025 Oct 23. pii: 1657. [Epub ahead of print]14(21):
    Myosin-19 and Miro Regulate Mitochondria-Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture.
    Aya Attia, Katarzyna Majstrowicz, Samruddhi Shembekar, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Martin Bähler.
      Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs.
    Keywords:  Miro1/2; Myosin 19; OXPHOS; TRAK; cristae; mitochondria; outer mitochondrial membrane
    DOI:  https://doi.org/10.3390/cells14211657
  49. Front Digit Health. 2025 ;7 1415202
    Aligning with regulatory agencies for the use of digital health technologies in drug development: a case study from Parkinson's disease.
    Derek L Hill, Camile Carroll, Ramona Belfiore-Oshan, Diane Stephenson.
      Digital Health Technologies (DHTs) have been under investigation for many years as innovative tools for Parkinson's disease motor symptoms given their inherent high-frequency, sensitive, and objective measurement properties. DHTs used in drug development, can be defined as Drug Development Tools (DDT), though some DHTs may also be categorized as medical devices. The recent rapid increase in use of DHTs in clinical trials has been accompanied by a rapidly evolving regulatory landscape, resulting in a challenging environment for widespread implementation of DHTs in applications that will provide clear impact on pharmaceutical company drug development pipelines. Parkinson's disease represents a disease of escalating burden with high unmet need for therapies that are disease modifying. Early intervention is a key area of focus, yet the heterogeneity of symptoms and lack of biomarkers poses challenges for drug development. Furthermore, the technologies and device platforms, both hardware and software, are rapidly evolving, and the companies developing the underlying devices frequently have objectives and timelines that may not align with those of the pharmaceutical industry. DHTs therefore have a unique set of challenges in terms of devising meaningful measures, standardization of data collected, responding to evolving regulatory expectations, and ensuring alignment across stakeholders. There is a growing need for new models of collaboration to bring together diverse stakeholders required to achieve regulatory endorsement of DHTs for use as DDTs. Collaborations between stakeholders working on DHTs need to be firmly anchored in the regulatory ecosystem as many regulatory challenges in DHTs have parallels in other technologies. Furthermore, there is an especially urgent need to define the pre-competitive space in which DHT data can be shared, data collection standards devised, and novel analysis approaches that are robust to residual variability developed. Critical Path for Parkinson's Consortium's (CPP) Digital Drug Development Tool (3DT) initiative is highlighted as a case example to illustrate how pre-competitive public private partnerships can advance the regulatory maturity of digital health technology measures for use in clinical trials.
    Keywords:  Parkinson's disease; data sharing; digital health technologies; drug development; neurological disorders; regulatory framework
    DOI:  https://doi.org/10.3389/fdgth.2025.1415202
  50. BMC Psychiatry. 2025 Nov 13. 25(1): 1089
    Therapists' and patients' experiences with electronic patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) before and during treatment in community mental health services: a qualitative study in Norway.
    Eirik Roos, Thomas Hugaas Molden, Martin Schevik Lindberg, Heidi Westerlund, Karl Johan Johansen, Audun Havnen.
       BACKGROUND: The implementation of electronic patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) in community mental healthcare is a complex experience for both therapists and patients. Barriers need to be identified and overcome. The aims of this study were to examine how therapists and patients experienced the implementation of digital PROMs and PREMs in mental healthcare, and to identify those factors that promote positive experiences with mental health treatment supported by PROMs and PREMs.
    METHODS: In this descriptive qualitative study, we conducted focus group interviews with 19 therapists and individual interviews with six patients who had received low-intensity cognitive behavioural therapy interventions. All informants were interviewed about their experiences following the implementation of self-reported electronic measures in an outpatient treatment facility. The central question posed to all informants concerned their experience with electronic questionnaires. The interviews were analysed with a thematic approach using systematic text condensation.
    RESULTS: Both therapists and patients experienced initial barriers in the form of a lack of information and guidance about answering questionnaires. Both the therapists and patients experienced improved insight into symptoms and challenges. This enhanced awareness led to the patient being more actively involved in the formulation of objectives in the treatment process. Patients reported that the implementation of PROMs and PREMs led to better informed therapists who listened more actively and asked relevant questions about adherence and current struggles in daily life.
    CONCLUSION: Overall, patients with mental health problems need practical guidance on how to complete self-report questionnaires. By providing their own feedback, patients' self-awareness of their symptoms and challenges was strengthened, thereby facilitating discussions on how to best align treatment goals to treatment needs. Several patients highlighted the importance for PREMs of the therapists' attitudes and skills. The findings of this qualitative study suggest that both PROMs and PREMs can be implemented successfully in routine mental healthcare when care is taken to identify and overcome barriers.
    Keywords:  Community mental health; Experience with PROMs/PREMs; Qualitative study
    DOI:  https://doi.org/10.1186/s12888-025-07541-5
  51. Cell Host Microbe. 2025 Nov 12. pii: S1931-3128(25)00422-6. [Epub ahead of print]33(11): 1834-1836
    Brain hacks: Engineering a microbial factory for Parkinson's disease.
    Chin-Hsien Lin, Wei-Li Wu.
      Motor complications in Parkinson's disease (PD) are exacerbated by the pulsatile delivery of levodopa (L-DOPA). In this issue of Cell Host & Microbe, Padhi et al. engineer a microbiota-based therapeutic for sustained, non-fluctuating L-DOPA production, demonstrating therapeutic promise through stable dopamine signaling.
    DOI:  https://doi.org/10.1016/j.chom.2025.10.008
  52. Turk J Med Sci. 2025 ;55(5): 1130-1140
    Knowledge and attitudes about epilepsy of neurology outpatients in Türkiye.
    Ayşe Pınar Titiz, Abidin Erdal, Yaren Ağar, Buse Altunbaşak.
       Background/aim: We aimed to evaluate the level of epilepsy-related knowledge and attitude among neurology outpatients without an epilepsy diagnosis.
    Materials and methods: The Epilepsy Knowledge and Attitude Scale was applied to 331 adult patients who were evaluated with various diagnoses in the neurology outpatient clinic.
    Results: The participants comprised 331 people, 51.4% of whom were women and 48.6% of whom were men. The knowledge and attitude values increase significantly as the education level of our participants increased (p < 0.001). The knowledge and attitude scores of those who knew about an individual with epilepsy were significantly higher (p < 0.001). Attitude scale scores were higher in patients diagnosed with headache, multiple sclerosis, syncope, Behçet's disease, essential tremor and sleep disorders compared with other groups.
    Conclusion: This study focused on a subgroup of adults without epilepsy who had other neurological conditions. The findings may illuminate the critical role of education and public awareness in fostering more positive attitudes toward individuals with epilepsy, reducing stigma, and facilitating their social integration.
    Keywords:  Epilepsy; attitude; awareness; knowledge; stigma
    DOI:  https://doi.org/10.55730/1300-0144.6068
  53. Gut Microbes. 2025 Dec 31. 17(1): 2575923
    Design and application of synthetic human gut microbial communities.
    Min Soo Kim, Jordan E Bisanz.
      The gut microbiome shapes host health through a complex network driven by both host‒microbe and microbe‒microbe interactions. Disruption of these interactions, often referred to as dysbiosis, is associated with a range of infectious and chronic diseases. Owing to the success of fecal microbiota transplantation (FMT) for the treatment of recurrent Clostridioides difficile infection, FMT has been explored as a therapeutic option for a range of microbiota-associated conditions, including inflammatory bowel disease and obesity. However, the microbial diversity that is the greatest strength of FMT is also its greatest liability. Concerns relating to reliance on human donors, potential for transmission of multidrug-resistant organisms or undesirable phenotypes demonstrate a need for alternate approaches, including the generation of synthetic alternatives to FMT, which can be built in the laboratory from individual strains. Furthermore, these communities are powerful tools for conducting mechanistic research allowing for the generation of 'knockout' communities, which are not possible when working with undefined fecal transplants. This review examines strategies for designing synthetic microbial communities that represent a new generation of microbiome-derived therapies. We highlight how synthetic microbial communities are being used to answer mechanistic questions about host-microbiome interactions relevant to health and disease. Finally, we examine the current clinical translation of these communities as live biotherapeutic products (LBPs). While the regulatory frameworks for LBPs continue to evolve, early clinical successes illuminate the potential for synthetic microbial communities to treat complex human diseases through targeted manipulation and restoration of the gut microbiome.
    Keywords:  Microbiome; cancer; colonization resistance; defined microbial consortium; dysbiosis; immunotherapy; infectious disease; inflammable bowel disease; live biotherapeutic products; synthetic community
    DOI:  https://doi.org/10.1080/19490976.2025.2575923
  54. Cells. 2025 Nov 04. pii: 1730. [Epub ahead of print]14(21):
    Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.
    Hanieh Niktinat, Melinda Alviar, Marziyeh Kashani, Hamed Massoumi, Ali R Djalilian, Elmira Jalilian.
      Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration.
    Keywords:  aging; confocal microscopy; corneal nerves; extracellular vesicles (EVs); nerve regeneration; neurodegeneration; ocular surface disease; subbasal nerve plexus
    DOI:  https://doi.org/10.3390/cells14211730
  55. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70113
    STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
    Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.
       BACKGROUND: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4), traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
    METHODS: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg (HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
    RESULTS: We found that non-obese skmSTX4-iKO male mice (> 50% reduced STX4 abundance, soleus and gastrocnemius ***p < 0.001, tibialis anterior (TA) ****p < 0.0001) developed insulin resistance (**p < 0.01), together with reduced energy expenditure (AUC *p < 0.05), respiratory exchange ratio (AUC **p < 0.01) and grip strength (*p < 0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p < 0.0001). Mitochondrial morphological damage was heterogenous in STX4-depleted muscle, presenting with small fragmented mitochondria (****p < 0.0001) and decreased electron transport chain (ETC) abundance (CI ***p < 0.001, CII *p < 0.05, CIV **p < 0.01) in oxidative soleus muscle, whereas glycolytic-rich TA fibres displayed enlarged swollen mitochondria (****p < 0.0001) with no change in ETC abundance. Notably, > 60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p < 0.0001) also decreased ETC abundance (CI **p < 0.01, CII ***p < 0.001, CIV **p < 0.01) without changes in mitochondrial glucose metabolism, as shown by [U-13C]glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p < 0.05) and siSTX4 L6.GLUT4myc myotubes (*p < 0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p < 0.05) and Tfam (*p < 0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA **p < 0.01, protein *p < 0.05), NRF1 (mRNA **p < 0.01 and protein *p < 0.05) and Tfam (mRNA *p < 0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using the mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p < 0.05) and mitochondria-lysosome colocalization (*p < 0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p < 0.05, PINK1 **p < 0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN **p < 0.01, PINK1 *p < 0.05).
    CONCLUSIONS: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.
    Keywords:  STX4; mitochondria; muscle; quality control
    DOI:  https://doi.org/10.1002/jcsm.70113
  56. Chin Clin Oncol. 2025 Oct;14(5): 56
    Natural compounds targeting mitochondrial metabolism in cancer therapy: a literature review.
    Grazielle Silva Paz, Janaina Fernandes.
       BACKGROUND AND OBJECTIVE: Cancer is a public health problem and is considered the leading cause of death around the globe. Despite the advances in cancer therapies, many patients suffer from adverse side effects and drug resistance. Among the cancer hallmarks, metabolic reprogramming is essential for supporting the higher energy demand of cancer cells. Due to the Warburg effect, a misconception that oxidative phosphorylation (OXPHOS) and other mitochondrial-related metabolic pathways are dispensable for tumor cells was created. Nowadays, many studies have been demonstrating the importance of mitochondria and their metabolism to cancer bioenergetics and progression. Through this review, we aim to show natural compounds that regulate mitochondrial metabolism to exert their anticancer activity.
    METHODS: In this literature review, studies found in PubMed, in English and published between 1925-2025 were considered.
    KEY CONTENT AND FINDINGS: Throughout this review, we discussed the importance of mitochondrial metabolism for carcinogenesis, updated and brought new natural products as potential therapies to target mitochondrial metabolism to counteract cancer progression. Furthermore, we discussed the future directions to overcome the limitations of the use of natural products as anticancer compounds.
    CONCLUSIONS: Natural compounds can act in different pathways of mitochondrial metabolism to exert their antitumoral effects, however, some limitations need to be overcome. Developing natural product-based hybrids through the conjugation of natural compounds with bioactive molecules has gained interest to surpass these limitations, representing a good strategy to enhance the anticancer treatment effectiveness of natural products.
    Keywords:  Natural compounds; metabolism and cancer; mitochondria
    DOI:  https://doi.org/10.21037/cco-25-51
  57. Indian J Pharmacol. 2025 Nov 01. 57(6): 367-370
    Orphan drugs: The final frontier in the fight against rare diseases.
    Sandhya Rajaram, Bikash Medhi.
      
    DOI:  https://doi.org/10.4103/ijp.ijp_979_25
  58. BMC Pulm Med. 2025 Nov 10. 25(1): 516
    Extracellular vesicles in pulmonary diseases: roles and therapeutic potential.
    Madison Coward-Smith, Razia Zakarya, Brian Gg Oliver, Richard Y Kim, Chantal Donovan.
      Extracellular vesicles (EVs) are small lipid bilayer packages responsible for cellular communication. Increasing clinical and experimental evidence strongly links EVs to homeostasis and the pathogenesis of disease. In this review, we provide a brief overview of EVs and their biological significance in pulmonary disease. We outline the current challenges in diagnosis and treatment of lung diseases and discuss the rationale for exploring EVs as a novel therapeutic avenue. Beyond their biomarker potential, we outline the role and potential for therapeutic targeting of EVs in the pathogenesis of asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and infectious diseases. We also explore the current literature on the use of stem cell derived EVs to drive lung repair and regeneration in inflammatory diseases. Lastly, we highlight challenges and limitations of the study of EVs in pulmonary disease and provide future perspectives with exciting opportunities for translation into therapy.
    Keywords:  Extracellular vesicles; Immune modulation; Infection; Pulmonary disease; Therapeutic opportunity
    DOI:  https://doi.org/10.1186/s12890-025-03965-7
  59. Cell Signal. 2025 Nov 10. pii: S0898-6568(25)00651-5. [Epub ahead of print] 112236
    The molecular mechanisms of cuproptosis and its role in central nervous system diseases.
    Mingyuan Xu, Yumei An, Xiaoyan Liu, Xianzhe Li, Xinqi Huang, Qiuyang Gu, Mengchun Xue, Jun Xue, Luyang Tao, Haiyan Shan, Xiping Chen, Mingyang Zhang.
      Copper is an essential micronutrient in the brain, serving as a critical enzymatic cofactor indispensable for neuronal function and homeostasis. In recent years, cuproptosis, a new regulated form of cell death mechanistically distinct from pyroptosis and ferroptosis, has emerged as a pivotal player in the pathogenesis of central nervous system disorders. This review provides a systematic synthesis of brain-specific copper homeostasis, detailing the roles of blood-brain barrier transporters, glial-mediated copper buffering, and neuron-specific copper chaperones in maintaining cerebral copper balance. We delineate three core molecular pathways driving cuproptosis in the CNS and highlight their cell-type-specific manifestations. Furthermore, by converging clinical observations with preclinical evidence, we elucidate the pathogenic links between cuproptosis and major CNS disorders, including acute injuries, neurodegenerative disorders, and gliomas, clarifying the distinct triggers and disease-specific contributions of cuproptosis in each condition. Building on these insights, we propose a disease-classified therapeutic strategy targeting cuproptosis, identify promising diagnostic and prognostic biomarkers and advocate for future research into organ-specific cuproptosis regulation. This review offers a conceptual foundation for advancing mechanistic understanding and developing precision therapeutics for CNS diseases rooted in copper dysregulation.
    Keywords:  Brain; Cell death; Cognitive function; Copper; Cuproptosis; Nervous system
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112236
  60. Toxicol Mech Methods. 2025 Nov 11. 1-24
    M3Hep: A Multimodal Hepatotoxicity Prediction Model Combining Mitochondrial Toxicity and Masking Strategy.
    Yang Liu, Yu Xie, Xiao Wang, Yingxu Liu, Simeng Zhang, Lidan Zheng, Qian Ge, Lingxi Gu, Yanmin Zhang, Jinfeng Liu, Yadong Chen, Mengyi Lu, Haichun Liu.
      Drug hepatotoxicity is one of the primary reasons for drug clinical trial failures and market withdrawals, with mitochondrial dysfunction being one of the mechanisms inducing drug hepatotoxicity. Manifestation of mitochondrial toxicity occurs when mitochondria are damaged or their functions are inhibited. This study introduces M3Hep, a novel multimodal framework that integrates SMILES, molecular graphs, and mitochondrial toxicity through a masking strategy to improve hepatotoxicity prediction. A total of 8,459 mitochondrial toxicity samples and 6,418 hepatotoxicity samples were collected for constructing the mitochondrial toxicity prediction model and M3Hep, respectively. To fully utilize the collected hepatotoxicity samples, this study developed a mitochondrial toxicity prediction model to predict mitochondrial toxicity for molecules without experimental mitochondrial toxicity data, achieving an AUC of 0.96 for the mitochondrial toxicity prediction model. The ablation study results of M3Hep indicate that incorporating mitochondrial toxicity enhances the performance of hepatotoxicity prediction models, further demonstrating the connection between mitochondrial toxicity and hepatotoxicity. M3Hep outperforms most baseline models across all metrics, with its AUC reaching up to 0.81. Moreover, in terms of the MCC metric, M3Hep surpasses all commonly used hepatotoxicity prediction tools collected, with a value of 0.49. In order to better understand the prediction mechanism of M3Hep, we conducted an interpretability analysis based on the GNNExplainer and SHAP methods.
    Keywords:  Deep learning; Hepatotoxicity; Masking strategy; Mitochondrial toxicity; Multimodal model
    DOI:  https://doi.org/10.1080/15376516.2025.2588277
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