bims-polgdi Biomed News
on POLG disease
Issue of 2025–12–28
sixty-six papers selected by
Luca Bolliger, lxBio
  1. Turnover and Quality Control of Mitochondrial DNA.
  2. Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.
  3. Mechanisms of Intracellular Selection of Mitochondrial DNA.
  4. Basic Science and Pathogenesis.
  5. A systematic analysis of mitochondrial aminoacyl tRNA synthetase variants in a rare disease cohort.
  6. Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
  7. Mitochondrial DNA Variation in the Aging Human Cerebral Cortex and Cerebellum.
  8. Biomarkers.
  9. Model organisms in POLG-related disorders: insights from yeast to multicellular systems.
  10. Basic Science and Pathogenesis.
  11. Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
  12. Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
  13. Basic Science and Pathogenesis.
  14. Exosomes in aging and age-related disorders: mechanisms, therapeutic potentials, and challenges.
  15. Senotherapeutics for Brain Aging Management.
  16. I've Never Heard of This! An Approach to Child and Family-Centred Care for Children and Young People With Rare Diseases.
  17. TAG-PL: A Universal Proximity Labeling Platform for Mapping Mitochondrial Proteomes and Organelle Interactions under Stress.
  18. Nanoparticulate delivery and targeting of RNA to the brain.
  19. Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
  20. Mitochondrial Reticulum in Skeletal Muscles: Proven and Hypothetical Functions.
  21. Targeting mitochondrial autophagy for anti-aging.
  22. Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.
  23. Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
  24. Anthracyclines effect on mitochondrial function and biogenesis in normal blood cells of hodgkin lymphoma patients.
  25. Drug Development.
  26. Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging.
  27. Basic Science and Pathogenesis.
  28. Emerging nano-delivery systems for targeting mitochondria.
  29. CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.
  30. Global trends and perspectives in mitophagy on neurodegenerative diseases: a scientometric analysis over 20 years.
  31. Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
  32. Basic Science and Pathogenesis.
  33. Editorial: Insights in aging, metabolism and redox biology: 2024.
  34. A Zebra in Horse's Clothing: Rethinking the Diagnosis of Rare Diseases.
  35. Basic Science and Pathogenesis.
  36. Mitochondrial fission and fusion in inflammatory diseases: mechanisms and therapeutic implications.
  37. Cardiolipin's multifaceted role in immune response: a focus on interacting proteins.
  38. Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.
  39. Potential of exosomes for targeted therapy in neuroinfectious disease management: crossing the blood-brain barrier.
  40. Basic Science and Pathogenesis.
  41. Basic Science and Pathogenesis.
  42. Advances in Laboratory Methodologies and Biological Matrices for the Study and Management of Rare Ocular Genetic Diseases.
  43. Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
  44. CircRNAs: Novel biomarkers and therapeutic targets for diseases of the central nervous system.
  45. Basic Science and Pathogenesis.
  46. Developing Topics.
  47. Crossroads between autoimmunity and cancer: Underlying mechanisms and clinical implications.
  48. Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle.
  49. TARGETFLOW:An automated literature mining pipeline for accelerating the discovery of high-potential targets in rare and mature diseases.
  50. ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
  51. Basic Science and Pathogenesis.
  52. Bringing together clinical and physical sciences to deliver translational ageing research: the UK experience.
  53. From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
  54. Basic Science and Pathogenesis.
  55. Antibiotics and Cellular Senescence: An Unexplored Territory.
  56. SIRT3-mediated mitochondrial reprogramming: emerging therapeutic paradigms in peripheral neuropathy and neuropathic pain.
  57. Basic Science and Pathogenesis.
  58. Policy evaluation frameworks for rare diseases: a scoping review.
  59. Mitochondria in Developing Brain: Contribution of Deviations to Higher Susceptibility to Neurodegeneration in Latter Periods of Life.
  60. Oncology-Derived Strategies for Age-Related Diseases: Intersections of Oncogenesis, Senescence, and Immunity.
  61. Basic Science and Pathogenesis.
  62. A Novel Variant in the TAMM41-Associated Mitochondrial Myopathy.
  63. Promising Results With NAD Supplementation in Rare Diseases With Premature Aging and DNA Damage.
  64. Drug Development.
  65. Basic Science and Pathogenesis.
  66. Cerebellar deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia.
  1. Biochemistry (Mosc). 2025 Dec;90(12): 1849-1861
    Turnover and Quality Control of Mitochondrial DNA.
    Wolfram S Kunz.
      The quantitative content of mitochondrial DNA (mtDNA) - a multicopy circular genome - is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).
    Keywords:  determinants of cellular mtDNA content; mtDNA degradation; mtDNA maintenance; mtDNA maintenance disorders; mtDNA replication
    DOI:  https://doi.org/10.1134/S0006297925602485
  2. J Transl Med. 2025 Dec 23. 23(1): 1415
    Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.
    Lei Lyu, Beibei Qie, Yanjie He, Feilong Chen, Bao Liu.
      Mitochondria function as the primary energy hubs of cells and possess semi-autonomous genetic characteristic. Mutations in mitochondrial DNA (mtDNA) frequently lead to severe illness and even premature death. The rapid advancement of gene therapy offers promising potential for correcting such disorders. This review first aims to delineate the mechanisms of gene therapy strategies applicable to mitochondrial diseases, including the allotopic expression of mtDNA in the nucleus, mitochondrial-targeted nuclease cleavage, and mtDNA-targeted base editing. It also discusses in detail the clinical efficacy of mtDNA allotopic expression and the preclinical progress of other strategies. Furthermore, the unique physiological features of mitochondria, such as heteroplasmy and independent molecular transport mechanisms, pose distinct challenges for the clinical implementation of mitochondrial gene therapy strategies. Accordingly, this review elaborates on the current limitations of each approach. Finally, it highlights potential optimization directions to address these challenges, emphasizing that understanding heteroplasmy dynamics and their corresponding phenotypes, ensuring the safe delivery and tissue-specific expression of therapeutic elements, and maintaining long-term therapeutic specificity and efficiency are essential for the clinical translation of mitochondrial gene therapy.
    Keywords:  Allotopic expression; Base editing; Mitochondrial DNA; Mitochondrial disorders; Nuclease
    DOI:  https://doi.org/10.1186/s12967-025-07420-3
  3. Biochemistry (Mosc). 2025 Dec;90(12): 1919-1928
    Mechanisms of Intracellular Selection of Mitochondrial DNA.
    Georgii Muravyov, Dmitry A Knorre.
      Eukaryotic cells contain multiple mitochondrial DNA (mtDNA) molecules. Heteroplasmy is coexistence in the same cell of different mtDNA variants competing for cellular resources required for their replication. Here, we review documented cases of emergence and spread of selfish mtDNA (i.e., mtDNA that has a selective advantage in a cell but decreases cell fitness) in eukaryotic species, from humans to baker's yeast. The review discusses hypothetical mechanisms enabling preferential proliferation of certain mtDNA variants in heteroplasmy. We propose that selfish mtDNAs have significantly influenced the evolution of eukaryotes and may be responsible for the emergence of uniparental inheritance and constraints on the mtDNA copy number in germline cells.
    Keywords:  heteroplasmy; intracellular selection; mitochondrial DNA; mitophagy; mtDNA quality control; selfish gene
    DOI:  https://doi.org/10.1134/S0006297925603296
  4. Alzheimers Dement. 2025 Dec;21 Suppl 1 e102364
    Basic Science and Pathogenesis.
    Sara Yunta-Sánchez, Regina Mengual-Fenollar, Juan Pedro Bolaños, Rubén Quintana-Cabrera.
       BACKGROUND: In the nervous system, mitochondria can be transferred between neural cells through intercellular tunneling nanotubes (TNTs), microvesicles, or as free organelles. This transfer not only alters the mitochondrial content and respiration of recipient neural cells but also triggers a profound rewiring of their physiology, with glial cells and immune responses playing key roles in this reconfiguration.
    METHOD: Primary co-cultures of neurons and glial cells, along with in vivo analysis of mitochondrial transfer in mouse brains, were monitored using kinetic microscopy, flow cytometry, and metabolic flux analyses to explore the physiological changes in neural cells. Mitochondrial DNA (mtDNA) transmission was tracked through RT-PCR and ARMS-PCR to examine hierarchical transfer and acquisition.
    RESULT: Communication between neural cells, particularly through TNTs, shows dynamic mitochondrial transfer, regulated by mitochondrial transport, fusion, and fission events. These events respond to structural and signaling changes in intercellular communication, mainly via TNTs. As a result, transmitted mitochondria reconfigure the content, metabolism, and mtDNA composition in recipient neurons and astrocytes. Notably, we observe a significant role of microglia and astrocytes upon mitochondrial acquisition in mouse brains, suggesting inflammatory events that may coordinate mitochondrial transfer as key regulators of metabolic rewiring and cognitive effects in the nervous system.
    CONCLUSION: Our findings provide evidence that a multilayered mitochondrial transfer is a critical mechanism for reconfiguring neural metabolism, immune responses, and overall neural physiology.
    DOI:  https://doi.org/10.1002/alz70855_102364
  5. Eur J Hum Genet. 2025 Dec 27.
    A systematic analysis of mitochondrial aminoacyl tRNA synthetase variants in a rare disease cohort.
    Thiloka E Ratnaike, M Eren Kule, Ida Paramonov, Leslie Matalonga, Kiran Polavarapu, Catarina Olimpio, Rita Horváth.
      Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenotypically heterogenous but often present with significant neurological features such as childhood-onset encephalopathy and seizures. As such, these conditions are a diagnostic challenge. We present an approach that systematically quantifies phenotypic similarity of individuals with an mt-aaRS variant to published cases, to aid variant interpretation, in RD-Connect-a large Europe-wide rare disease cohort. Across 98 individuals with a mt-aaRS gene of interest, we prioritised 38 individuals with 63 variants following bioinformatic and manual analyses. We additionally reviewed Exomiser prioritisation using a pre-defined gene list for neurological disorders within the RD-Connect Genome-Phenome Analysis Platform (GPAP). We were able to generate likely diagnoses in 11 individuals and VUS findings in 13 individuals, following careful phenotype similarity analysis using a phenotype-genotype dataset generated from 234 published individuals. Four of these 24 individuals did not have an Exomiser-ranked gene variant in the GPAP. Therefore, this approach, using individual-level curated phenotype-genotype data to support variant interpretation, can highlight potentially significant variants that may not be captured by current pipelines. This workflow can be replicated in other heterogeneous rare diseases to support clinical practice.
    DOI:  https://doi.org/10.1038/s41431-025-01990-y
  6. Mol Neurobiol. 2025 Dec 27. 63(1): 329
    Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD.
    Mahalaxmi Iyer, Masako Kinoshita, Dibbanti HariKrishna Reddy, Harysh Winster Suresh Babu, Vikas Lakhanpal, Mukesh Kumar Yadav, Jayalakshmi Krishnan, Vignesh Palanivel, Salmanul Faris, Khushboo Chauhan, Balachandar Vellingiri.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in dopamine depletion and impaired motor function. Growing evidence implicates mitochondrial dysfunction as a central driver of PD pathogenesis with many PD-associated genes and proteins localized are localized near mitochondria and they also have major functions in proper functioning of mitochondria. Among mitochondrial regulators, the transcriptional co-activator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) orchestrates oxidative stress response, mitochondrial biogenesis and inflammatory pathways whereas mitochondrial transcription factor A (TFAM) is essential for maintaining mitochondrial DNA (mtDNA) integrity and copy number variations. Dysregulation of TFAM contributes to mtDNA stress mediated oxidative stress and neurodegeneration whereas experimental studies demonstrate that TFAM overexpression or enzyme replacement enhances neuronal survival and functions. Therefore, in this review we have highlighted the PGC-1α-TFAM regulatory axis as a central hub linking mitochondrial dysfunction, neuroinflammation and oxidative stress in PD. We further discuss therapeutic opportunities aimed at modulating PGC-1α and TFAM to restore mitochondrial homeostasis, underscoring their potential as promising yet underexplored targets for slowing or halting PD progression.
    Keywords:  Mitochondria; PGC-1α; Parkinson’s Disease; TFAM; Therapeutics
    DOI:  https://doi.org/10.1007/s12035-025-05611-z
  7. Aging Cell. 2026 Jan;25(1): e70340
    Mitochondrial DNA Variation in the Aging Human Cerebral Cortex and Cerebellum.
    North American Brain Expression Consortium
      Somatic differences in mitochondrial DNA (mtDNA) have been observed with aging and between brain regions for mutations, structural variation, and abundance, which are represented by single nucleotide variants (SNVs), large deletions, and copy number, respectively. We used bioinformatic methods to interrogate mtDNA changes and their relation to cortical and cerebellar aging using whole genome sequencing data from the North American Brain Expression Consortium. This dataset contained 292 unpaired postmortem samples from frontal cortex (n = 143) and cerebellum (n = 149), ranging in age from 0.4 to 100 years and without neurological diagnoses (i.e., controls). Our analyses included (a) evaluation of mtDNA copy number using fastMitoCalc; (b) quantification of large mtDNA deletions using Splice-Break2; (c) analysis of homoplasmic and heteroplasmic SNVs; and (d) mitochondrial genome-wide associations between SNVs and large deletions. For mtDNA deletions specifically, we expanded our previous analyses to include the predicted effects on mitochondrial complexes (I-V), mitochondrial-derived microproteins, and tRNAs. MtDNA copy number significantly decreased in the cortex with age. MtDNA deletions increased in both brain regions with age, with a more dramatic slope in the cortex. These large deletions had significantly more effect on mitochondrial Complex I than other mitochondrial-encoded complexes (III-V); likewise, deletions had significantly more effect on mtALTND4 and SHMOOSE than other annotated microproteins. Heteroplasmic SNVs increased with age in cortex but not cerebellum. Finally, three common SNVs (T14798C, G12372A, and C14766T) significantly associated with large mtDNA deletions (7816-14,807, 12,369-14,004, and 8775-14,771) and altered the length of the repeat sequence associated with the 5' or 3' breakpoint.
    DOI:  https://doi.org/10.1111/acel.70340
  8. Alzheimers Dement. 2025 Dec;21 Suppl 2 e104338
    Biomarkers.
    Shampa Ghosh, Krishna Kumar Singh, Amit Kumar Pandey, Suchita Jha, Jitendra Kumar Sinha.
       BACKGROUND: Mitochondrial dysfunction is an integral feature of both aging and neurodegenerative diseases, where it significantly contributes to disease progression. It is, therefore, of the utmost importance to understand the underlying mechanisms so that effective therapeutic approaches can be developed. This article delves into specific pathways where mitochondrial dysfunction occurs in aging and neurodegenerative conditions in the hope of discovering potential targets for intervention.
    METHODS: A comprehensive literature review was done to synthesize current knowledge on mitochondrial dysfunction in ageing and neurodegeneration. It focused on the key cellular and molecular pathways that include changes in mitochondrial structure and function, disruptions in energy metabolism, and their impact on cellular homeostasis.
    RESULTS: In short, the overall data point to complex interactions between the processes of aging, neurodegenerative disease and mitochondrial dysfunction. During aging, mitochondria become functionally less effective, characterized by decreased ATP levels, impaired oxidative phosphorylation and increased reactive oxygen species production. Different neurodegenerative diseases- Alzheimer's disease, Parkinson's disease, Huntington's disease-had specific abnormalities in mitochondria, including deficient mitophagy, altered dynamics of mitochondria, and mutation in mitochondrial DNA. These cause neuronal cell death and accelerate progression of the diseases.
    CONCLUSION: This study elucidates the diverse mechanisms that connect mitochondrial dysfunction with both ageing and neurodegenerative diseases. Various pathways identified in this review are considered critical areas for therapeutic intervention aimed at preserving mitochondrial integrity and subsequently reducing detrimental impact of ageing and neurodegeneration on cellular function. These mechanisms offer more complex avenues for research into these critical pathways that should lead to novel treatments for age-related and neurodegenerative conditions.
    DOI:  https://doi.org/10.1002/alz70856_104338
  9. Cell Death Dis. 2025 Dec 26.
    Model organisms in POLG-related disorders: insights from yeast to multicellular systems.
    Raquel Brañas Casas, Giovanni Risato, Alessandro Zuppardo, Carlo Viscomi, Francesco Argenton, Mara Doimo, Nicola Facchinello, Natascia Tiso.
      Mitochondrial genetic diseases are complex disorders that impair cellular energy production, leading to diverse clinical manifestations across multiple organ systems. These diseases arise from mutations in either mitochondrial DNA or nuclear DNA. Among nuclear DNA-related cases, mutations in POLG and POLG2, which encode subunits of mitochondrial DNA polymerase γ, are particularly significant, causing conditions such as Alpers-Huttenlocher syndrome and progressive external ophthalmoplegia. Model organisms have been instrumental in elucidating POLG-related disease mechanisms and advancing therapeutic strategies. Saccharomyces cerevisiae (budding yeast) provided insights into fundamental mitochondrial functions, while Caenorhabditis elegans (roundworm) helped explore POLG's roles in multicellular organisms. Drosophila melanogaster (fruit fly) has been pivotal in studying neurological aspects, and Mus musculus (mouse) models contributed to understanding systemic effects in mammals. Recently, Danio rerio (zebrafish) has emerged as a promising vertebrate model for drug screening, due to its optical transparency and genetic tractability. Each model system offers unique advantages, collectively bridging the gap between basic research and clinical applications. This review will examine in vivo models used in POLG disorder research, highlighting their contributions to understanding disease mechanisms and therapeutic advancements.
    DOI:  https://doi.org/10.1038/s41419-025-08366-6
  10. Alzheimers Dement. 2025 Dec;21 Suppl 1 e105994
    Basic Science and Pathogenesis.
    Anysja Roberts, Lesya Novikova, Ian Weidling, Xiaowan Wang, Alexander Paul Gabrielli, Colton R Lysaker, Heather M Wilkins, Russell H Swerdlow.
       BACKGROUND: Alzheimer's is a disease of aging and is currently defined as the accumulation of amyloid beta in the brain. During aging our mitochondrial function declines and this can lead to mitochondrial dysfunction. Accordingly, the mitochondria cascade hypothesis was developed and suggests mitochondria drive the characteristics found in Alzheimer's Disease (AD). The present research is focused on developing mitochondrial dysfunction models that can be used to model and study AD. This will enable us to determine if the decline in mitochondrial function results in AD hallmarks such as amyloid beta accumulation in the brain.
    METHOD: SH-SY5Y cells and iPSC derived neurons were treated with 0.5 mM IMT1 to block mitochondrial transcription. SY5Y cells underwent treatment for 5-days and neurons for 2-weeks. Additionally, vehicle control groups were maintained for both cell lines. Mitochondrial DNA (mtDNA) copy numbers were measured with digital droplet PCR and mitochondrial RNA levels were measured with reverse transcription PCR. Western blots were used to measure changes in protein levels. Finally, seahorse assays were used to conduct mitochondrial stress tests and measure cellular oxygen consumption rates (OCR).
    RESULT: Following treatment, SY5Y mtDNA levels were significantly reduced, with mt-TL1 DNA levels declining by 95% and D-Loop DNA levels by 90%. Mt-ND1 RNA levels were also impacted with a 90% reduction in SY5Y cells and 68% reduction in neurons. Additionally, mt-CO2 protein levels were reduced by 81% in treated neurons. Finally, mitochondrial function was significantly reduced in treated SY5Y cells as indicated by a 64% decrease in mitochondrial OCR levels.
    CONCLUSION: Our findings indicate IMT1 treatment successfully reduces mitochondrial transcription as revealed by lower mt-RNA and protein levels. Additionally, SY5Y treatment resulted in lower mtDNA copy numbers, aligning with lower mtDNA levels found in AD patients. Further, the decline in SY5Y mitochondrial activity suggests IMT1 induces mitochondria dysfunction. These findings indicate our model initiates mitochondrial dysfunction while demonstrating AD like characteristics, enabling us to use IMT1 treatment to model and study AD. Additional studies are ongoing to further characterize DNA, RNA, protein, enzymatic, and metabolic changes in both cell lines.
    DOI:  https://doi.org/10.1002/alz70855_105994
  11. Front Med. 2025 Dec 26.
    Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
    Guoling Zeng, Rongpei Liu, Xiaotian Li, Zhaoqi Lv, Lei Cui, Xiong Zhang, Jianyong Wang.
      Mitochondrial disorders are highly heterogeneous and can manifest as a spectrum of clinically heterogeneous disorders that affect multiple organ systems. Herein, we report a Chinese female patient carrying mitochondrial DNA m.3243A>G mutation who sequentially experienced myoclonic epilepsy with ragged red fibers, mitochondrial neurogastrointestinal encephalomyopathy, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. This report expands the current understanding of phenotypic heterogeneity in mitochondrial disorders.
    Keywords:  m.3243A>G; mitochondrial disorders; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); myoclonic epilepsy with ragged red fibers (MERRF)
    DOI:  https://doi.org/10.1007/s11684-025-1186-7
  12. Front Neurol. 2025 ;16 1657852
    Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
    Gülhan Karakaya Molla, Özlem Ünal Uzun, Hanım Babazade Agakisili, Emine Genç, Zümrüt Arslan Gülten, Tarık Yıldırım, Aydan Sezgin Ersoy, Belkıs Ak, Aliye Gülbahçe, Sevil Yıldız, Nafiye Emel Çakar, Meryem Karaca, Tanyel Zübarioğlu, Burcu Öztürk Hişmi, Şahin Erdöl, Hasan Önal, Bülent Kara, Gülden Fatma Gökçay.
       Introduction: Stroke-like episodes (SLE) are defined as events characterized by the sudden onset of neurological symptoms with clinical manifestations similar to those of a stroke. However, they are distinguished by the presence of radiological lesions that do not conform to single vascular territory. MELAS syndrome, which is characterized by metabolic encephalopathy, lactic acidosis, and SLE, has been identified as the first genetically defined and most widely known mitochondrial cause of SLE. It has been demonstrated that SLE may occur in the course of a variety of mitochondrial diseases, including those that are the result of nuclear DNA mutations.
    Objective: In this retrospective, multicenter, observational cohort study, we sought to determine the clinical, radiological, EEG, and genetic characteristics of patients with mitochondrial gene mutations presenting with SLE and the frequency and treatment of SLE.
    Methods: Thirty-four patients with a genetically diagnosed mitochondrial disease from 9 paediatric metabolic disease centres in the Marmara Region of Turkey were included in the study, of whom 13 pateints had SLEs. Demographic characteristics, symptoms, clinical features, cranial MRI, EEG findings, and genetic characteristics were evaluated.
    Conclusion: In this study, stroke-like episodes in genetically defined mitochondrial disorders were most frequently observed in MELAS and POLG mutations, and rarely in CoQ10 deficiency, Leigh syndrome cases. Cranial MRI findings are often frontotemporal in location and inconsistent with vascular distribution, and focal epileptiform activity on EEG are diagnostically significant. In MELAS, clinical improvement was observed in patients when L-arginine was initiated in the acute period. The findings emphasise that SLE should be evaluated in the differential diagnosis of sudden onset neurological symptoms in mitochondrial diseases.
    Keywords:  CoQ10 deficiency; MELAS; POLG mutations; mitochondrial diseases; stroke-like episodes
    DOI:  https://doi.org/10.3389/fneur.2025.1657852
  13. Alzheimers Dement. 2025 Dec;21 Suppl 1 e106610
    Basic Science and Pathogenesis.
    Maggie N Benson, Keith P Smith, Vivien Csikos, Heather M Wilkins.
       BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder marked by amyloid beta (Aβ) plaques and neurofibrillary tangles. Studies have revealed that damaged mitochondria accumulate across various AD disease models, suggesting disrupted mitochondrial quality control pathways. Mitophagy-the cellular process that removes dysfunctional mitochondria-has been shown to be impaired in AD, though its exact relationship to disease mechanisms remains unclear. This study investigates the relationship between mitophagy mechanisms and AD pathophysiology.
    METHODS: Whole brain from 5xFAD and wild-type (WT) mice was use to collect whole cell, mitochondrial, and autophagosome components (AP). Mitochondrial DNA (mtDNA) copy number was measured from whole brain and AP fractions using qPCR. iPSC-derived cerebral organoid models were generated from both non-AD and sporadic AD (sAD) sources. These models were then separated into AP fractions and mtDNA copy number was measured using qPCR. Postmortem human brain was fractionated to collect whole cell, mitochondrial, and AP fractions from non-demented (ND) and sAD subjects. Aβ levels were measured in fractions using ELISA kits. iPSCs where used to derive neurons from ND and sAD subjects and lysosome number and autophagosome events were measured using LysoTracker and DAPRed fluorescent dyes.
    RESULTS: We observed a significant reduction in AP mtDNA content from 5xFAD mice from 2 months of age, while whole brain mtDNA was elevated in 5xFAD mice at 2 months of age but reduced at 12 months of age. Organoids derived from sAD iPSC donors also had reduced AP mtDNA content. Aβ levels were increased in whole and AP fractions in 5xFAD mouse samples, cerebral organoid models, and human postmortem brain. iPSC derived neurons from sAD donors had reduced lysosome content and autophagy events.
    CONCLUSIONS: Overall mitophagy is impaired across mouse and iPSC models of AD. Associations with Aβ pathology and other underlying mechanisms requires further investigation.
    DOI:  https://doi.org/10.1002/alz70855_106610
  14. J Transl Med. 2025 Dec 24. 23(1): 1423
    Exosomes in aging and age-related disorders: mechanisms, therapeutic potentials, and challenges.
    Sahar Safaei, Sepideh Sohrabi, Pouya Zahmatkesh, Mohammad Sadegh Soltani-Zangbar, Leili Aghebati Maleki.
      Aging is accompanied by a gradual decline in physiological resilience and an increased risk of chronic diseases collectively known as age-related disorders, including neurodegeneration, cardiovascular disease and osteoarthritis. Exosomes nano-sized extracellular vesicles have emerged as critical mediators in the aging process and related pathologies. By moving bioactive cargo such as proteins, lipids and mRNAs exosomes facilitate intercellular communication and modulate processes central to aging, including inflammation, immune response, senescence, and tissue repair. Exosomes contribute to "inflamm-aging," influence stem cell function, and reflect age-associated molecular alterations, positioning them as potential biomarkers for early diagnosis and disease monitoring. Understanding dual role of exosomes as both contributors to aging and platforms for intervention offers new avenues for promoting healthy longevity and mitigating the burden of age-associated diseases. Also, their inherent stability, low immunogenicity, and capacity for targeted delivery make exosomes promising candidates for therapeutic applications in regenerative medicine and anti-aging interventions. This review synthesizes current knowledge on exosome biogenesis, composition, and functional roles in aging and age-related diseases. We discuss emerging evidence supporting their use as diagnostic and prognostic tools and their potential in cell-free therapies aimed at modulating age-related decline. Despite their promise, several challenges impede clinical applications. Addressing these limitations will be essential to fully harnessing the therapeutic potential of exosomes in aging. Notwithstanding these obstacles, exosomes exhibit significant potential for personalized and combinatorial therapies. Understanding the dual role of exosomes as both contributors to aging and tools for its modulation may open new avenues for interventions to promote healthy longevity.
    Keywords:  Age-related disorders; Aging; Cellular senescence; Exosomes
    DOI:  https://doi.org/10.1186/s12967-025-07379-1
  15. Neurol Int. 2025 Dec 15. pii: 204. [Epub ahead of print]17(12):
    Senotherapeutics for Brain Aging Management.
    Timur Saliev, Prim B Singh.
      Brain aging is a progressive process marked by cellular dysfunction, chronic inflammation, and increased susceptibility to neurodegenerative diseases. A growing body of evidence identifies cellular senescence, the accumulation of non-dividing, metabolically active cells with a pro-inflammatory secretory profile (SASP), as a key contributor to cognitive decline and brain aging. This review explores the emerging field of senotherapeutics, which includes senolytics (agents that eliminate senescent cells) and senomorphics (agents that suppress SASP without killing cells), as potential strategies to manage brain aging. We summarize recent preclinical studies demonstrating that senotherapeutics can reduce neuro-inflammation, improve synaptic plasticity, and enhance cognitive function in aged animal models. Additionally, we highlight early-phase clinical trials investigating senolytic compounds in Alzheimer's disease and discuss key challenges, including the delivery of drugs to the brain, biomarker development, and long-term safety. The review concludes that senotherapeutics, particularly when combined with personalized and multimodal approaches, represent a promising avenue for mitigating age-related cognitive decline and promoting healthy brain aging.
    Keywords:  brain aging; inflammation; neurodegenerative disease; pro-inflammatory secretory profile (SASP); senolytics; senomorphics; senotherapeutics
    DOI:  https://doi.org/10.3390/neurolint17120204
  16. J Paediatr Child Health. 2025 Dec 22.
    I've Never Heard of This! An Approach to Child and Family-Centred Care for Children and Young People With Rare Diseases.
    Lisa J Ewans, Kris Pierce, Eleanor Farley, Rachel Bowden, Carolyn Shalhoub, Elizabeth Emma Palmer.
      Paediatricians strive to deliver best practice care for their patients. However, when they encounter a child with one of the over 8000 rare diseases, a majority (> 70%) of which have a genetic cause, it is challenging to find clinical guidelines and point-of-care resources to support their practice. This article provides a framework for a collaborative management approach for rare diseases. It draws on the team's experience in delivering multidisciplinary clinics for ultra-rare conditions, running a rare disease registry and undiagnosed disease programme, and in founding a rare disease patient advocacy group for SCN2A-related conditions. This article signposts useful resources to facilitate paediatricians in delivering 'wraparound' rare disease care that is comprehensive, holistic and child and family-centred. These include Australia's first National Recommendations for Rare Disease Health Care and the RARE (Rare Awareness Rare Education) portal led by the national peak body for people living with a rare disease, Rare Voices Australia. Six key approaches are suggested that paediatricians can incorporate into their clinical practice to deliver high quality care for each child and young person with a rare disease. This includes strategies to support a timely diagnosis, including accessing undiagnosed disease programmes and linking children, young people and their caregivers with peers, patient advocacy groups and rare disease registries to reduce isolation and uncertainty. As less than 5% of rare diseases are currently amenable to a targeted therapy, it also suggests resources and approaches to facilitate access to and shared decision-making about research and novel advanced therapeutics.
    Keywords:  coordinated care; patient advocacy groups; rare disease
    DOI:  https://doi.org/10.1111/jpc.70267
  17. J Proteome Res. 2025 Dec 23.
    TAG-PL: A Universal Proximity Labeling Platform for Mapping Mitochondrial Proteomes and Organelle Interactions under Stress.
    Enming Miao, Xuyang Yue, Zhixiong Tao, Hongqiang Qin, Mingliang Ye.
      Mitochondrial dysfunction induces numerous diseases, yet current proximity labeling methods require gene transfection and membrane potential-sensitive probes, limiting their use in hard-to-transfect cells and disease models. We developed TAG-PL (Tailored Antibody-Guided Proximity Labeling), a transfection-free approach for in-depth mapping of the mitochondrial proteome, achieving >90% specificity and identifying >450 mitochondrial proteins─more than the coverage of existing nontransfection methods. Applied to heat-stressed macrophages, TAG-PL revealed dynamic mitochondrial proteome remodeling, including antioxidant responses and metabolic shifts during heat stress. Notably, we discovered physical interactions between stress granules and mitochondria, identifying 10 interaction mediators (including MSRA and UBA1). These findings establish stress granules as regulatory hubs for organelle dynamics and immune responses. TAG-PL's high performance and broad applicability across diverse sample types, particularly immune cells and tissues, make it a powerful tool for dissecting mitochondrial function in disease models without genetic manipulation.
    Keywords:  SG−mitochondria interaction; antibody-guided proximity labeling; mitochondrial proteome
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00855
  18. Biochim Biophys Acta Rev Cancer. 2025 Nov;pii: S0304-419X(25)00222-7. [Epub ahead of print]1880(6): 189480
    Nanoparticulate delivery and targeting of RNA to the brain.
    Aditya Gupta, Raghu Ramanathan, Chittalsinh M Raulji, Ram I Mahato.
      The blood-brain barrier (BBB) presents a critical challenge in treating central nervous system (CNS) disorders, particularly aggressive brain cancers such as glioblastoma (GBM) and medulloblastoma (MB). RNA therapies exploit endogenous cellular machinery to modulate gene expression, targeting previously undruggable pathways. RNA and CRISPR gene therapies hold transformative potential for brain cancer but demand breakthroughs for enhanced drug transport across the BBB. While clinical achievements in non-CNS diseases validate their efficacy, interdisciplinary collaboration is essential to advance nanoparticles (NPs) engineering, immune evasion, and non-invasive delivery for CNS applications. NPs are indispensable for advancing RNA therapies in brain cancer, with lipid nanoparticles (LNPs) and viral vectors leading clinical translation. Innovations in targeting (e.g., GLUT1, RVG peptide, ApoE mimetic peptide) and non-invasive delivery (e.g., focused ultrasound) are critical to overcome the BBB limitations. This review highlights the different strategies that can be utilized to deliver RNA-based therapies to the brain and summarizes the recent clinical efforts to deliver the RNA.
    Keywords:  CRISPR; Glioblastoma; Medulloblastoma; Oligonucleotide; mRNA
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189480
  19. Mol Ther. 2025 Dec 24. pii: S1525-0016(25)01064-0. [Epub ahead of print]
    Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
    Sandra R Bacman, Wendy Shoop, C Spencer Henley-Beasley, Rhese Thompson, Jose Domingo Barrera-Paez, Lise-Michelle Theard, Monica Rodriguez-Silva, Cassandra Gorsuch, Elisabeth R Barton, Carlos T Moraes.
      Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load which was maintained up to forty-two weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.041
  20. Biochemistry (Mosc). 2025 Dec;90(12): 1957-1969
    Mitochondrial Reticulum in Skeletal Muscles: Proven and Hypothetical Functions.
    Lora E Bakeeva, Valeriya B Vays, Irina M Vangeli, Chupalav M Eldarov, Vasily A Popkov, Ljubava D Zorova, Savva D Zorov, Dmitry B Zorov.
      The mitochondrial reticulum of skeletal muscles has been characterized in the 1970-80s. It has been suggested and then proven its role is delivering energy in a form of transmembrane potential on the mitochondrial inner membrane throughout the cell volume, followed by ATP synthesis by the mitochondrial ATP synthase. However, the data on the mitochondrial ultrastructure still remains a subject to criticism. To exclude the possibility of artifacts caused by the sample preparation for electron microscopy, we compared the structure of mitochondria in the ultrathin sections of muscle fibers observed by electron microscopy and in intact fibers stained with a membrane potential-dependent dye and visualized by confocal microscopy. The comparison was carried out for mice and naked mole rats known for their superior longevity. The obtained results confirmed previous findings regarding the structure of mitochondrial reticulum. A model suggesting the functioning of giant mitochondria as intracellular structures preventing tissue hypoxia was proposed.
    Keywords:  hypoxia; membrane potential; mitochondria; mouse; naked mole rat; oxygen transport; reticulum; ultrastructure
    DOI:  https://doi.org/10.1134/S000629792560190X
  21. Cell Death Discov. 2025 Dec 24.
    Targeting mitochondrial autophagy for anti-aging.
    Wenjun Shan, Yuling Liu, Ruying Tang, Longfei Lin, Hui Li, Hongjun Yang.
      Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.
    DOI:  https://doi.org/10.1038/s41420-025-02913-y
  22. Mol Brain. 2025 Dec 25.
    Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.
    Akihiko Nishijima, Mutsumi Yokota, Soichiro Kakuta, Akihiro Yamaguchi, Kei-Ichi Ishikawa, Hideyuki Okano, Wado Akamatsu, Nobutaka Hattori, Masato Koike.
      Mitochondrial dysfunction and abnormalities in mitochondrial quality control contribute to the development of neurodegenerative diseases. Parkinson's disease is a neurodegenerative disease that causes motor problems mainly due to the loss of dopaminergic neurons in the substantia nigra pars compacta. Axonal mitochondria in neurons reportedly differ in properties and morphologies from mitochondria in somata or dendrites. However, the function and morphology of axonal mitochondria in human dopaminergic neurons remain poorly understood. To define the function and morphology of axonal mitochondria in human dopaminergic neurons, we newly generated tyrosine hydroxylase (TH) reporter (TH-GFP) induced pluripotent stem cell (iPSC) lines from one control and one PRKN-mutant patient iPSC lines and differentiated these iPSC lines into dopaminergic neurons in two-dimensional monolayer cultures or three-dimensional midbrain organoids. Immunostainings with antibodies against axonal and dendritic markers showed that axons could be better distinguished from dendrites of dopaminergic neurons in the peripheral area of three-dimensional midbrain organoids than in two-dimensional monolayers. Live-cell imaging and correlative light-electron microscopy in peripheral areas of midbrain organoids derived from control TH-GFP iPSCs demonstrated that axonal mitochondria in dopaminergic neurons had lower membrane potential and were shorter in length than those in non-dopaminergic neurons. Although the mitochondrial membrane potential did not significantly differ between dopaminergic and non-dopaminergic neurons derived from PRKN-mutant patient lines, these differences tended to be similar to those in control lines. These results were also largely consistent with those of our previous study on somatic mitochondria. The findings of the present study indicate that midbrain organoids are an effective tool to distinguish axonal from dendritic mitochondria in dopaminergic neurons. This may facilitate the analysis of axonal mitochondria to provide further insights into the mechanisms of dopaminergic neuron degeneration in patients with Parkinson's disease.
    Keywords:  Axonal mitochondria; Dopaminergic neurons; Electron microscopy; Live-cell imaging; Midbrain organoids
    DOI:  https://doi.org/10.1186/s13041-025-01268-w
  23. Epigenomics. 2025 Dec 23. 1-18
    Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
    Phyo W Win, Julia Nguyen, Elly H Shin, Tyler S Nagano, Brent Selimi, Katie Hong, Anahita M Meybodi, Bradley P Yates, Emma V Burke, David E Carter, Gregory A Newby, Charles Newcomb, Dan E Arking, Christina A Castellani.
       AIMS: Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease.
    MATERIALS AND METHODS: Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harboring a mitochondrial transcription factor A (TFAM) knockout generated via CRISPR-Cas9, and matched control lines.
    RESULTS: We identified 2924 differentially methylated sites, 67 differentially methylated regions, and 102 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 24 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand signaling pathway, ABCD1/2 gene activity, and cell signaling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression.
    CONCLUSIONS: We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodeling relevant to development, aging, and complex disease.
    Keywords:  Mitochondria; epigenome; mitochondrial DNA; mitochondrial DNA copy number; transcriptome
    DOI:  https://doi.org/10.1080/17501911.2025.2603883
  24. Sci Rep. 2025 Dec 24.
    Anthracyclines effect on mitochondrial function and biogenesis in normal blood cells of hodgkin lymphoma patients.
    Gianmario Sambuceti, Simona Coco, Vanessa Cossu, Sonia Carta, Francesco Lanfranchi, Chiara Ghiggi, Davide Ceresa, Kamila Pana, Monica Colombo, Silvia Marconi, Maddalena Ghelardoni, Serena Losacco, Francesca Vitale, Sabrina Chiesa, Anna Maria Orengo, Matteo Bauckneht, Emanuele Angelucci, Cecilia Marini.
      The preferential accumulation of anthracyclines in the mitochondrial matrix has been proposed to trigger a self-perpetuating vicious cycle with mitochondrial DNA (mtDNA) alteration and redox stress enhancing one each other to lead to a progressive mitochondrial impairment. To test this hypothesis, we monitored oxygen consumption rate (OCR) and mt-DNA copy number (mtDNA-CN) of peripheral blood mononuclear cells (PBMCs) harvested from 23 patients with Hodgkin lymphoma (HL) submitted to adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) for the whole treatment, according to a Deauville score ≤ 3 after two cycles of chemotherapy at the interim PET/CT. PBMCs were isolated before treatment (baseline), at interim and one month after End of Therapy (EoT). Baseline data were compared with 23 healthy subjects selected according to a case-control criterion. OCR was estimated under control condition, after blockade of ATP-synthase, and of mitochondrial Complexes I and III. mtDNA-CN was assayed by droplet digital PCR and normalized against nuclear DNA. Mitochondrial DNA mutational status was assayed by next generation sequencing and alignment to reference genome after sequencing depth equalization. At diagnosis, mitochondrial OCR was lower in HL PBMCs than in controls, despite a preserved mitochondrial asset, testified by the mtDNA-CN. In the 18 subjects with complete remission at EoT PET/CT, both variables decreased back to the baseline values. By contrast, in the 5 patients with persistent disease, both mitochondrial OCR and mtDNA-CN remained elevated. ABVD therapy alters mitochondrial function and biogenesis of normal PBMCs whose metabolic pattern might represent a possible marker of treatment effectiveness.
    Keywords:  Anthracyclines; Glucose metabolism.; Hodgkin lymphoma; Mitochondrial DNA; Mitochondrial respiration
    DOI:  https://doi.org/10.1038/s41598-025-31980-5
  25. Alzheimers Dement. 2025 Dec;21 Suppl 5 e103550
    Drug Development.
    Malik White, Rikke Han Kofoed, Chinaza Lilian Dibia, Nathalie Vacaresse, Luis Fernando Rubio-Atonal, Brandy Laurette, Sheng-Kai Wu, Sofia Samuelsson, Marie-Eve Paquet, Kullervo Hynynen, Isabelle Aubert.
       BACKGROUND: Recombinant adeno-associated viruses (AAVs) hold promise for brain disorders but often require intracranial injection, limiting therapeutic reach and being invasive. Intravenous (i.v.) AAV delivery is restricted by the blood-brain barrier (BBB), reducing efficiency. Recent AAV variants can cross the BBB, enabling widespread brain transduction. MRI-guided focused ultrasound (FUS) transiently modulates BBB permeability, enhancing gene delivery in small or large brain regions targeted.
    HYPOTHESIS: We hypothesize that combining IV BBB-penetrating AAVs with FUS will optimize gene delivery, enabling both widespread and region-specific transduction for neurodegenerative diseases.
    METHODS: Three-month-old C57BL/6 mice received i.v. AAV-PHP.V1.CAG.TdTomato (V1) and AAV9.CAG.EYFP, followed by FUS targeting various brain regions. Immunohistochemistry and confocal microscopy were done 3 weeks post-delivery.
    RESULTS: Our findings demonstrate that FUS enhances targeted gene delivery for AAV9 and V1 while maintaining global expression in the brain for V1, offering a non-invasive strategy for precise (AAV9) or widespread and locally enriched (V1) gene therapy.
    CONCLUSION: This approach could improve treatments for neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
    DOI:  https://doi.org/10.1002/alz70859_103550
  26. Genes Dis. 2026 Mar;13(2): 101719
    Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging.
    Tingting Liu, Jingwen Li, Haojie Wu, Junbo Qiao, Jianshe Wei.
      Parkinson's disease (PD) is a complex neurodegenerative disorder that poses significant burden on patients and families. Its exact cause is unknown, resulting in limited effective treatments. Mitochondrial dysfunction, linked to genetics, aging, oxidative stress, and environmental factors, is central to PD. Healthy elderly individuals have a compensatory mitochondrial DNA (mtDNA) mechanism in brain cells, but this mechanism is impaired in PD patients, leading to mtDNA reduction, respiratory chain dysfunction, decreased adenosine triphosphate (ATP) synthesis, and inadequate neuron energy. Aging increases oxidative stress, impairing mitochondrial function. Mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra causes neuronal loss and disease progression. Aging microglia also play a crucial role, with a reduced capacity to clear neurotoxic substances, especially in the substantia nigra. A decrease in triggering receptor expressed on myeloid cells 2 (TREM2) gene expression shifts microglia to a pro-inflammatory phenotype, exacerbating neuroinflammatory responses and protein deposition. Down-regulation of the C-X3-C motif chemokine ligand 1 (CX3CL1)/C-X3-C chemokine receptor 1 (CX3CR1) signaling pathway increases the expression of pro-inflammatory cytokines, accelerating neuronal loss and disease progression. Recent research has identified a new astrocyte aging regulatory mechanism involving the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, promoting astrocyte aging and exacerbating dopamine neuronal loss and motor dysfunction. Understanding PD pathogenesis, especially mitochondrial dysfunction, aging, and glial cell changes, is crucial for developing effective treatments.
    Keywords:  Aging; Astrocytes; Microglia; Mitochondrial dysfunction; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.gendis.2025.101719
  27. Alzheimers Dement. 2025 Dec;21 Suppl 1 e100362
    Basic Science and Pathogenesis.
    Maria Clara Zanellati.
       BACKGROUND: Dysfunctional organelle communication networks are a common hallmark of various neurodegenerative diseases, including Alzheimer's disease (AD). Imaging organelles and their interactions in iPSC-derived neurons that harbor disease-associated mutations holds promise for understanding the mechanistic basis of neurodegeneration.
    METHOD: We developed a method for multispectral imaging of eight organelles simultaneously in live cells and used this method to visualize organelle morphology and dynamics (morphodynamics) along neuronal differentiation. We transfected induced pluripotent stem cells (iPSCs) and iPSC-derived cortical neurons (iNeurons) with genetically encoded organelle markers and collected multispectral z-stack and timelapse images at five-time points throughout neuronal differentiation and maturation: iPSCs, and iNeurons at day 7, day 14, day 21, and day 28. Raw images were then subjected to linear unmixing and run through a Napari-InferSubC image analysis pipeline for segmentation and analysis of approximately 1400 morpho-metrics including organelle volume, size, shape, and number, as well as number and volume of the contacts between organelles (2- to 6-way).
    RESULT: We observed dramatic remodeling of organelles during differentiation of iPSCs into iNeurons. For example, endoplasmic reticulum (ER) and mitochondria volumes increased as iPSCs differentiated into cortical neurons. We observed an increase in the overall number of the contacts throughout iNeuron maturation, accompanied by an increase in higher order contacts (3- and 4-way contacts). Examples of organelle contacts that increased during iNeuron differentiation and maturation include ER-mitochondria, known to be dysregulated in AD and Parkinson disease; mitochondria-lysosome, previously reported defective in Charcot-Marie-Tooth; and ER-peroxisome. We found that expression of VAPB, which mediates ER-peroxisome contacts and is mutated in ALS, increases as iPSCs differentiate into iNeurons. This contact is implicated in the production of plasmalogens, which are essential for the growth and maintenance of synapses in the nervous system. Knockdown of VAPB reduced plasmalogen levels and prevented the formation of synapses during iNeuron differentiation.
    CONCLUSION: We uncovered a novel role for VAPB-mediated ER-peroxisome contacts in neuronal differentiation, suggesting that multi-spectral imaging can be used to interrogate organelle morphology and contacts during neuronal differentiation and neurodegeneration. As a future direction, we will use this method to reveal defects in organelle communication networks in iNeurons with AD-associated mutations.
    DOI:  https://doi.org/10.1002/alz70855_100362
  28. Nanoscale. 2025 Dec 22.
    Emerging nano-delivery systems for targeting mitochondria.
    Agata N Burska, Kristina E Raish, Dinmukhamet Bayandy, Vesselin N Paunov.
      This review aims to provide a comprehensive analysis of the potential of mitochondria-targeting nanosystems as a novel therapeutic approach for treating a wide range of diseases. It explores the underlying mechanisms of mitochondrial dysfunction in disease progression and shows how nanotechnology offers an innovative platform for delivering targeted therapies directly to mitochondria. We also highlight the role of mitochondria in cellular function and disease pathology particularly in cancer, followed by a consideration of the therapeutic potential of targeting these organelles. We explore the recent development and design principles of mitochondria-targeting nanosystems, assessing their applications and challenges and finally outline future research directions, emphasizing the importance of overcoming current limitations to expand the use of these nanosystems in medicine. This is intended to provide valuable insights into the promising connection of mitochondrial biology and nanotechnology, with the goal of advancing innovative treatments for various diseases.
    DOI:  https://doi.org/10.1039/d5nr03935e
  29. Biogerontology. 2025 Dec 22. 27(1): 27
    CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.
    Arsene Mutombo Menga, Xin Hong, Lei Zhu.
      Aging is marked by progressive dysfunction in cellular maintenance pathways, including mitochondrial impairment, reduced autophagic capacity, and accumulation of senescent cells, which contribute to chronic low-grade inflammation. The transmembrane protein CD47 best known for delivering a "don't eat me" signal through SIRPα is increasingly recognized as an important modulator of several aging-related processes. Its upregulation in aged or inflamed tissues can inhibit the clearance of damaged or senescent cells, reinforce inflammatory signaling through pathways such as NF-κB, and influence metabolic and autophagy-related regulation in a context-dependent manner. This review synthesizes current evidence identifying CD47 as an integrative node that intersects with multiple hallmarks of aging. We examine its roles across cardiovascular, neurodegenerative, and metabolic pathologies, and evaluate the emerging therapeutic landscape targeting the CD47-SIRPα axis. Although CD47 blockade has shown promise in enhancing immune clearance and improving tissue homeostasis, clinical translation remains challenged by on-target toxicities such as anemia and by age-dependent variability in immune responsiveness. Targeting CD47 therefore represents a mechanistically grounded but inherently complex strategy for mitigating age-related functional decline.
    Keywords:  Age-related diseases; Aging; CD47; Phagocytosis; Senescence
    DOI:  https://doi.org/10.1007/s10522-025-10370-4
  30. Front Med (Lausanne). 2025 ;12 1666909
    Global trends and perspectives in mitophagy on neurodegenerative diseases: a scientometric analysis over 20 years.
    Haiyan Wu, Minheng Zhang, Lei Zhang, Hongwei Liu, Haixia Fan.
       Background: The investigation of mitophagy in neurodegenerative diseases has grown significantly, yet a comprehensive global insight remains limited. This study conducts a scientometric analysis to map the research landscape related to mitophagy in neurodegenerative diseases.
    Methods: We conducted a bibliometric analysis of 2,566 publications (2004 to 11 June 2025) from Web of Science Core Collection and Scopus. To mitigate bias in trend analyses, incomplete 2025 data were excluded from publication growth and curve fitting but retained for other analyses. Data were analyzed via Bibliometrix R package, VOSviewer, Scimago Graphica, and CiteSpace to map mitophagy research evolution.
    Results: The field showed exponential growth with peak productivity in 2021. The United States led publication output, with institutions from the USA, UK, and China forming the core of robust international collaborations, while maintaining the highest citation impact. Influential researchers included Tavernarakis, Nektarios and Reddy, P. Hemachandra, with prominent journals such as International Journal of Molecular Sciences, Cells and Autophagy, serving as key publication venues. Cluster analysis revealed thematic structures centered on "Parkinson's disease," "mitochondrial dysfunction," "oxidative stress," and "fission/fusion mechanisms", with additional focus on "Parkin-mediated mitophagy" and "neurodegenerative diseases." Research evolved from foundational studies through mechanistic exploration to translational applications. Emerging trends include "post-translational modifications (PTMs)," "chaperone-mediated autophagy," "gut microbiota," "mitochondrial quality control," and therapeutic investigations of compounds like "curcumin" and "melatonin."
    Conclusion: This first comprehensive scientometric analysis underscores the expanding interest in mitophagy as a crucial molecular mechanism in neurodegenerative diseases. Our findings establish a framework for developing novel therapeutic interventions such as mitochondrial quality control modulators and compounds like curcumin and melatonin targeting mitophagy dysfunction in neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; PINK1/Parkin; mitochondrial dysfunction; mitophagy; neurodegenerative diseases; oxidative stress
    DOI:  https://doi.org/10.3389/fmed.2025.1666909
  31. Autophagy. 2025 Dec 26.
    Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
    Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.
      Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.
    Keywords:  ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons
    DOI:  https://doi.org/10.1080/15548627.2025.2610450
  32. Alzheimers Dement. 2025 Dec;21 Suppl 1 e097913
    Basic Science and Pathogenesis.
    Jaroslav Bendl.
       BACKGROUND: Neurodegenerative diseases and serious mental illnesses often exhibit overlapping molecular characteristics, underscoring the need for integrated datasets to unravel shared and distinct mechanisms. Existing studies are fragmented, employing varied cohorts and methodologies, which hinders comprehensive cross-disorder comparisons. To address this, linking molecular, cellular, genetic, and clinical data at scale is essential for advancing our understanding of these complex conditions.
    METHOD: The PsychAD consortium has created a resource of unprecedented scale, generating single-nucleus RNA sequencing (snRNA-seq) and genotype data from dorsolateral prefrontal cortex samples of 1,494 human donors. This dataset spans over 6.3 million nuclei from donors with diverse diagnoses, including Alzheimer's disease, Parkinson's disease, schizophrenia, and bipolar disorder, alongside neurotypical controls. High-throughput sequencing, rigorous quality control, and computational methods were employed to ensure reliable cell-type-specific profiles and facilitate cross-disease analyses.
    RESULT: The PsychAD dataset provides high-resolution cellular taxonomy, identifying 8 major cell classes and 67 subtypes. It offers insights into transcriptional and genetic alterations associated with neurodegenerative and psychiatric disorders and highlights shared molecular pathways. Donor metadata, such as neuropsychiatric symptom profiles and neuropathological assessments, enrich the dataset's value for targeted disease investigations. Open-access tools enable users to explore cell-type-specific gene expression, identify phenotype-associated cells, and map new datasets to the PsychAD reference framework.
    CONCLUSION: The PsychAD dataset is a transformative resource for the neuroscience community, offering integrated, high-quality data to study neurodegenerative and psychiatric diseases. Publicly accessible through the AD Knowledge Portal, it supports collaboration and re-use, providing a foundation for novel integrative analyses, tool development, and discovery of therapeutic targets. In this session, we will demonstrate how to leverage these data and tools for advancing research across the field.
    DOI:  https://doi.org/10.1002/alz70855_097913
  33. Front Aging. 2025 ;6 1750125
    Editorial: Insights in aging, metabolism and redox biology: 2024.
    Ruben K Dagda, Jianhua Zhang.
      
    Keywords:  NAD+; ROCK inhibitor; autophagy and mitophagy; lactate; lifestyles including sleep/fasting/exercise; mitochondria and mitochondrial DNA; neurodegeneration; rapamycin
    DOI:  https://doi.org/10.3389/fragi.2025.1750125
  34. Mol Genet Genomic Med. 2025 Dec;13(12): e70172
    A Zebra in Horse's Clothing: Rethinking the Diagnosis of Rare Diseases.
    Rajeev Dutta, Cathy Duong, Virginia Kimonis, Changrui Xiao.
       INTRODUCTION: Rare diseases sometimes present with deceptively common symptoms, complicating diagnosis and decisions about genetic testing. While testing for rare disease offers important benefits, it also carries risks that warrant careful consideration.
    METHODS: We review illustrative cases of rare diseases, along with current screening and diagnostic practices, to reexamine guiding principles for genetic testing. The analysis focuses on balancing clinical utility, patient-centered care, and broader policy implications.
    RESULTS: We propose a number of recommendations to guide testing, including ruling out common causes before proceeding, ensuring the presentation is atypical for other common conditions, confirming consistency with a specific, treatable rare disease entity or group, assessing patient or family capacity for informed decision-making, and matching test invasiveness to expected diagnostic utility. Comparison with newborn screening and diagnostic testing highlights discrepancies between these principles and common practices, highlighting the difficulty of achieving consistency.
    CONCLUSIONS: Establishing uniform guidelines for genetic testing remains challenging, particularly given the limited knowledge surrounding rare disorders. Coordinated efforts are needed to protect patient interests, assess the utility of diagnoses across varied contexts, and ensure that both clinical practice and policy development maximize benefits while minimizing harms.
    Keywords:  diagnosis; genetic testing; rare and undiagnosed diseases; zebra
    DOI:  https://doi.org/10.1002/mgg3.70172
  35. Alzheimers Dement. 2025 Dec;21 Suppl 1 e107394
    Basic Science and Pathogenesis.
    Sarwan Ali, Basilio Cieza, Giuseppe Tosto.
       BACKGROUND: Imputation is still a crucial technique in genomic studies to infer untyped variants, enhancing the coverage and power of genome-wide association studies. However, its accuracy can vary, especially for rare variants and across populations. Using genotype data from ADSP (Alzheimer's Disease sequencing Project), we conducted I) traditional imputation with a single round of genotype imputation ("SI") and II) two (or more) rounds of imputation ("DI") on data progressively passed through quality control and again imputed. We tested the performance of either approach by estimating the amount of imputation errors using whole genome sequencing data (WGS) from ADSP as gold standard.
    METHOD: For 196 Caribbean Hispanics, we estimated the error rates only in SNPs within chromosome 1 imputed at optimal quality (R^2≥ 80%) and across minor allele frequency (MAF) brackets: common (MAF ≥ 0.05), uncommon (0.01 ≤ MAF < 0.05), rare (0.001 ≤ MAF < 0.01), ultra-rare (MAF < 0.001) and overall. We tested the entire sample and then separately for individuals with ≥50% African genetic ancestry (AFR).
    RESULT: Overall, DI showed significant lower error rates compared to SI (2.65% vs. 4.23%, Wilcoxon p-value < 0.001). This result was consistent across MAF (Table 1), in rare (2.99% vs. 3.37%), uncommon (2.93% vs. 3.50%), and ultra-rare variants (3.08% vs. 3.43%). In individuals with predominant AFR, imputation errors were more frequently observed compared to those with low AFR, especially for rare and ultra-rare variants; nevertheless, DI maintained significant lower error rates across all MAF categories (Table 2).
    CONCLUSION: Our findings demonstrate that multiple rounds of imputation generally outperform the traditional single one in terms of accuracy, particularly for rare and ultra-rare variants. This improvement is confirmed in groups that have shown higher error rates after traditional imputation, such as individuals with predominant African ancestry (Sariya et al. 2019). These results highlight a valuable and easy approach for enhancing the quality of imputed data across populations, which could lead to more robust genetic association studies.
    DOI:  https://doi.org/10.1002/alz70855_107394
  36. J Transl Med. 2025 Dec 24.
    Mitochondrial fission and fusion in inflammatory diseases: mechanisms and therapeutic implications.
    Wenjing Xu, Xinru Xu, Yaonan Zhang, Fenfen Li, Daozong Xia.
      
    Keywords:  Inflammatory diseases; Inflammatory pathways; Mitochondrial dynamics; Therapeutic targets; Translational medicine
    DOI:  https://doi.org/10.1186/s12967-025-07605-w
  37. Front Immunol. 2025 ;16 1680326
    Cardiolipin's multifaceted role in immune response: a focus on interacting proteins.
    Zhuodong Chai, Yuqi Zhou, Sukria Hossain, Khanh Huynh, Sahelosadat Hajimirzaei, Yan Zhang, Jiaqian Qi, Guoying Zhang, Zhenyu Li, Yinan Wei.
      Cardiolipin is a unique and essential phospholipid that plays a pivotal role in cellular function. In eukaryotic cells, it is predominantly localized within the mitochondrial membranes, with the highest concentration in the inner mitochondrial membrane (IMM). Recent studies have highlighted the multifaceted role of cardiolipin in immune regulation. This review aims to provide a comprehensive overview of specific proteins that directly interact with cardiolipin and to elucidate how these interactions underlie its diverse and critical functions in innate immunity. In addition, we discuss the involvement of cardiolipin in various pathological conditions in which its protein interactions contribute to immune dysregulation.
    Keywords:  cardiolipin; inflammasome; innate immunity; protein-lipid interaction; pyroptosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1680326
  38. Aging Dis. 2025 Dec 21.
    Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.
    Jiehui Li, Gajendra Kumar, Yuqing Yan, Mengmeng Wang, Ling Xu, Haige Wu, Ye Gao, Yi Wang, Yingyi Fan, Ying Bai.
      Alzheimer's disease (AD) is a progressive neurological disease characterized by a decline in cognitive abilities and memory loss. Mitochondrial dysfunction is a major factor in early pathological changes; however, its precise pathogenic mechanisms are not yet fully understood. Mitochondria are essential for neuronal energy generation, calcium ion balance regulation, apoptosis control, and production of reactive oxygen species. Among the various mitochondrial changes, the imbalance between fission and fusion is closely linked to β-amyloid deposition and tau pathology, forming a vicious cycle. The electron transport chain (ETC) produces more than 90% of cellular ATP and is damaged in AD. However, most studies simply refer to "mitochondrial dysfunction" in general terms without detailing specific changes in ETC complexes and their subunits. This review aims to provide a detailed overview of the dynamics and ETC complex dysfunction observed in AD for therapeutic targets.
    DOI:  https://doi.org/10.14336/AD.2025.1046
  39. Tissue Barriers. 2025 Dec 26. 2607157
    Potential of exosomes for targeted therapy in neuroinfectious disease management: crossing the blood-brain barrier.
    Sarad Pawar Naik Bukke, Shikha Yadav, Shatrudhan Prajapati, Satla Shobha Rani, M Sunitha Reddy, Chandrashekar Thalluri, Ananda Kumar Chettupalli, Narayana Goruntla, Bhupalam Pradeepkumar, Zohre Eftekhari, Yasodha Krishna Janapati, Alrazi Eisa Shogar, Tadele Mekuriya Yadesa.
      Neuroinfectious diseases such as meningitis, encephalitis, and myelitis continue to be a significant health issue especially in low- and middle-income nations where the timely identification and successful treatment are mostly not yet available. There is also the complicating factor of the restrictive nature of the blood-brain barrier (BBB) which greatly limits the passage of antimicrobial and anti-inflammatory agents through into the central nervous system. Exosomes which are nano-sized extracellular vesicles released by a vast variety of cells have been proposed as a promising solution to overcome this barrier because of their natural biocompatibility, low immunogenicity and capacity to enter the BBB by receptor-mediated, adsorptive-mediated and carrier-mediated processes. This review critically discusses the structural and functional dynamics of the BBB in infection, the recent discoveries in the exosome trafficking pathways, and the diagnostic and therapeutic role of exosomes in infection, including infections related to HIV-associated neurocognitive disorders, tuberculous meningitis, cryptococcal meningitis, neurotoxoplasmosis. Special consideration will be given to engineered exosomes and how they could be used to improve targeted delivery of drugs, decrease systemic toxicity and offer minimally invasive biomarkers platforms to detect disease earlier. He/she points possible solutions to CNS infections by combining mechanistic understanding with newly acquired pre-clinical and clinical results, this review emphasizes the increasing promise of exosome-based nanomedicine as a transformational technology.
    Keywords:  Blood–brain barrier; drug delivery; exosomes; extracellular vesicles; neuroinfectious diseases
    DOI:  https://doi.org/10.1080/21688370.2025.2607157
  40. Alzheimers Dement. 2025 Dec;21 Suppl 1 e099985
    Basic Science and Pathogenesis.
    Nien Yeh Daphne Yu, Shea J Andrews, Lifang Hou, Kristine Yaffe.
       BACKGROUND: Mitochondrial dysfunction has been implicated in various age-related health issues and neurodegenerative disorders, but the role of mtDNA mutations is underexplored, especially in younger and more diverse populations. One key aspect of mtDNA is heteroplasmy, the presence of more than one allele in mtDNA, which may contribute to mitochondrial dysfunction. Additionally, mitochondrial haplogroups are maternally inherited groups of mtDNA variations that reflect ancestral lineages and may influence disease risk. Here, we evaluated the effects of mitochondrial heteroplasmy (mtHz) burden and mitochondrial haplogroup (mtHg) on cognition at mid-life.
    METHOD: We studied 2308 participants from the Coronary Artery Risk Development in Young Adults study (mean age 45.25 ± 3.55 years, 58.2% female, 45.5% Black, and 55.5% White at baseline). Heteroplasmy burden 5 years from baseline was measured by the sum of Mitochondrial Local Constraint Score, which takes each variant's observed-to-expected ratio adjusted by its homoplasmy count in population to calculate the constraint effect of the variant. Haplogroups were determined with reference to PhyloTree Build 17. We conducted multivariate linear regression to investigate associations of mtHg and mtHz to cognitive outcomes assessed 10 years from baseline, adjusting for baseline age, sex, race, and years of education. Race-stratified analysis was conducted to determine mtHg effects within race, with common haplogroups H and L3 as reference for White and Black participants respectively.
    RESULT: There was no association between heteroplasmy burden and cognitive function. Haplogroups in macro-haplogroup L was significantly associated with worse cognitive outcome across all participants, particularly in processing speed and global cognition. mtHg N was associated with improved processing speed among White participants, and with better executive function, verbal memory, and global cognition among Black participants. mtHg K was associated with worse executive function among White participants. However, none of the race-specific associations were significant after adjusting for multiple comparisons.
    CONCLUSION: Our findings suggest potential associations between mtHg and cognitive performance, pointing to mtDNA variation as a possible factor of mid-life cognitive health. Race-stratified results underscore the need to account for different haplogroup distributions within racial groups and warrants further investigation to clarify the underlying genetic, environmental, and social contributors.
    DOI:  https://doi.org/10.1002/alz70855_099985
  41. Alzheimers Dement. 2025 Dec;21 Suppl 1 e102361
    Basic Science and Pathogenesis.
    Dimitri Budinger.
       BACKGROUND: Microglia are crucial for maintaining brain health and neuronal function. A novel mechanism of microglia-neuron interaction, mediated by direct intercellular connections, namely through tunnelling nanotubes (TNTs), has recently been described between these cell types (Scheiblich et al., 2024). Preliminary data in mice cells suggest that microglia can form TNTs with neurons and free those from pathological protein aggregates made of hyperphosphorylated tau or α-syn, and promoting protein degradation (Scheiblich et al., 2024). Additionally, microglia were shown to share their healthy mitochondria with burdened neurons through TNT, reducing oxidative stress and restoring neuronal health. Failure of such a neuroprotective mechanism may, in turn, be causative for neurodegeneration. Beyond supporting individual cells, TNT-mediated interactions enhance the collective function of microglial and neuronal populations, mitigating inflammation and neuronal dysfunction.
    METHOD: We employ induced pluripotent stem cells (iPSCs) derived from Alzheimer's disease patients and healthy controls. These iPSCs are differentiated into cortical neurons and microglia, then cocultured to investigate TNT formation and the dynamics of aggregated protein transfer between these cell types, using high resolution microscopy techniques. Additionally, we evaluate how disease genotypes influence TNT formation parameters.
    RESULT: Our findings confirm the presence of TNTs between iPSC-derived neurons and microglia. We show that the genetic background of these cells influences TNT morphology, including their length, diameter, and the number of TNTs per cell. Live imaging analyses further reveal that TNT dynamics-such as their formation speed, persistence over time, and the transfer kinetics of aggregated proteins and organelles-differ between control and patient-derived cultures.
    CONCLUSION: In conclusion, this study confirms the formation of tunneling nanotubes (TNTs) between iPSC-derived neurons and microglia, revealing their role in clearing pathological protein aggregates and exchanging organelles. Genetic background significantly influences TNT morphology and dynamics, affecting neuroprotective processes. These findings deepen our understanding of microglia-neuron interactions and highlight TNTs as potential therapeutic targets in neurodegenerative diseases.
    DOI:  https://doi.org/10.1002/alz70855_102361
  42. Cells. 2025 Dec 15. pii: 1988. [Epub ahead of print]14(24):
    Advances in Laboratory Methodologies and Biological Matrices for the Study and Management of Rare Ocular Genetic Diseases.
    Fabiana D'Esposito, Bruna Lo Sasso, Cosimo Giuseppe Mazzotta, Francesco Cappellani, Marco Zeppieri, Daniela Bronzi, Rosario Iemmolo, Rosario Campisi, Teresio Avitabile.
      Rare genetic ocular diseases represent a heterogeneous group of disorders that significantly impair visual function and quality of life. Despite their clinical relevance, many of these conditions remain insufficiently characterized due to complex molecular mechanisms and diagnostic limitations. Recent advances in molecular diagnostics, particularly Next-Generation Sequencing (NGS), have enabled comprehensive and accurate identification of pathogenic variants, offering novel insights into genotype-phenotype correlations and supporting precision medicine approaches. In parallel, the use of alternative biological matrices such as tear fluid has emerged as a promising non-invasive strategy for biomarker discovery and disease monitoring. Tear-based omics, including proteomics and transcriptomics, have identified diagnostic signatures and pathogenic mediators such as non-coding RNAs, microRNAs, and tRNA-derived fragments (tRFs). Among these, tRF-1001 has shown potential both as a biomarker and therapeutic target in ocular neovascular conditions through its modulation of angiogenic pathways. The objective of this review is to show the integration of two rapidly advancing yet frequently isolated fields: next-generation sequencing-based genomics and tear-fluid molecular profiling, positioning them as complementary foundations of precision ophthalmology for rare inherited retinal and optic nerve disorders. Previous reviews have mainly concentrated on either genetic diagnosis or ocular surface biomarkers separately; however, we have introduced a convergent model wherein genomic data furnish diagnostic and prognostic clarity, while tear-omics deliver dynamic, minimally invasive assessments of disease activity, treatment efficacy, and persistent neurovascular stress. By explicitly connecting these two aspects, we have delineated how multi-matrix, multi-omics approaches can expedite early diagnosis, facilitate personalized longitudinal monitoring, and direct focused treatment interventions in rare ocular genetic illnesses.
    Keywords:  biomarkers; inherited retinal dystrophies; microRNA; precision ophthalmology; rare ocular diseases; tRNA-derived fragments; tear-omics
    DOI:  https://doi.org/10.3390/cells14241988
  43. Cells. 2025 Dec 09. pii: 1956. [Epub ahead of print]14(24):
    Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
    Surim Bang, So-Hyun Choi, Seung Min Jeong.
      Mitochondrial fatty acid oxidation (FAO) has long been recognized as a central pathway for energy production, providing acetyl-CoA, NADH, and FADH2 to sustain cellular growth and survival. However, recent advances have revealed that FAO exerts far broader roles beyond bioenergetics. FAO contributes to redox balance by generating NADPH for antioxidant defense, regulates protein acetylation through acetyl-CoA availability, and modulates stress signaling pathways to support cellular adaptation under nutrient or genotoxic stress. These emerging insights establish FAO as a metabolic hub that integrates energy homeostasis with redox regulation, epigenetic modification, and stress responses. Dysregulation of FAO has been increasingly implicated in aging and diverse pathologies, including cellular senescence, obesity, cancer and fibrosis. In this review, we highlight recent findings and provide an updated perspective on the expanding roles of mitochondrial FAO in stress responses and aging, with particular emphasis on its potential as a therapeutic target in age-associated diseases.
    Keywords:  acetylation; age-related diseases; fatty acid oxidation; redox homeostasis; stress response
    DOI:  https://doi.org/10.3390/cells14241956
  44. Biochem Biophys Rep. 2026 Mar;45 102394
    CircRNAs: Novel biomarkers and therapeutic targets for diseases of the central nervous system.
    Jiafang Cui, Ling Shen, Bing Han.
      Circular RNAs (circRNAs) are a class of covalently closed, non-coding RNA molecules characterized by their exceptional stability and tissue-specific expression. Once considered splicing artifacts, they have emerged as pivotal regulators in cellular pathophysiology, particularly within the central nervous system (CNS), where they are highly abundant. This review synthesizes the current understanding of the biogenesis, molecular functions, and regulatory roles of circRNAs in major CNS disorders, underscores their significant potential as next-generation diagnostic and prognostic biomarkers, as well as promising therapeutic targets. Moving from bench to bedside, the review critically examines the burgeoning landscape of circRNA-based therapeutics. We assess the promise and limitations of current delivery platforms, including exosomes and lipid nanoparticles (LNPs), with special attention to the formidable challenge of traversing the blood-brain barrier (BBB). To conclude, we outline the prevailing challenges and future perspectives, emphasizing that the development of more sensitive detection methods and optimized delivery systems is paramount to translating the immense potential of circRNAs into tangible clinical solutions for CNS diseases.
    Keywords:  Biomarkers; Central nervous system diseases; Circular RNAs (circRNAs); Drug delivery; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102394
  45. Alzheimers Dement. 2025 Dec;21 Suppl 1 e104761
    Basic Science and Pathogenesis.
    Siddhi S Joshi, Josslen Thieschafer, Ling Li.
       BACKGROUND: APOE, produced by astrocytes in the brain, is encoded by three alleles-ε4, ε3, ε2. APOE undergoes lipidation to form high-density lipoprotein like particles (HDL) that are crucial for cholesterol homeostasis, anti-inflammation, and protein clearance. GWAS studies have identified apolipoprotein E4 (APOE4) as the greatest genetic risk factor for developing sporadic Alzheimer's disease (AD). APOE isoforms exhibit differential effects on pathological hallmarks of AD including amyloid plaque load, neurofibrillary tangles and inflammatory responses (ε4>ε3>ε2). Moreover, bioenergetic alterations, mainly decreased glucose utilization, imbalanced mitochondrial flux and increased oxidative stress, have been implicated in AD. However, the impact of APOE4 on mitochondrial health and bioenergetic functions in AD is poorly understood. We hypothesize that APOE isoforms differentially impact mitochondrial function with APOE4 increasing susceptibility to mitochondrial damage in AD.
    METHODS: Cellular models of astrocytes were used. Primary mouse astrocytes were derived from humanized APOE3 and APOE4 mice. Isogenic APOE3 and APOE4 human iPSC lines were differentiated into astrocytes using published protocols. Astrocytes were treated with synthetic amyloid-β (Aβ) aggregates, tau isolates from transgenic PS19 mice of tauopathy, and cytokines to recapitulate accumulation of Aβ, neurofibrillary tangles and neuroinflammation in vitro. Rates of mitochondrial respiration, glycolysis and preference to key respiratory substrates were assessed in treated astrocytes using Seahorse flux analyzers. Mitochondrial membrane potential (MMP) was assessed using JC-1 dye.
    RESULTS: APOE4 disrupts mitochondrial bioenergetics by impairing mitochondrial respiration and over activating glycolysis in comparison to APOE3. APOE4 astrocytes also exhibit decreased MMP. Intriguingly, APOE4 astrocytes mainly rely on glucose as a fuel and are unable to utilize endogenous fatty acids for energy metabolism. Treatment with aggregated Aβ further exacerbates bioenergetic imbalance and decreases rate of ATP generation in APOE4 astrocytes in contrast to APOE3 astrocytes. Moreover, APOE genotype exerts differential effects on mitochondrial function in response to treatments with tau isolates and cytokines, respectively.
    CONCLUSION: This study provides experimental evidence of APOE4 linked mitochondrial dysfunction in astrocytes. APOE genotype differentially impacts mitochondrial health and bioenergetics in response to pathological stressors of AD. Future studies are warranted to assess the impact of astrocytic APOE4-associated mitochondrial dysfunction on pathogenic processes of AD in vivo.
    DOI:  https://doi.org/10.1002/alz70855_104761
  46. Alzheimers Dement. 2025 Dec;21 Suppl 7 e108430
    Developing Topics.
    Fanpeng Zhao.
       BACKGROUND: Mitochondrial dysfunction is a major pathological event of neurodegeneration including Alzheimer's disease (AD). Expanding evidence demonstrate that an altered balance in mitochondrial dynamics is an important mechanism leading to mitochondrial and neuronal dysfunction during neurodegeneration. Thus, it is of great interest to test if restoration of mitochondrial dynamics has beneficial role in AD treatment.
    METHOD: 5xFAD mouse model of AD was used to test whether MFN2 OE or MFN2 activator rescues mitochondrial dysfunctions and neurodegeneration. Behavioral tests, mitochondrial analysis, electrophysiological study, RNA-seq and biochemical analysis were applied to examine the brain pathology in the AD mouse model.
    RESULT: In this study, we observed fragmented and damaged mitochondria in 5xFAD mouse brains, along with impaired mitochondrial respiration of synaptosome at 6 months. Restoration of mitochondrial dynamics by conditional overexpression (OE) of mitofusin-2 (MFN2) in forebrain neurons rescues mitochondrial fragmentation and dysfunction in 5xFAD mouse brains. Importantly, MFN2 OE protects against long-term potential reduction, synaptic loss, oxidative stress damage, amyloid plaque size, neuroinflammation and cognitive deficits in 5xFAD mice at 6 months. Amyloid plaque burden and neuronal death in plaque-enriched layer V cortical regions can be alleviated in 5xFAD mice by MFN2 OE at 10 months. RNA sequencing (RNA-seq) reveals disturbed transcriptomic profiles including increased inflammatory responses in 5xFAD mice, which is reversed by MFN2 OE. Specifically, MFN2 OE inhibits microglial activation, proinflammatory cytokine production, and NLRP3 inflammasome activation in 5xFAD mice. Lastly, intraperitoneal injection of compound BAY2402234, a brain penetrant MFN2 activator, rescues mitochondrial fragmentation, oxidative damage, and memory deficits in 5xFAD mice.
    CONCLUSION: Overall, our study demonstrated that the restoration of mitochondrial dynamics by inhibition of mitochondrial fragmentation can protect against neurodegeneration in 5xFAD mouse model and mitochondrial dynamic could be a promising therapeutic target for AD.
    DOI:  https://doi.org/10.1002/alz70861_108430
  47. Physiol Rev. 2025 Dec 22.
    Crossroads between autoimmunity and cancer: Underlying mechanisms and clinical implications.
    Ada Gjyrezi, Charalampos Skarlis, Clio Mavragani, Paraskevi Giannakakou.
      Autoimmune diseases arise from an aberrant immune response against self-antigens, whereas cancer often develops when the immune system fails to effectively detect and destroy malignant cells. Although historically viewed as distinct entities with opposing immune mechanisms, recent findings highlight significant overlaps in their immunological pathways. This review explores the intricate interplay between autoimmunity and cancer, focusing on immune surveillance, checkpoint regulation, cytokine signaling, and genetic susceptibility. In addition, we discuss epidemiological links, including the heightened risk of malignancy in patients with autoimmune disorders and the autoimmune manifestations often triggered by cancer immunotherapies. We place particular emphasis on shared molecular signatures, predictive biomarkers, and the bidirectional immune modulation that arises from checkpoint inhibitors and biologic agents. Finally, we address the major clinical challenges in managing patients who present with both conditions and propose future research directions aimed at refining immunotherapeutic strategies.
    Keywords:  autoimmunity; cancer; cancer immunotherapy; immune dysregulation; immunosurveillance
    DOI:  https://doi.org/10.1152/physrev.00012.2025
  48. Comp Biochem Physiol A Mol Integr Physiol. 2026 Jan;pii: S1095-6433(25)00143-6. [Epub ahead of print]311 111944
    Body mass shapes mitochondrial NADH and NADPH sources in mammalian skeletal muscle.
    Mélanie Boël, Yann Voituron, Damien Roussel.
      Here, we investigate whether the elevated mitochondrial H2O2 release in small mammals arises from a tradeoff between NAD-dependent enzymes, which synthesizes NADH to support high oxidative phosphorylation, and NADP-dependent enzymes, which generates NADPH to detoxify H2O2 within the matrix. We measured the activities of NAD- and NADP-dependent enzymes in skeletal muscle mitochondria from mammal species ranging from 4 g to 600 kg. The activities of the two most active NADPH-producing enzymes increased, whereas NAD-dependent enzyme activities declined with body mass. Therefore, small mammals prioritize NADH synthesis at the expense of NADPH, increasing the oxidative cost of mitochondrial metabolism.
    Keywords:  Allometry; Mammals; Mitochondria; NADPH; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.cbpa.2025.111944
  49. MethodsX. 2025 Dec;15 103735
    TARGETFLOW:An automated literature mining pipeline for accelerating the discovery of high-potential targets in rare and mature diseases.
    Shuhan Guo, Tianxiang Shang, Yuzhu Pan, Yingjia Wu, Yan Li, Mohan Zhou.
      To expedite the early stages of drug development for diseases lacking established target databases, and to enhance knowledge updating in well-studied disease domains, this paper introduces TARGETFLOW, an automated literature-mining pipeline. The workflow begins by automatically retrieving literature, downloading relevant abstracts, and constructing a comprehensive database. After performing selective text cleaning and data preprocessing, it leverages large language models (LLMs) to conduct intelligent literature screening, followed by code-based whitespace tokenization. Subsequently, rule-based filtering is applied to extract high-potential therapeutic targets for the specified disease. To validate the effectiveness of this pipeline, three hypotheses were formulated: (1) An effective pipeline should be capable of identifying high-potential therapeutic targets for the given disease; (2) For diseases with established target databases, the pipeline should be able to detect novel and emerging targets not yet included in existing databases; and (3) The pipeline should also be applicable to rare or emerging diseases that lack mature target databases. Then, rheumatoid arthritis (RA), a common disease, and idiopathic pulmonary fibrosis (IPF), a rare disease, were selected as case studies. The results demonstrated the method's reliability (high-potential target validation rate: 56 %), innovativeness (new target validation pass rate: 100 %), and generalizability (IPF target literature support rate: 88.9 %).
    Keywords:  Automated pipeline; Literature mining; Named entity recognition; Natural language processing; Rare diseases; Targets discovery
    DOI:  https://doi.org/10.1016/j.mex.2025.103735
  50. Biochemistry (Mosc). 2025 Dec;90(12): 1929-1943
    ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
    Anna S Lapashina, Danila O Tretyakov, Boris A Feniouk.
      Oxidative phosphorylation in mitochondria is the main source of ATP in most eukaryotic cells. Concentrations of ATP, ADP, and AMP affect numerous cellular processes, including macromolecule biosynthesis, cell division, motor protein activity, ion homeostasis, and metabolic regulation. Variations in ATP levels also influence concentration of free Mg2+, thereby extending the range of affected reactions. In the cytosol, adenine nucleotide concentrations are relatively constant and typically are around 5 mM ATP, 0.5 mM ADP, and 0.05 mM AMP. These concentrations are mutually constrained by adenylate kinases operating in the cytosol and intermembrane space and are further linked to mitochondrial ATP and ADP pools via the adenine nucleotide translocator. Quantitative data on absolute adenine nucleotide concentrations in the mitochondrial matrix are limited. Total adenine nucleotide concentration lies in the millimolar range, but the matrix ATP/ADP ratio is consistently lower than the cytosolic ratio. Estimates of nucleotide fractions show substantial variability (ATP 20-75%, ADP 20-70%, AMP 3-60%), depending on the organism and experimental conditions. These observations suggest that the 'state 4' - inhibition of oxidative phosphorylation in the resting cells due to the low matrix ADP and elevated proton motive force that impedes respiratory chain activity - is highly unlikely in vivo. In this review, we discuss proteins regulating ATP levels in mitochondria and cytosol, consider experimental estimates of adenine nucleotide concentrations across a range of biological systems, and examine the methods used for their quantification, with particular emphasis on the genetically encoded fluorescent ATP sensors such as ATeam, QUEEN, and MaLion.
    Keywords:  ADP; ATP; ATP synthase; ATeam; adenine nucleotide translocator (ANT); mitochondria
    DOI:  https://doi.org/10.1134/S0006297925603338
  51. Alzheimers Dement. 2025 Dec;21 Suppl 1 e100654
    Basic Science and Pathogenesis.
    Arisa Tamura, Marie Noguchi, Taro Saito, Akiko Asada, Kanae Ando.
       BACKGROUND: The abnormal accumulation of the microtubule-binding protein tau is a pathological feature in a group of neurodegenerative diseases called tauopathy. Tau accumulation is thought to cause neuronal death, while underlying mechanisms are not fully understood. In cellular and animal models and data from patients suffering from tauopathy, various mitochondrial abnormalities have been reported. In this study, we aimed to elucidate the causal relationships among these abnormalities and their contribution to tau-induced neurodegeneration.
    METHOD: In Drosophila, human tau expression causes neurodegeneration without the formation of neurofibrillary tangles. Tau proteins exist mainly in detergent-soluble form with phosphorylation at disease-related sites, suggesting that this model recapitulates the early stage of tau abnormality and toxicity of soluble tau. We used this model to analyze the effects of tau on ATP levels and the activity of OXPHOS complexes biochemically. Mitochondrial membrane potential and ROS levels were analyzed by imaging. mRNA levels were analyzed by qRT-PCR. To analyze neurodegeneration, vacuole areas in the optic lobes were quantified with paraffin sections.
    RESULT: We found that tau expression reduces ATP levels and increases oxidative stress in the brain. Mitochondrial membrane potential was elevated, and the activities of OXPHOS complex I (CI) and those of supercomplexes were reduced. mRNA expression of OXPHOS genes was upregulated, and mitochondrial quantity was similar, suggesting that lowered CI activity is not due to a reduction in mitochondrial quantity or gene expression but disruption of CI at the protein level. To investigate the causal relationships of these mitochondrial changes in tau-induced neurodegeneration, we analyzed the effects of the co-expression of bellwether (blw), encoding the alpha subunit of complex V, with tau. Co-expression of blw suppressed tau-induced photoreceptor degeneration. blw co-expression did not restore ATP levels or lower ROS in tau-expressing flies, but corrected hyperpolarization and increased CI activity.
    CONCLUSION: Our results indicate that tau causes mitochondrial hyperpolarization and lowers CI activity in vivo. Since suppression of mitochondrial hyperpolarization correlates with increased CI activity and suppression of neurodegeneration, targeting mitochondrial hyperpolarization may be a novel strategy to mitigate tau toxicity.
    DOI:  https://doi.org/10.1002/alz70855_100654
  52. BMC Proc. 2025 Dec 22. 20(Suppl 1): 1
    Bringing together clinical and physical sciences to deliver translational ageing research: the UK experience.
    Lewis Steell, Chloe Hinchliffe, Rachel Cooper, Miles D Witham.
      
    DOI:  https://doi.org/10.1186/s12919-025-00354-0
  53. J Child Neurol. 2025 Dec 23. 8830738251404115
    From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
    Sofia Corbaz, Daniela Alejandra Pibernus, Mariana Amina Loos, María Mercedes Pérez, María Celeste Buompadre, Francisco Martín García, María Paula Rodriguez, Carlos Rugilo, Marisa Armeno, Go Hun Seo, Rin Khang, Cristina Noemi Alonso, Hilda Verónica Aráoz.
      Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.
    Keywords:  Ketogenic diet; Leigh syndrome; PDHA1; mitochondrial disease; pyruvate dehydrogenase deficiency
    DOI:  https://doi.org/10.1177/08830738251404115
  54. Alzheimers Dement. 2025 Dec;21 Suppl 1 e107425
    Basic Science and Pathogenesis.
    Julie R Korenberg.
       BACKGROUND: Down syndrome (DS) is a leading model for studying therapeutic implications of co-occurring conditions, including Alzheimer's disease (AD), intellectual disabilities (ID), and disturbances in cardiovascular (CV), pulmonary (P), and immune (Im) systems. These conditions cause significant suffering and remain unmet medical needs. Recent advances in iPSCs (induced pluripotent stem cells) derived from individuals with DS have helped accelerate research translation to clinical care.
    METHOD: This study presents a unique panel of iPSCs designed to explore the contributions of distinct chromosomes, genomic genes, and gender to AD, ID, and CV, P, and Im systems. The Utah iPSC collection includes 17 cell lines from individuals with DS, most of which have paired fibroblast and lymphoblastoid cell lines. These individuals underwent deep phenotyping, including multimodal neural imaging, cognition assessments, and data from seven independent Pan-Omics databases. The panel includes samples from identical twins discordant for DS, partial trisomies (three without APP duplication), and individuals with genetic variants such as apolipoprotein e2/e2. We used proteomics, phosphoproteomics, RNA sequencing, microRNA analysis, metabolomics, and lipidomics to examine gene influences, including APP, IFNAR, ITSN1, DYRK1A, TTC3, DSCAM, MMU17, and their homologs.
    RESULT: The iPSC panel provides valuable insights into AD, DS, and related systems by distinguishing gene influences. Integration of 14 multidimensional datasets-spanning behavioral, cognitive, and neural imaging data-offers a detailed view of brain function, behavior, and organ development. This comprehensive approach allows for the dissection of AD and DS pathogenesis and the modeling of multiple human organs and cell types CONCLUSION: This work creates a comprehensive resource to understand DS at the organismal, cellular, and systems levels. The Utah iPSC collection is an invaluable tool for accelerating research translation into therapeutic strategies to improve the quality of life for individuals with DS and related conditions.
    DOI:  https://doi.org/10.1002/alz70855_107425
  55. Biochemistry (Mosc). 2025 Dec;90(12): 1883-1896
    Antibiotics and Cellular Senescence: An Unexplored Territory.
    Roman A Zinovkin, Nataliya D Kondratenko.
      Antibiotics are certainly the most important agents in the fight against human and animal bacterial infections. Widespread use of antibiotics has a positive impact on the treatment of infectious diseases but may be accompanied by serious side effects. Clinical aspects of these side effects are well understood, but nonspecific molecular targets are not fully recognized. It is generally known that many antibiotics can damage mitochondria, intracellular organelles responsible for aerobic metabolism as well as regulating a number of important processes, including cellular redox balance and inflammatory responses. Mitochondrial dysfunction commonly leads to the development of oxidative stress and inflammation, which are known stimuli of cellular senescence. On the other hand, the same stimuli could induce death of senescent cells. Thus, mitotoxic antibiotics could influence both the cellular senescence process and elimination of senescent cells. The effect of antitumor antibiotics on the induction of cell aging has been studied in detail, but the effect of antibacterial antibiotics on this process is still essentially unknown. This review aims to draw attention of the researchers to the possibility of accelerated cellular aging induced by common antibacterial antibiotics and to discuss potential mechanisms of this process.
    Keywords:  antibiotics; cellular senescence; mitochondria; reactive oxygen species; side effects
    DOI:  https://doi.org/10.1134/S0006297925602758
  56. Free Radic Biol Med. 2025 Dec 22. pii: S0891-5849(25)01452-2. [Epub ahead of print]
    SIRT3-mediated mitochondrial reprogramming: emerging therapeutic paradigms in peripheral neuropathy and neuropathic pain.
    Yogesh Mishra, Ashutosh Kumar.
      Peripheral neuropathy is a debilitating condition resulting from peripheral nerve damage or dysfunction, primarily caused by aging, obesity, diabetes, cancer chemotherapy, HIV infection, ischemia, or trauma. It manifests as sensory, motor, and autonomic impairments, with symptoms such as numbness, tingling, weakness, and pain, most commonly affecting the hands and feet. Among these, neuropathic pain is the most debilitating, often worsening at night and contributing to insomnia, mood disturbances, depression, and reduced quality of life. Mitochondrial dysfunction is a key pathological hallmark in the onset and progression of peripheral neuropathy and neuropathic pain. Sirtuin 3 (SIRT3), a NAD+-dependent mitochondrial deacetylase, plays a crucial role in maintaining mitochondrial homeostasis by deacetylating >250 lysine residues across ∼115 mitochondrial proteins. Through this mechanism, SIRT3 regulates mitochondrial energy metabolism, oxidative phosphorylation, calcium buffering, redox balance, membrane integrity, DNA repair, proteostasis, biogenesis, dynamics, mitophagy, and autophagy. Emerging evidence suggests that reduced SIRT3 expression and activity contribute to mitochondrial dysfunction associated with peripheral neuropathy and neuropathic pain. Conversely, its restoration has been shown to improve mitochondrial health, suppress nitro-oxidative and inflammatory nerve damage, and alleviate neuropathic symptoms. This review critically examines the role of mitochondrial dysfunction in the pathogenesis of peripheral neuropathy and neuropathic pain. Furthermore, we summarize recent advances in SIRT3 biology, regulation, and acetylproteome, highlighting their implications for mitochondrial function and neuroprotection. Lastly, we provide a comprehensive analysis of literature supporting SIRT3 as a promising therapeutic target, discussing strategies to enhance its expression or activity through lifestyle modifications, natural compounds, small molecules, and genetic approaches. These insights may pave the way for novel therapeutic interventions in peripheral neuropathy and neuropathic pain.
    Keywords:  Lysine deacetylation; Mitochondrial function; Neuropathic pain; Peripheral neuropathy; SIRT3; SIRT3 activator; Therapeutic target
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.035
  57. Alzheimers Dement. 2025 Dec;21 Suppl 1 e103262
    Basic Science and Pathogenesis.
    Büşra Şengül, Zuhal Yurttaş, Tugay Çamoğlu, Bilge Nur Bilge, Sümeyra Ildız, Nazlıcan İlhan, Erdinc Dursun, Duygu Gezen-Ak.
       BACKGROUND: Mitochondrial dysfunction in energy metabolism is considered one of the early features of neurodegenerative diseases (1). In Parkinson's disease (PD), mitochondrial functions are among the earliest disrupted neurodegeneration pathways (2). The translocation of alpha-synuclein (α-syn), encoded by the SNCA gene, the major protein of Lewy bodies seen in PD, to mitochondria has been demonstrated (3). Although the importance of α-syn in PD pathology is known, its specific roles within mitochondria must be better understood (4). In this study, we aimed to investigate the regulatory effects of SNCA gene overexpression on the expression of mitochondrial DNA (mtDNA) encoded genes.
    METHOD: Human astrocytes were transfected with a plasmid carrying the SNCA gene and SNCA was overexpressed. The group transfected with the MOCK plasmid was used as a control. RNA isolations were performed 24 and 48 hours after SNCA transfection. Following cDNA synthesis, the expression of 13 respiratory complex genes encoded by mtDNA, two mitochondrial rRNA genes, and three mitochondrial tRNA genes was investigated using qRT-PCR. Statistical analysis of the results was performed using a one-way ANOVA test with GraphPad Prism 8.
    RESULT: After 24 hours of SNCA transfection, the expression of MTND2 (* p <0.05) and MTtRNA3 (* p <0.05; ** p <0.01) increased in the SNCA overexpression group compared to both the MOCK group and the control group. After 48 hours of SNCA transfection, in the SNCA group, mRNA expression levels of MTCYB, MTCO3, MTtRNA1, and MTD-loop were statistically significantly increased compared to the MOCK group (* p <0.05).
    CONCLUSION: These findings indicate that alpha-synuclein overexpression can modulate the expression of mitochondrial genes, highlighting its potential role in mitochondrial dysfunction associated with Parkinson's disease. This study provides new insights into the molecular interactions between alpha-synuclein and mitochondrial gene regulation, offering a basis for future investigations into its contribution to neurodegeneration in PD.
    DOI:  https://doi.org/10.1002/alz70855_103262
  58. BMC Health Serv Res. 2025 Dec 25.
    Policy evaluation frameworks for rare diseases: a scoping review.
    Mehtap Çakmak Barsbay, Muhammed Yusuf Aydamak.
       BACKGROUND: The epidemiological burden of rare diseases positions them as a global public health challenge. Because rare disease policies are heterogeneous and complex, evaluating their effectiveness requires a systematic and structured approach. Policy evaluation frameworks provide tools to understand how policies are defined, implemented, and assessed in different health systems. These frameworks help identify gaps in policy design and support the development of mechanisms to improve rare disease management. Although several policy evaluation methods have been proposed, no study has synthesized them in a structured and comparative manner. This study aims to map existing policy evaluation frameworks for rare diseases, describe their overarching structures, and propose recommendations for improvement.
    RESULTS: This scoping review followed the Context, Population and Concept (CPC) structure to guide the search strategy. Databases and grey literature were searched from inception to 1 May 2025. Ultimately, five studies were included for extraction and evaluation. The context, population and concept of the included studies were categorized into three thematic domains: policy focus, policy problem, and stakeholder groups and collaboration.
    CONCLUSIONS: The limited number of available frameworks underscores the need for further methodological development. While current approaches provide initial insights, they remain context-specific and lack a unified, transferable framework applicable to different health systems.
    Keywords:  Health policies; Health policy evaluation; Policy analysis; Policy evaluation frameworks; Rare diseases
    DOI:  https://doi.org/10.1186/s12913-025-13878-0
  59. Biochemistry (Mosc). 2025 Dec;90(12): 2027-2040
    Mitochondria in Developing Brain: Contribution of Deviations to Higher Susceptibility to Neurodegeneration in Latter Periods of Life.
    Natalia A Stefanova, Natalia A Muraleva, Diana V Sityaeva, Mikhail A Tyumentsev, Nataliya G Kolosova.
      It has been proven that the preclinical period of the sporadic (&gt;95% of cases) form of Alzheimer's disease (AD) can last for decades, but the question of when the disease begins to develop and what contributes to it remains open. It is hypothesized that vulnerabilities to AD may be influenced by anatomical and functional brain parameters formed early in life. This is supported by our research on the senescence-accelerated OXYS rats - a unique model of AD. The delayed brain maturation observed in these rats is associated with insufficient glial support, a key regulator of neural network function, and the development of AD signs in the OXYS rats is preceded and accompanied by the mitochondrial dysfunction. This raises the question of whether the structural and functional features of mitochondria could influence brain maturation and thus determine predisposition to the later development of AD signs. In this study, we compared mitochondrial biogenesis, their trafficking, and structural state in the neuronal cell bodies, axonal and dendritic processes, as well as activity of the mitochondrial dynamics processes in the prefrontal cortex and hippocampus of OXYS and Wistar rats (control) during the period of brain maturation completion (from birth to 20 days of age). Changes in the number and ultrastructural parameters of mitochondria were compared with the parameters of dynamics processes, assessed by the frequency of mitochondria undergoing fusion or fission, the content of the key biogenesis protein PGC-1α, and proteins mediating mitochondrial dynamics (mitofusins Mfn1 and Mfn2, dynamin-1-like protein DRP1). In OXYS rats, deviations in formation of the mitochondrial apparatus in the early postnatal period were identified, which may contribute to the delayed brain maturation of these rats, promote mitochondrial dysfunction, reduce synaptic density, and ultimately lead to the neuronal death and development of the early neurodegenerative changes.
    Keywords:  Alzheimer’s disease; early postnatal period; mitochondria; neurodegeneration; senescence-accelerated OXYS rats
    DOI:  https://doi.org/10.1134/S0006297925602874
  60. Aging Dis. 2025 Dec 22.
    Oncology-Derived Strategies for Age-Related Diseases: Intersections of Oncogenesis, Senescence, and Immunity.
    Hao Li, Jingzeng Wang, Chao Liu, Xiaofen Wu.
      Growing evidence has highlighted that the same biological pathways implicated in oncogenesis also regulate the aging process, by influencing the organism's capacity to surveil and respond to cellular aberrations. Emerging therapeutic strategies, including senolytic agents, metabolic modulators and immunotherapies, not only hold promises for cancer treatment, but offer possibilities for mitigating the degenerative consequences of aging. This review seeks to integrate recent developments, provides insights into the overlapping molecular pathways that underlie both cancer and age-related disorders, while offering an in-depth exploration of the subtle dynamics in immune system, and explores how certain cancer therapies can be leveraged for managing age-related conditions. Furthermore, it illustrates the critical role of immune restoration as a therapeutic mechanism and examines the key considerations and potential pitfalls when adapting cancer treatments to age-related diseases.
    DOI:  https://doi.org/10.14336/AD.2025.1168
  61. Alzheimers Dement. 2025 Dec;21 Suppl 1 e103044
    Basic Science and Pathogenesis.
    Djuna K Von Maydell, Shannon Wright, Colin Staab, Ping-Chieh Pao, Oisin King, Julia Maeve Bonner, Andrea Spitaleri, Liwang Liu, Ching-Chi Chiu, Daniel Leible, Chung Jong Yu, Aine Ni Scannail, Mingpei Li, Carles A Boix, Hansruedi Mathys, Guillaume Leclerc, Gloria Suella Menchaca, Gwyneth Welch, Agnese Graziosi, Noelle Leary, George Samaan, Manolis Kellis, Li-Huei Tsai.
       BACKGROUND: Rare loss-of-function variants in the lipid transporter ABCA7 are among the strongest genetic risk factors for Alzheimer's disease. However, the mechanisms by which these variants increase risk and their relevance to the larger at-risk population remain largely unknown, limiting therapeutic development.
    METHOD: To investigate this, we performed single-nuclear RNA sequencing on brain samples from a rare cohort of ABCA7 loss-of-function variant carriers (12 carriers and 24 matched non-carrier controls). We compared these transcriptional results with available post-mortem data from ABCA7 p.Ala1527Gly carriers (135 carriers and 240 controls). This analysis was further complemented by molecular dynamic simulations and functional studies using iPSC-derived neurons and neurospheroids.
    RESULTS: In the human brain, excitatory neurons, which express the highest levels of ABCA7, displayed transcriptional disruptions in lipid metabolism, mitochondrial function, and synaptic signaling. Overlapping transcriptional changes were identified in carriers of the common AD-risk variant ABCA7 p.Ala1527Gly, predicted by molecular dynamic simulations to disrupt ABCA7 structure. We confirmed similar transcriptional changes in iPSC-derived human neurons carrying ABCA7 loss-of-function variants. These cells showed triglyceride buildup, disrupted phosphatidylcholine metabolism, and impaired mitochondrial function, especially in regulating membrane potential and supporting respiration. Treatment with CDP-choline, a dietary precursor for phosphatidylcholine synthesis, restored mitochondrial function, reversed many transcriptional defects, and reduced amyloid-β pathology in ABCA7 loss-of-function neurons.
    CONCLUSION: These findings suggest that phosphatidylcholine disruption may underlie metabolic and pathological defects in the context of impaired ABCA7, with potential relevance to a broader population. In line with a growing body of evidence, these findings implicate lipid dysfunction in Alzheimer's disease etiology and suggest therapeutic avenues for a subset of at-risk individuals.
    DOI:  https://doi.org/10.1002/alz70855_103044
  62. Am J Med Genet A. 2025 Dec 23.
    A Novel Variant in the TAMM41-Associated Mitochondrial Myopathy.
    Cristiane Araujo Martins Moreno, Clara Camelo Gontijo, Alulin Tacio Quadros Santos Monteiro Fonseca, Rita Horvath, David Schlesinger, Edmar Zanoteli.
      Pathogenic variants in TAMM41 were recently linked to mitochondrial myopathy, presenting with neonatal hypotonia, generalized weakness, developmental delay, ptosis, and ophthalmoparesis. Here, we present a long-term follow-up of an additional case, a Brazilian patient harboring a novel TAMM41 variant in compound heterozygosity with a previously described pathogenic variant. Patient exhibited mild developmental delay, acquired independent gait, but subsequently developed motor regression and weakness associated with recurrent infections, severe axial involvement, and marked restrictive pulmonary dysfunction. Muscle biopsy revealed decreased COX and SDH staining, which may serve as an important diagnostic clue for this condition. This case expanded the genetic spectrum of TAMM41-related mitochondrial myopathy and provided a brief review of disorders associated with reduced SDH staining.
    DOI:  https://doi.org/10.1002/ajmga.70034
  63. Aging Cell. 2026 Jan;25(1): e70319
    Promising Results With NAD Supplementation in Rare Diseases With Premature Aging and DNA Damage.
    Vilhelm A Bohr.
      Nicotinamide adenine dinucleotide (NAD) has garnered significant attention in recent years due to its central role in cellular metabolism and its potential as a supplement to promote health and longevity. While numerous human studies indicate that NAD supplementation offers benefits with minimal or no side effects, some studies show no observable advantages. This discrepancy highlights the importance of identifying individuals who are most likely to benefit from NAD-based interventions. One critical factor in the efficacy of NAD supplementation relates to its declining levels in certain individuals, driven by various causes of NAD depletion. NAD is a vital substrate for numerous enzymatic processes, notably those involving poly-ADP-ribose polymerase (PARP) enzymes. PARP enzymes, especially PARP1, play a pivotal role in DNA repair by detecting and signaling DNA damage. Excessive activation of PARP, hyperparylation, is frequently observed in DNA repair disorders where DNA damage accumulates due to defective repair mechanisms. This hyperparylation has been implicated in the pathogenesis of several premature aging diseases. Such conditions often involve defective DNA repair pathways, elevated parylation levels, and associated mitochondrial dysfunction, factors that contribute to accelerated cellular aging. In model systems that mimic these disorders, as well as in emerging human studies, NAD supplementation has demonstrated promising benefits, including improved DNA repair capacity and improved mitochondrial function. These findings suggest that NAD supplementation could serve as an effective intervention for rare genetic diseases characterized by premature aging and DNA repair deficiencies. More broadly, these insights open new avenues for general aging research.
    DOI:  https://doi.org/10.1111/acel.70319
  64. Alzheimers Dement. 2025 Dec;21 Suppl 5 e103983
    Drug Development.
    Kimberly Scearce-Levie, Pierce Ogden, Isabel Albuja, Fabliha Anam, Anisha Anand, John Avera, Allie Braun, Sean Carroll, Marshall Case, Karen Duffy, Alvaro Garcia, Alex Gerew, Jack Gourdeau, Hala Haddad, Glenn Hauk, Yendee Ho-Rath, Gleb Kuznetsov, Shane Lofgren, Ainaz Malekoltojari, Roasa Mehmood, Naveen Mehta, Mike Nichols, Maggie Prescott, Supriva Ravichandran, Alex Reis, Manan Shah, Tianxiao Sun, Erik Swanson, Brian Wipke, Kate Nudel.
       BACKGROUND: Central nervous system (CNS) diseases are difficult to treat due to the blood-brain barrier (BBB), which prevents many therapeutics from reaching the brain. Receptor-mediated transcytosis (RMT) shows promise for transporting macromolecules across the BBB, but current targeting methods lack CNS specificity and cell-type selectivity. The number of validated "Portals" (BBB receptors with demonstrated RMT in vivo) is limited due to historical screening constraints.
    METHOD: We conducted the most comprehensive in vivo evaluation of BBB shuttles and Portals to date, screening over 3,000 candidates against 68 potential Portal targets in mice. Our novel pooled in vivo screening technology, mCodes™, allowed us to simultaneously assess quantitative tissue distribution for up to 100 molecules per animal with high precision.
    RESULT: This approach revealed the "Transcytosome," an expanded set of Portal targets capable of facilitating RMT across the BBB. Detailed pharmacokinetic and biodistribution analyses of select novel Portals demonstrate distinct properties compared to well-characterized targets like transferrin receptor (TfR) and CD98. Novel portals were discovered that demonstrated optimal characteristics for therapeutic strategies targeting extracellular pathologies like Abeta, as well as intracellular pathologies like Tau. These portals offer promising avenues for further research and development in the pursuit of effective treatments for Alzheimer's disease.
    CONCLUSION: These newly identified Portal receptors may enable unprecedented control over biodistribution, enhancing CNS delivery, cell-type specificity, regional targeting, and reduced peripheral effects. By substantially expanding the known Portal landscape, our work provides a foundation for developing biologics with precisely engineered tissue distribution profiles that are sculpted to meet the intended product profiles for specific therapeutic approaches. The Transcytosome represents a crucial step toward realizing the full therapeutic potential of biologics in CNS diseases such as Alzheimer's.
    DOI:  https://doi.org/10.1002/alz70859_103983
  65. Alzheimers Dement. 2025 Dec;21 Suppl 1 e097660
    Basic Science and Pathogenesis.
    Danyeong Kim, Da-Eun Jeong, Yunseo Gong, Hongjae Ahn, Min Ju Kang, Seong Soo A An.
       BACKGROUND: ATP10B encoded a phospholipid flippase, essential for maintaining cellular homeostasis, which was implicated in the pathogenesis of Parkinson's disease (PD). Previous studies suggested an association between ATP10B dysfunction and PD, still the relationship between ATP10B and alpha-synuclein remained unclear. In this study, a novel ATP10B R303W mutation was identified in a patient with familial PD. While ATP10B was linked to PD, this would the first study to explore its role in alpha-synuclein metabolism, a critical hallmark of PD pathology. By establishing cellular model of expressing ATP10B R303W, its effects on mitochondrial and lysosomal functions and alpha-synuclein were investigated.
    METHOD: CRISPR/Cas9 technology was used to transfect HEK293 cells with ATP10B R303W and SNCA A53T, as a positive control. Successful transfections were confirmed by Sanger sequencing. ATP10B and LC3 gene expressions were analyzed by RT-qPCR. Alpha-synuclein levels in the supernatant, cytosol, and membrane fractions were measured. Mitochondrial dysfunction was assessed using TMRE and MitoTracker, and lysosomal dysfunction was evaluated by monitoring pH changes, and enzyme activity. Alpha-synuclein phagocytosis was analyzed by confocal microscopy.
    RESULT: ATP10B R303W and SNCA A53T mutations were successfully generated. Compared to HEK293 cells (negative control), ATP10B and LC3 gene expressions were reduced in ATP10B R303W and SNCA A53T cells. Alpha-synuclein levels were elevated in cytosolic and membrane fractions of ATP10B R303W and SNCA A53T cells, but decreased in the supernatants of ATP10B R303W cells. Both mutations exhibited reduced mitochondrial membrane potentials. ATP10B R303W cells also showed the increased lysosomal pH, and reduced enzyme activities. Confocal microscopy confirmed the diminished alpha-synuclein phagocytosis in ATP10B R303W cells.
    CONCLUSION: This study established ATP10B R303W as a novel pathogenic associated mutation with PD. We demonstrated that ATP10B R303W disrupted mitochondrial and lysosomal functions, increasing cytosolic and membrane-bound alpha-synuclein while reducing its secretion and phagocytosis. These findings directly linked the ATP10B dysfunctions to alpha-synuclein dynamics, contributing to PD pathology. The familial nature of this mutation underscored its relevance in hereditary PD. Future studies should target ATP10B to restore cellular homeostasis and mitigate alpha-synuclein aggregation.
    DOI:  https://doi.org/10.1002/alz70855_097660
  66. Brain Res Bull. 2025 Dec 24. pii: S0361-9230(25)00516-7. [Epub ahead of print] 111704
    Cerebellar deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia.
    Lauren N Miterko-Myers, Lauren E Peacoe, Lita Duraine, Zhongyuan Zuo, Roy V Sillitoe.
      Deep brain stimulation (DBS) improves motor function in a growing list of movement diseases including Parkinson's disease, dystonia, and tremor. There is evidence that DBS may also be effective in ataxia. It is not known why DBS is effective, but modulating cell activity and conferring neuroprotection are hypothesized to underlie its benefits. Understanding the effects of DBS on neurons is paramount to extending its clinical use in the treatment of various motor and non-motor diseases. Here, we stimulated the cerebellum of Car8 waddles (Car8wdl) mice, given the cerebellum's important role in ataxia pathophysiology. Using transmission electron microscopy, we tested the effects of therapeutic neuromodulation on Purkinje cell subcellular structures, including the mitochondria and their proximity to the endoplasmic reticulum (ER). In the absence of stimulation, we found increased putative mitochondria-ER contacts in Car8wdl Purkinje cells as well as mitochondrial size and density alterations. Low-frequency cerebellar DBS rescued mitochondrial density, but not size or putative contacts in Car8wdl Purkinje cells. Although increased mitochondrial density and sustained ER contact are specific to DBS treatment, they do not determine efficaciousness. These data uncover a mode of intracellular plasticity in Purkinje cells after stimulation, enhancing our mechanistic understanding of DBS for cerebellar disorders.
    Keywords:  CAR8; Cerebellum; Deep Brain Stimulation; Endoplasmic Reticulum; Mitochondria; Purkinje cell; Transmission Electron Microscopy
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111704
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