bims-polgdi Biomed News
on POLG disease
Issue of 2026–09–27
forty-two papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
  2. Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase γ.
  3. How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
  4. Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
  5. Characterization of the Mitochondrial Genome Landscape in MSCs, iPSCs and iMSCs from Osteoarthritis Patients and Healthy Donors.
  6. Clinical perspectives on mitochondria in cancer.
  7. Genomic Strategies in Pediatric Care: Addressing Rare Diseases in Children.
  8. SIRT1 in Senescence: Mitochondria and Immune Crosstalk.
  9. LLM-enabled Natural History Study Analysis to Support Rare Disease Research.
  10. ATAD3A structurally links mtDNA replication and mitochondrial fission.
  11. Natural Small Molecules Targeting Mitochondrial Quality Control for the Treatment of Metabolic Diseases: Mechanisms, Novel Formulations, and Translational Perspectives.
  12. Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.
  13. Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications.
  14. Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.
  15. The European Health Data Space and biobanking in Europe: synergies, tensions and the future governance of data-driven health research.
  16. Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration.
  17. Online Patient Support Communities as Sources of Support, Risk, and Research for Rare or Contested Conditions.
  18. The Oxidative-Mitochondrial-Inflammatory Axis in Retinitis Pigmentosa: Extracellular mtDNA as Biomarker and Therapeutic Read-Out.
  19. Mitochondrial Transplantation Suppresses mtDNA-cGAS/STING-Mediated Innate Immunity by Enhancing PINK1/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis.
  20. Mitochondrial Quality Control Links Exercise to Sterile Inflammation in the Cardiovascular System: A Narrative Review.
  21. CRISPR-Cas9 and precision editing technologies linking functional genomics to clinical translation in genetic diseases.
  22. Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.
  23. Mitochondria Meet the Lung Microbiome: A Bidirectional Dialogue in Inflammation and Respiratory Diseases.
  24. Letter to the Editor: Innovative Clinical Pharmacology, Modeling, and Simulation Strategies for Accelerating Rare Disease Drug Development.
  25. Maternal lineage tracing using mtDNA from unbuffered formalin-fixed autopsy tissues in India.
  26. Blood biomarkers of oxidative stress and mitochondrial dysfunction in Parkinson's disease and Alzheimer's disease.
  27. From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).
  28. Changes in protein markers of the mitochondrial respiratory chain and quality control in a mouse model of psychosis.
  29. Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
  30. Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.
  31. Mitochondria-ER contact sites in neurological disorders.
  32. Assessing mitochondrial phenotypes in a cybrid model of dry age-related macular degeneration.
  33. Genome Sequencing in Pediatrics: Expanded Use Requires Strong Stewardship.
  34. Therapeutic oligonucleotides as genetic medicines: The current state and future perspective.
  35. Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
  36. Mitochondrial perturbation adapts the proteome from early to advanced immune responses.
  37. Machine-Readable Database for Genotype-Phenotype Analyses in Rare Diseases Using FKTN-related Congenital Muscular Dystrophies as a Prototype.
  38. AlphaGenome Atlas: in silico mutagenesis of the entire human genome improves prioritization and interpretation of non-coding variants.
  39. Epilepsy with myoclonic-atonic seizures: a comprehensive review with emphasis on current and emerging pharmacotherapies.
  40. Prime Editing: An Overview.
  41. Beyond Precision: A Multidimensional Framework for Selecting Genetic Medicine Platforms.
  42. Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
  1. Int J Mol Sci. 2026 Sep 17. pii: 8270. [Epub ahead of print]27(18):
    Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
    Chung-Lin Lee, Chih-Kuang Chuang, Ya-Hui Chang, Huei-Ching Chiu, Yuan-Rong Tu, Yun-Ting Lo, Jun-Yi Wu, Huang-Ying Huang, Hsiang-Yu Lin, Shuan-Pei Lin.
      Inherited mitochondrial cardiomyopathies arise from pathogenic variants affecting oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin remodeling, protein import, cofactor metabolism, and mitochondrial dynamics or proteostasis. These disorders may be cardiac-predominant or part of multisystem disease. Their overlapping cardiac phenotypes suggest convergence on interacting pathways of energetic stress, cristae disruption, calcium imbalance, and redox injury, but do not establish a universal requirement for defective mitophagy. Mitochondrial quality control encompasses protein surveillance, membrane remodeling, dynamics, biogenesis, and organelle disposal; mitophagy is one component. We critically examine the hypothesis that inadequate clearance of damaged mitochondria contributes to progression in a subset of genotypes and disease stages. Disease-specific studies provide support in selected Barth syndrome models, whereas findings in frataxin deficiency vary with model and assay. We distinguish mitochondrial delivery to lysosomes, dynamic turnover measurements, and changes in pathway markers, and identify indirect evidence from acquired heart disease and fatty acid oxidation deficiency. Therapeutic evidence is separated into cellular, animal, and human studies and approved indications. Elamipretide has accelerated approval for muscle-strength improvement in patients with Barth syndrome weighing at least 30 kg; cardiac disease modification remains unconfirmed. Gene replacement has reached early clinical testing, including adeno-associated virus-mediated frataxin gene delivery (AAV-FXN), whereas mitochondrial genome editing and selective mitophagy modulation remain investigational. We propose testable predictions addressing progression, selective rescue, and treatment timing, together with outcomes that would challenge the hypothesis. This framework supports genotype- and stage-specific investigation without assuming that enhanced mitophagy will benefit every mitochondrial cardiomyopathy.
    Keywords:  Barth syndrome; Friedreich ataxia; cardiolipin; elamipretide; gene therapy; mitochondrial cardiomyopathy; mitochondrial quality control; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms27188270
  2. Nucleic Acids Res. 2026 Sep 22. pii: gkag925. [Epub ahead of print]54(18):
    Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase γ.
    Viktoriia Sokolova, Gina Buchel, Sarah Strock, Ashok R Nayak, Dmitry Temiakov.
      Defects in human mitochondrial DNA (mtDNA) replication can lead to somatic mutations associated with a range of devastating mitochondrial diseases. However, the molecular mechanisms governing the earliest steps of mtDNA replication and their fidelity remain poorly understood. Here, we found that DNA polymerase gamma (Polγ) forms stable complexes with RNA-DNA primer-template substrates, exhibiting greater stability and lower misincorporation than on DNA-primed substrates. Structural analysis revealed that Polγ interacts with the 2'-OH groups of ribose within the first four nucleotides of the primer, explaining the stability of complexes that utilize RNA primers. Although Polγ requires TWINKLE to extend RNA primers, its intrinsic strand-displacement activity allows it to extend DNA primers independently. Structural data further show that the strand-separation mechanism in human Polγ is distinct from that of its yeast paralog, Mip1, and involves previously unresolved elements-the catcher and a GP loop in the exonuclease domain-that support intrinsic strand-displacement synthesis by Polγ. Structure-guided mutagenesis of elements involved in strand separation supports these structural observations. Together, our study provides mechanistic insight into mtDNA replication initiation and strand separation and has implications for understanding the molecular basis of mitochondrial disease.
    DOI:  https://doi.org/10.1093/nar/gkag925
  3. Commun Biol. 2026 Sep 24. pii: 1248. [Epub ahead of print]9(1):
    How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
    Pierre-Jean Desmaison, Giulia Bertolin.
      Mitochondria are traditionally viewed as a homogeneous network supporting cellular energy production. However, increasing evidence reveals substantial heterogeneity across biological scales, from intramitochondrial microdomains to specialised mitochondrial populations within cells and tissues. These subpopulations differ in morphology, metabolism, bioenergetics, and spatial organisation, reflecting adaptation to local functional demands. In this Review, we discuss the mechanisms underlying mitochondrial heterogeneity, the emerging concept of mitochondrial subclasses, their functional integration within cellular metabolism, and the challenge of distinguishing stable subclasses from transient states. We propose a shift from a network-based view toward a dynamic mitochondrial ecosystem with important implications for physiology and disease.
    DOI:  https://doi.org/10.1038/s42003-026-11029-7
  4. Int J Mol Sci. 2026 Sep 11. pii: 8086. [Epub ahead of print]27(18):
    Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
    Yongxu Chen, Chunsheng Wang.
      Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder in which variable symptom profiles, progression rates, and treatment responses likely reflect distinct but partially convergent pathogenic mechanisms. Among these, mitochondrial dysfunction recurs across both familial and sporadic PD; however, this broad concept alone cannot explain disease heterogeneity. To preserve mitochondrial homeostasis, cells rely on a complex mitochondrial quality control (MQC) system that encompasses protein import and proteostasis, redox surveillance, organellar dynamics and positioning, biogenesis, and selective elimination of damaged mitochondria. MQC also depends on coordination with other organelles, particularly the endoplasmic reticulum and lysosomes. In this review, we discuss how different layers of MQC maintain mitochondrial integrity and how these pathways are functionally coupled. We further consider how an MQC-based framework may help explain the clinical heterogeneity of PD, including selective neuronal vulnerability, subtype formation, and divergent disease progression, and how it can frame recent therapeutic advances aimed at biologically stratified intervention.
    Keywords:  Parkinson’s disease; heterogeneity; mitochondrial quality control; selective vulnerability; stratified transformation
    DOI:  https://doi.org/10.3390/ijms27188086
  5. Genes (Basel). 2026 Sep 11. pii: 1101. [Epub ahead of print]17(9):
    Characterization of the Mitochondrial Genome Landscape in MSCs, iPSCs and iMSCs from Osteoarthritis Patients and Healthy Donors.
    Vasileios Konteles, Ioanna Papathanasiou, Maria Tzetis, Eugenios Goussetis, Kostantinos Malizos, Aspasia Tsezou.
      Background/Objectives: Osteoarthritis (OA) is strongly associated with mitochondrial dysfunction, oxidative stress, and the accumulation of mitochondrial DNA (mtDNA) alterations in several joint-associated cell types, including chondrocytes, synoviocytes, and mesenchymal stromal cells (MSCs). These alterations contribute to impaired cellular homeostasis and reduced regenerative potential. In this study, we systematically characterized mtDNA heteroplasmy and variant distribution across bone marrow MSCs, induced pluripotent stem cells (iPSCs) and induced MSCs (iMSCs) derived from OA patients and healthy donors. Methods: Ultra-deep mitochondrial genome sequencing was integrated with transcriptomic and miRNome analyses to investigate mitochondrial remodeling during cellular reprogramming, encompassing changes in mtDNA heteroplasmy, variant distribution, mtDNA copy number and associated transcriptomic adaptations of nuclear-encoded mitochondrial pathways. Results: OA-derived MSCs exhibited a markedly increased heteroplasmic burden, followed by decrease in mtDNA copy number and accumulation of non-synonymous variants, particularly within OXPHOS-related genes, including MT-ND1-5, MT-ATP8, MT-CO1, and MT-RNR1/2. Reprogramming into iPSCs and subsequent differentiation into iMSCs were associated with an increase in mtDNA copy number and a progressive reduction in heteroplasmic variants predicted to have pathogenic potential, including m.7913C>T and m.7821G>A, as well as substantial reduction in heteroplasmic variant burden within several mitochondrial genes, suggesting mitochondrial genome remodeling during cellular reprogramming. Multiomic analysis further revealed coordinated deregulation of mitochondrial-associated nuclear genes and ceRNA regulatory networks involving lncRNAs MEG3 and SNHG14, along with multiple mitochondria-related miRNAs. These findings suggest post-transcriptional regulations associated with mitochondrial adaptation in iMSCs Conclusion: Collectively, our findings suggest that cellular reprogramming is associated with mitochondrial genomic reorganization in the donor-matched cell populations examined. These exploratory observations support the utility of iMSCs as a relevant model for studying OA-associated mitochondrial alterations and as a potential tool for regenerative approaches in OA.
    Keywords:  iMSCs; mitochondrial SNVs; ncRNAs; osteoarthritis; transcriptome
    DOI:  https://doi.org/10.3390/genes17091101
  6. Jpn J Clin Oncol. 2026 Sep 24. pii: hyag160. [Epub ahead of print]
    Clinical perspectives on mitochondria in cancer.
    Hiroko Watanabe, Yosuke Togashi.
      Mitochondria have emerged as key determinants of cancer development and therapeutic response, extending their role beyond cellular energy production. Alterations in mitochondrial metabolism, mitochondrial DNA (mtDNA), dynamics, and quality control can support tumor growth and adaptation to the tumor microenvironment, while mitochondrial fitness also shapes the function and persistence of antitumor immune cells. Thus, mitochondrial biology represents a dynamic interface between tumor cells and the immune microenvironment. This review focuses on translating mitochondrial biology into clinical cancer applications in addition to recent advances in mitochondrial research. We evaluate mitochondrial alterations and mtDNA as diagnostic, prognostic, and predictive biomarkers, alongside strategies to selectively exploit cancer mitochondrial vulnerabilities while boosting antitumor immunity. We address key hurdles in therapeutic selectivity and discuss future perspectives for integrating mitochondrial targeting into precision oncology.
    Keywords:  cancer metabolism; immunotherapy; mitochondria
    DOI:  https://doi.org/10.1093/jjco/hyag160
  7. Children (Basel). 2026 Sep 04. pii: 1194. [Epub ahead of print]13(9):
    Genomic Strategies in Pediatric Care: Addressing Rare Diseases in Children.
    Natàlia Caelles-Gramunt, Jordi Pijuan.
       BACKGROUND: Rare diseases collectively affect millions of children worldwide and are a major cause of pediatric morbidity, mortality, and lifelong disability. Although most have a genetic basis, obtaining a timely molecular diagnosis remains challenging because of substantial clinical and genetic heterogeneity. Advances in genomic medicine are transforming rare disease diagnosis and establishing genomics as the center of precision medicine.
    METHODS: This review summarizes current evidence on genomic approaches for pediatric rare diseases, including established and emerging sequencing technologies, their clinical applications, implementation challenges, and future directions.
    RESULTS: Whole-genome sequencing is increasingly being adopted as a first-line genomic test for suspected rare genetic disorders, particularly when the phenotype is heterogeneous or does not point to a specific diagnosis. Conventional cytogenetic and targeted molecular techniques remain important complementary approaches for selected phenotypes, variant classes, and orthogonal confirmation. Gene panels are effective for well-defined phenotypes, whereas whole-exome sequencing remains a high-yield approach for genetically heterogeneous disorders, particularly when whole-genome sequencing is not available or is not clinically indicated. Long-read whole-genome sequencing expands diagnostic capacity by detecting structural variants, repeat expansions, complex rearrangements, and non-coding pathogenic variants that frequently escape short-read technologies. Emerging multi-omics approaches further improve variant interpretation and help resolve previously unsolved cases. Beyond diagnosis, molecular findings guide personalized clinical management, genetic counselling, reproductive planning, and access to targeted therapies and genotype-driven clinical trials. However, broad implementation is constrained by challenges in variant interpretation, ethical and legal considerations, data governance, workforce capacity, cost, and inequitable access to genomic services. Artificial intelligence, international data-sharing initiatives, and coordinated healthcare networks are helping overcome these barriers and improve diagnostic equity.
    CONCLUSIONS: Whole-genome sequencing is increasingly emerging as a first-line genomic strategy for pediatric rare diseases, while complementary technologies, expert phenotyping, and iterative data interpretation remain essential for comprehensive and accurate diagnosis and equitable access to genomic medicine.
    Keywords:  genome sequencing; genomic medicine; molecular diagnosis; precision medicine; rare diseases
    DOI:  https://doi.org/10.3390/children13091194
  8. Biology (Basel). 2026 Sep 08. pii: 1573. [Epub ahead of print]15(18):
    SIRT1 in Senescence: Mitochondria and Immune Crosstalk.
    Jirapat Namkaew, Pornparn Kongpracha, Tanakamol Mahawan, Thiranut Jaroonwitchawan.
      Cellular senescence is one of the hallmarks of aging. These growth-arrested cells actively secrete inflammatory mediators that reshape the tissue microenvironment and fuel age-related pathology. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that regulates senescence largely through its control over mitochondrial integrity and inflammatory signaling. SIRT1 levels and activity fall with age, and this decline directly promotes senescence. SIRT1 maintains mitochondrial function through three interconnected pathways: PGC-1α-driven mitochondria biogenesis, FOXO-dependent antioxidant defense, and mitophagic clearance of damaged organelles. When SIRT1 activity is in an unsteady state, mitochondria become unhealthy. This leads to excessive ROS generation and the leakage of mitochondrial DNA (mtDNA) into the cytosol, which activates the innate immune pathway, consequently resulting in the production of inflammatory cytokines that further inhibit SIRT1. This self-amplifying loop drives cells to irreversible senescence. In this study, we integrate the current understanding of the SIRT1-mitochondria-immune axis within the framework of senescence by examining the biological roles of SIRT1 and the mechanisms that lead to its reduction with aging, while also exploring the interrelated mitochondrial pathways and inflammatory signaling. Furthermore, we assess possible therapeutic strategies targeting this axis and highlight essential questions that necessitate additional research.
    Keywords:  SASP; SIRT1; aging; cellular senescence; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/biology15181573
  9. medRxiv. 2026 Sep 20. pii: 2026.09.17.26363303. [Epub ahead of print]
    LLM-enabled Natural History Study Analysis to Support Rare Disease Research.
    Kevin Li, Eric Sid, Qian Zhu.
       BACKGROUND: Rare diseases affect an estimated 300 million people worldwide, yet the research needed to guide diagnosis and treatment is often fragmented across multiple unstructured literature sources. Natural history studies (NHS) are a key source of this evidence, but manually extracting structured information from NHS publications can be tedious and does not scale.
    METHODS: We have developed a proof-of-concept for an information extraction pipeline testing three opensource large-language models (LLMs) -- Athena-v3-AWQ, Google's Gemma3-27B, and Meta's Llama-3.1-70B-Instruct, to extract key NHS characteristics from PubMed abstracts curated from a Chan Zuckerberg Initiative disease research state model corpus (302 gold-standard and 8,338 full-corpus abstracts), and compared the models on efficiency, extraction completeness, and expert-rated accuracy.
    RESULTS: All three models processed abstracts with success rates exceeding 99%. However, Gemma achieved the best overall performance, with the highest expert-rated accuracy (68.0% of outputs rated "good" vs. 36.0% for Llama and 10.0% for Athena) and the fastest runtime on the full corpus (~16 minutes for 3,547 abstracts), despite Llama scoring higher on the automated Token F1 metric (0.874 vs. 0.723), highlighting a divergence between automated and human evaluation. Athena's lower performance was largely attributable to verbatim copying rather than synthesis of extracted content.
    CONCLUSIONS: These findings illustrate how locally deployed open-source LLMs can extract structured NHS characteristics at scale, thus supporting their use to accelerate evidence synthesis in rare disease research.
    DOI:  https://doi.org/10.64898/2026.09.17.26363303
  10. bioRxiv. 2026 Jun 25. pii: 2026.06.23.733767. [Epub ahead of print]
    ATAD3A structurally links mtDNA replication and mitochondrial fission.
    Nitish Dua, Boyuan Ma, Samantha Oviedo, Hamidreza Rahmani, Tumara Boyd, Donghyun Park, R Luke Wiseman, Danielle A Grotjahn.
      Mitochondrial function depends on the maintenance of its genome, and disruptions in copy number and distribution are hallmarks of mitochondrial disorders. Mitochondrial DNA (mtDNA) replication is spatially and temporally linked to mitochondrial division (i.e., fission). However, the signal that coordinates these two events, which are physically separated by the barrier of two mitochondrial membranes, remains unknown. To gain insight into this coordination, we employed correlative cryo-electron tomography (cryo-ET) to analyze the microenvironment surrounding replicating nucleoids. Mitochondrial regions containing replicating mtDNA exhibit a unique membrane architecture defined by the presence of clustered, membrane-spanning tethers that traverse the inner membrane space. Using a combination of superresolution microscopy and genetically encoded cryo-ET tagging technology, we identify these tethers as the AAA+ ATPase ATAD3A. We further show that ATAD3A knockdown reduces recruitment of the mitochondrial fission machinery, whereas overexpression promotes its recruitment and subsequent fission. Our work suggests that ATAD3A forms nanoscale linkages that coordinate these two distinct processes, revealing a new structural paradigm for organellar communication across distinct membrane-defined environments.
    Highlights: Replicating mitochondrial DNA (mtDNA) nucleoids are surrounded by a distinct membrane microenvironment.ATAD3A forms membrane-spanning tethers enriched at replicating mtDNA sites.ATAD3A enrichment is necessary and sufficient to recruit mitochondrial fission machinery and induce fission at mtDNA replication sites.ATAD3A structurally couples mtDNA replication state to mitochondrial fission across distinct organellar subcompartments.
    DOI:  https://doi.org/10.64898/2026.06.23.733767
  11. Pharmaceuticals (Basel). 2026 Sep 05. pii: 1402. [Epub ahead of print]19(9):
    Natural Small Molecules Targeting Mitochondrial Quality Control for the Treatment of Metabolic Diseases: Mechanisms, Novel Formulations, and Translational Perspectives.
    Chongyan Zhao, Yuan Gao, Ting Zhou, Lei Sun, Qingsong Qu.
      Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria are central organelles that integrate energy metabolism with stress signaling. They participate in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, while also regulating reactive oxygen species generation, mitochondrial DNA-related inflammatory signaling, calcium homeostasis, and cell death. Under chronic metabolic stress, the mitochondrial quality control (MQC) system shifts from adaptive repair toward decompensation, characterized by impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, defective mitophagy, disrupted proteostasis and mitochondrial unfolded protein response, increased oxidative stress, and impaired metabolic reprogramming. Natural small molecules possess structural diversity and multi-target, multi-pathway regulatory properties. They can modulate multiple MQC processes and improve mitochondrial function and metabolic phenotypes in preclinical models. Novel formulations, structural optimization, and mitochondria-targeted delivery can further improve their solubility, bioavailability, tissue exposure, and subcellular localization, thereby enhancing therapeutic efficacy and translational potential. This review systematically summarizes the mechanisms of MQC dysregulation in metabolic diseases, the evidence supporting natural small-molecule interventions, and strategies for formulation and delivery optimization. Future studies should strengthen causal validation of MQC, quantify intramitochondrial drug exposure, and incorporate clinically relevant endpoints to facilitate the translation of natural small-molecule MQC modulators.
    Keywords:  metabolic diseases; mitochondria; mitochondrial quality control; mitochondrial targeting strategy; natural small molecules
    DOI:  https://doi.org/10.3390/ph19091402
  12. Mol Neurobiol. 2026 Sep 21. pii: 912. [Epub ahead of print]63(1):
    Intercellular Mitochondrial Transfer in the Nervous System: Roles of Tunneling Nanotubes, Mitochondrial Extracellular Vesicles, and Neuroimmune Bioenergetic Interactions.
    Xing Wei, Fuxian Liu, Jingxi Yao, Peng Feng, Fuchun Xue, Zhenggang Shi.
      Mitochondria are essential organelles that maintain neuronal bioenergetics, redox homeostasis, calcium signaling, and immune regulation. Traditionally, mitochondrial dysfunction has been primarily considered as an intracellular event associated with neuronal injury and neurodegeneration. However, accumulating evidence indicates that mitochondria and mitochondrial components can be transferred between cells, forming an intercellular communication network that dynamically regulates tissue homeostasis and disease progression. Intercellular mitochondrial transfer occurs through contact-dependent pathways, mainly mediated by tunneling nanotubes (TNTs), and contact-independent pathways involving mitochondrial extracellular vesicles (MitoEVs), mitochondria-derived extracellular vesicles (MDEVs), and extracellular mitochondria. In the nervous system, these pathways establish functional interactions among neurons, astrocytes, microglia, satellite glial cells, endothelial cells, and stem cells. Transferred functional mitochondria can restore bioenergetic deficits, whereas damaged mitochondria or mitochondrial components may act as danger-associated molecular patterns (DAMPs) to amplify neuroinflammation. Here, we summarize the molecular mechanisms and biological functions of intercellular mitochondrial transfer in the nervous system, emphasizing its dual roles in bioenergetic rescue, mitochondrial quality control, and neuroimmune regulation. Understanding these processes may provide new insights into neurological disease mechanisms and therapeutic strategies targeting mitochondrial communication.
    Keywords:  Bioenergetics; Intercellular mitochondrial transfer; Mitochondrial extracellular vesicles; Neuroimmune interactions; Neuroinflammation; Tunneling nanotubes
    DOI:  https://doi.org/10.1007/s12035-026-06224-w
  13. Front Immunol. 2026 ;17 1903643
    Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications.
    Ze Chang, Guannan Liu, Jinshan Zhang, Hailin Lei, Haiyan Quan, Ying Piao.
      Hepatocellular carcinoma (HCC) develops in a chronically injured liver where metabolic adaptation, oxidative stress, innate immune signalling, and immune tolerance are already intertwined. Mitochondria connect these processes: they sustain tumour-cell fitness, yet damaged organelles expose mitochondrial DNA (mtDNA) as an intracellular and intercellular danger signal. Persistent reactive oxygen species, altered mitochondrial dynamics, nucleoid instability, and incomplete mitophagy-lysosomal clearance can oxidise, fragment, and displace mtDNA. The resulting material may remain in the cytosol, circulate freely or in protein-associated complexes, or be transferred within extracellular vesicles. These forms are not immunologically equivalent. Cytosolic mtDNA favours cGAS-STING access; endocytosed material can engage endolysosomal TLR9; and oxidised mtDNA can cooperate with mitochondrial reactive oxygen species, ATP, cardiolipin, and ionic perturbation in NLRP3 inflammasome-associated signalling. Redox remodelling also alters interferon responsiveness, inflammasome competence, and myeloid-cell metabolism, allowing recipient cells to assign different meanings to a similar mitochondrial signal. We integrate these mechanisms into an acute immune activation-chronic immune adaptation continuum. Transient, spatially restricted, and efficiently cleared danger can support antigen presentation and effector recruitment, whereas recurrent or poorly cleared signalling can become embedded in suppressive myeloid remodelling, lymphocyte dysfunction, and spatial immune escape. Direct HCC studies support treatment-induced mtDNA-STING activation, hypoxic extracellular-vesicle-mediated mtDNA transfer, macrophage TLR9 signalling, and TFAM-mtDNA-NLRP3 coupling. The transition between immune states remains a testable synthesis, not an established linear pathway. Therapeutic intervention should be matched to signal form, recipient-cell competence, timing, spatial context, and hepatic reserve; pathway activation alone is an inadequate guide.
    Keywords:  hepatocellular carcinoma; immunotherapy; innate immunity; mitochondrial DNA; mitochondrial danger signals; redox signalling; tumour immune escape; tumour immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1903643
  14. Antioxidants (Basel). 2026 Aug 22. pii: 1051. [Epub ahead of print]15(9):
    Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.
    Giuseppe Petito, Maria Ventriglia, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Francesco Manfrevola, Flora Guerra, Lucia Bertuccini, Giulia Ricci, Gilda Cobellis, Antonia Lanni, Cecilia Bucci, Roberta Romano, Rosalba Senese.
      Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPRmt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPRER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); Endoplasmic Reticulum stress; Mitochondrial Quality Control (MQC); TDP-43; mitochondrial Unfolded Protein Response (UPRmt); mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15091051
  15. Front Genet. 2026 ;17 1932078
    The European Health Data Space and biobanking in Europe: synergies, tensions and the future governance of data-driven health research.
    Laura Grech, Nikolai Paul Pace.
      The European Health Data Space (EHDS) represents the most ambitious attempt to date to create a common legal, technical and governance framework for the use of health data across the European Union. Its adoption creates a new infrastructure for both primary use, focusing on cross-border access to electronic health records for care, and secondary use, centred on research, innovation, public health, regulatory science and policymaking. In parallel, European biobanking has matured into a core research infrastructure supporting genomic medicine, biomarker discovery, rare disease research and precision public health. The convergence of EHDS-enabled electronic health records, BBMRI-ERIC-associated biobanks, and the 1+ Million Genomes initiative offers a plausible route towards federated, large-scale, molecularly informed health systems in Europe. This article critically examines that opportunities and challenges arising from this convergence. It argues that the EHDS and biobanking are complementary but not automatically interoperable. Biobanks provide depth: biospecimens, molecular assays, longitudinal cohorts and consented research infrastructures. The EHDS provides breadth: population-scale clinical trajectories, regulatory gateways, Health Data Access Bodies and Secure Processing Environments. The 1+ Million Genomes and Genomic Data Infrastructure initiatives provide a genomics-specific federated layer that may connect these ecosystems through standards such as GA4GH, Beacon, Phenopackets and FHIR-Genomics. However, substantial obstacles remain. These include uneven digital maturity across Member States, immature representation of biospecimen and omics metadata in clinical data models, unresolved interactions between EHDS opt-out mechanisms and biobank consent, fragmented national interpretations of the GDPR, sustainability constraints, environmental costs of petabyte-scale computing, and the risk that artificial intelligence trained on biased or incomplete datasets will reproduce health inequities. We argue that EHDS-biobank integration should not be regarded solely as a technical exercise. Rather, it represents a governance challenge involving trust, reciprocity, legal interpretation, standards development, infrastructure investment and public legitimacy. Without coordinated action, the EHDS may create a formally integrated yet substantively unequal data ecosystem. Conversely, with deliberate design and effective governance, it has the potential to provide Europe with a trustworthy, federated and clinically actionable research infrastructure.
    Keywords:  1+ million genomes; BBMRI-ERIC; European Health Data Space; GDPR; artificial intelligence; biobanking; dynamic consent; federated analysis
    DOI:  https://doi.org/10.3389/fgene.2026.1932078
  16. Cells. 2026 Sep 17. pii: 1683. [Epub ahead of print]15(18):
    Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration.
    Mateusz Mamala, Izabela Skowron, Karolina Marczuk, Arkadiusz Bujas, Jolanta Harasiuk, Julita Kulbacka.
      Mitochondrial dysfunction is a recurrent but context-dependent feature of neurodegenerative disease, and its position in the pathogenic cascade differs fundamentally between disorders. This narrative review argues that this heterogeneity, rather than mitochondrial biology itself, determines therapeutic tractability. We synthesize evidence on mitochondrial regulation of neuronal development, organelle quality control, redox signaling and neuroinflammation; on oxidative biomarkers, whose clinical use remains constrained by limited disease specificity, methodological heterogeneity and insufficient longitudinal validation; and on therapeutic strategies ranging from antioxidants and NAD+ augmentation to mitochondrial genome engineering, targeted delivery and organelle transfer. A consistent pattern emerges across these domains: broadly acting interventions have repeatedly failed in sporadic disease, whereas the strongest translational signals arise where mitochondrial dysfunction is genetically anchored and pathway-proximal. Mitochondrial modulation is therefore unlikely to provide a universal disease-modifying strategy, but remains a useful, carefully targeted addition for patient groups identified by genetic or specific biological markers.
    Keywords:  mitochondrial DNA; mitochondrial dysfunction; mitochondrial therapeutics; mitophagy; neurodegeneration; oxidative stress; redox biomarkers
    DOI:  https://doi.org/10.3390/cells15181683
  17. J Med Internet Res. 2026 09 18. 28 e111170
    Online Patient Support Communities as Sources of Support, Risk, and Research for Rare or Contested Conditions.
    Vanessa Nirode.
       Unlabelled: When research, treatment, and support are scarce, where can people living with rare or contested conditions turn? In this News and Perspectives article, JMIR Correspondent Vanessa Nirode reports on the role that online patient support communities play, highlighting People Allergic to Me syndrome as a case study.
    Keywords:  PATM; People Allergic to Me syndrome ; online support communities; patient support groups; rare diseases; social support
    DOI:  https://doi.org/10.2196/111170
  18. Antioxidants (Basel). 2026 Sep 02. pii: 1110. [Epub ahead of print]15(9):
    The Oxidative-Mitochondrial-Inflammatory Axis in Retinitis Pigmentosa: Extracellular mtDNA as Biomarker and Therapeutic Read-Out.
    Rossella Grimaldi, Francesca Franco, Enzo Maria Vingolo.
      Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy (prevalence ~1:4000) and a leading Mendelian cause of working-age blindness. Despite marked genetic heterogeneity, its progression converges on a common secondary cascade of outer-retinal hyperoxia, increased reactive oxygen species (ROS), and mitochondrial dysfunction that drives cone degeneration and central vision loss. Because this oxidative cascade is largely genotype-independent and pharmacologically tractable, oxidative stress is a cross-cutting therapeutic target. Within it, mitochondrial DNA (mtDNA) is a key element: once released from damaged photoreceptors-free or within exosomes-it may act as a damage-associated molecular pattern (DAMP), engaging TLR9, cGAS-STING, and the NLRP3 inflammasome and sustaining chronic neuroinflammation. Extracellular mtDNA is therefore a potential integrative marker, simultaneously reflecting oxidative stress, mitochondrial dysfunction, cell death, and innate-immune activation. A central knowledge gap, however, remains: the mechanistic steps linking mtDNA to inflammation and to photoreceptor death have not been demonstrated in RP itself, and extracellular mtDNA has never been quantified in the ocular fluids of RP patients. In this review we appraise oxidative biomarkers in RP, propose extracellular mtDNA as a candidate biomarker of disease activity, and examine antioxidant and redox-modulating therapies-from N-acetylcysteine and elamipretide trials to DAMP-sensor inhibition-across experimental and clinical models. Finally, we propose extracellular mtDNA as a candidate pharmacodynamic endpoint and outline a path toward its validation.
    Keywords:  NLRP3 inflammasome; antioxidants; biomarker; cGAS–STING; extracellular vesicles; liquid biopsy; mitochondrial DNA; neuroinflammation; oxidative stress; retinitis pigmentosa
    DOI:  https://doi.org/10.3390/antiox15091110
  19. Antioxidants (Basel). 2026 Sep 04. pii: 1120. [Epub ahead of print]15(9):
    Mitochondrial Transplantation Suppresses mtDNA-cGAS/STING-Mediated Innate Immunity by Enhancing PINK1/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis.
    Wenjing Wang, Yuanbo Liu, Jipeng Song, Zouzou Yu, Zixiang Chen, Hu Jiao.
      Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach.
    Keywords:  adipose-derived stem cells; cGAS/STING signaling; fibrosis; innate immunity; keloids; mitochondrial transplantation; mitophagy
    DOI:  https://doi.org/10.3390/antiox15091120
  20. Antioxidants (Basel). 2026 Sep 07. pii: 1134. [Epub ahead of print]15(9):
    Mitochondrial Quality Control Links Exercise to Sterile Inflammation in the Cardiovascular System: A Narrative Review.
    Ying Wen, Pengfei Zhang, Xinyu Liao, Jiankang Liu, Yang Zhang, Xuyun Liu.
      Preservation of mitochondrial integrity has emerged as a central hub in the anti-inflammatory effect of exercise. This narrative review advances a framework in which mitochondrial damage-associated molecular patterns (mtDAMPs) serve as the mechanistic bridge between exercise and inflammation. Mitochondrial dysfunction releases mtDAMPs, including mitochondrial DNA (mtDNA), reactive oxygen species, cardiolipin, N-formyl peptides, and ATP, which activate cGAS-STING, the NLRP3 inflammasome, TLR9, AIM2, ZBP1, and NF-κB signaling. Crosstalk among these pathways allows mild mitochondrial damage to escalate into chronic inflammation. Exercise opposes this cascade through the AMPK-PGC-1α axis, which coordinately activates four mitochondrial quality control (MQC) modules: biogenesis, antioxidant defense, dynamics, and mitophagy. The cardiovascular system illustrates this framework, as myocardial inflammation runs mainly through mtDNA-cGAS-STING signaling and vascular inflammation through oxidized mtDNA-NLRP3 signaling, while cardiovascular aging engages both axes at once. Throughout, exercise refers to repeated training rather than to a single bout, and the framework targets middle-aged and older adults with, or at risk of, cardiovascular disease. The upstream half of the sequence, in which training raises mitochondrial content and antioxidant capacity, rests on human muscle biopsy data; the downstream half remains largely preclinical. MQC is therefore proposed as a testable target rather than an established one.
    Keywords:  cardiovascular system; exercise; inflammation; mitochondrial DAMPs; mitochondrial quality control
    DOI:  https://doi.org/10.3390/antiox15091134
  21. Clin Transl Med. 2026 Sep;16(9): e70764
    CRISPR-Cas9 and precision editing technologies linking functional genomics to clinical translation in genetic diseases.
    Zijing Wen, Jianming Su.
       BACKGROUND: CRISPR-Cas9 and derivative precision-editing platforms increasingly connect pathogenic variant interpretation with functional genomics and therapeutic development in genetic diseases. This narrative review focuses on a variant-mechanism-driven framework for matching editing strategies to mutation structure, functional consequence, disease-model evidence, delivery feasibility, safety risk, and translational readiness.
    MAIN BODY: The review summarizes how monogenic, polygenic, coding, non-coding, mitochondrial, and complex disease contexts influence the choice of canonical Cas9 editing, base editing, prime editing, Cas variants, CRISPR interference/activation, epigenome editing, and disease-model systems. It further compares ex vivo and in vivo delivery routes, safety assessment strategies, immunogenicity and genotoxicity concerns, and clinical implementation barriers, including CMC/manufacturing scalability, long-term follow-up, affordability, and regulatory oversight. Current evidence supports the clinical maturity of ex vivo hematopoietic editing, whereas most in vivo and precision-repair approaches remain constrained by delivery, durability, product heterogeneity, and safety uncertainties.
    CONCLUSION: The central conclusion is that future CRISPR-based interventions should be judged not only by editability, but by whether molecular correction can be translated into durable, safe, manufacturable, and clinically meaningful benefit.
    Keywords:  CRISPR‐Cas9; clinical translation; gene function research; genetic diseases; pathogenic mutations; precision editing
    DOI:  https://doi.org/10.1002/ctm2.70764
  22. Aging Cell. 2026 Oct;25(10): e70729
    Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.
    Yuyao Yin, Zijian Li.
      Mitochondria play a crucial role in cellular energy metabolism. The heart and brain require a continuous and stable energy supply. Energy production strongly depends on proper mitochondrial function. Mitochondrial fusion and fission, known as "plasticity", are vital for maintaining the normal physiological function of cells. Recent studies have shown that impaired mitochondrial dynamics are present in many aging-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and atherosclerotic cardio-cerebrovascular disease. The role of impaired mitochondrial dynamics in the pathophysiological process of aging-related diseases is being actively researched. We discovered that targeting proteins related to mitochondrial dynamics, especially those involved in fission and fusion, may offer new treatment strategies for these diseases. Various approaches, including aerobic interval and treadmill training and the use of drugs such as the antidiabetic agents metformin and dapagliflozin, the antihypertensive agent irbesartan, and certain traditional Chinese medicine components, have shown potential in alleviating imbalances in mitochondrial dynamics in aging-related cardio-cerebrovascular diseases. In this review, we systematically summarize recent research on alterations in mitochondrial dynamics in age-related cardio-cerebral diseases and explore therapeutic strategies targeting these alterations, which may offer new directions for improving cardiac and brain health and guiding clinical practice.
    Keywords:  age‐related disease; cardiovascular disease; fission and fusion; mitochondrial dynamics; neurodegenerative disease
    DOI:  https://doi.org/10.1111/acel.70729
  23. Biomedicines. 2026 Aug 31. pii: 1965. [Epub ahead of print]14(9):
    Mitochondria Meet the Lung Microbiome: A Bidirectional Dialogue in Inflammation and Respiratory Diseases.
    Carola Parolin, Emanuele Gentile, Cristina Pellegrino, Valentina Spada, Cristian Bassi, Silvia Sabbioni, Beatrice Vitali, Paolo Pinton, Alessandro Rimessi.
      The respiratory tract is a dynamic biological interface where microbiome, environmental exposure, epithelial integrity, and host metabolic regulation converge to maintain pulmonary homeostasis. Once considered sterile, the lung is now recognized as a low-biomass yet structured microbial ecosystem that contributes to immune calibration, colonization resistance, epithelial barrier function, and tissue resilience. Disruption of this equilibrium, known as pulmonary dysbiosis, has been increasingly associated with acute and chronic lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, asthma, bronchiectasis, and lung cancer. In parallel, mitochondria have emerged as central regulators of pulmonary cell function, extending beyond ATP production to control redox signaling, apoptosis, innate immunity, epithelial repair, and inflammatory responses. This review examines the bidirectional crosstalk between the respiratory microbiome and mitochondria as an integrated pathogenic axis in lung disease. Dysbiotic microbial communities and respiratory pathogens can induce mitochondrial stress through toxins, virulence factors, microbial metabolites, and pattern-recognition receptor activation, leading to mitochondrial alteration and the release of mitochondrial damage-associated molecular patterns. Conversely, dysfunctional mitochondria reshape the pulmonary microenvironment by altering oxygen consumption, nutrient availability, cytokine production, redox balance, and barrier repair, thereby favoring pathogen persistence and chronic inflammation. Understanding mitochondria-microbiome interactions may support precision medicine strategies that integrate microbial, metabolic, inflammatory, and bioenergetic biomarkers to improve the diagnosis, prognosis, and treatment of inflammatory-related lung diseases.
    Keywords:  dysbiosis; inflammation; microbiome; mitochondria; respiratory diseases
    DOI:  https://doi.org/10.3390/biomedicines14091965
  24. J Clin Pharmacol. 2026 Sep;66(9): e70303
    Letter to the Editor: Innovative Clinical Pharmacology, Modeling, and Simulation Strategies for Accelerating Rare Disease Drug Development.
    Sameed Hyder, Muhammad Amir Saeed.
      
    DOI:  https://doi.org/10.1002/jcph.70303
  25. Ann Hum Biol. 2026 Dec;53(1): 2720076
    Maternal lineage tracing using mtDNA from unbuffered formalin-fixed autopsy tissues in India.
    Kangana Aggarwal, Nidhi Sharma, Braja Kishore Mohapatra, Kamal Chauhan, Harpreet Singh, Prachi Shukla, Chittaranjan Behera.
       BACKGROUND: In India, autopsy tissues are routinely preserved in 10% unbuffered formalin, which induces extensive deoxyribonucleic acid (DNA) damage through cross-linking and fragmentation. However, mitochondrial DNA (mtDNA), owing to its high copy number and polymorphic regions, may remain recoverable when nuclear DNA profiling is not feasible.
    AIM: This study evaluated the feasibility of obtaining HV1 and HV2 mtDNA sequences from unbuffered formalin-fixed autopsy tissues and explored maternal lineage diversity within the study cohort.
    SUBJECTS AND METHODS: Seventy pairs of formalin-fixed autopsy tissues and reference samples (blood/buccal swabs) from first-degree maternal relatives were analysed. Total DNA was extracted using an organic method. HV1 and HV2 regions were amplified and sequenced using Sanger sequencing. Sequence variants were determined relative to the revised Cambridge Reference Sequence (rCRS), and haplogroups were assigned using the EMPOP haplogrouping tool.
    RESULTS: The formalin-fixed samples yielded complete HV1 and HV2 mtDNA sequences that were concordant with their corresponding maternal reference samples. A total of 34 haplogroups were observed, indicating maternal lineage diversity within the study cohort.
    CONCLUSION: These findings support the feasibility of mtDNA sequencing in unbuffered formalin-fixed tissues under routine mortuary conditions and provide exploratory mtDNA data relevant for forensic genetic research in the Indian context.
    Keywords:  India; Mitochondrial DNA; forensic analysis; formalin-fixed tissue; maternal lineage
    DOI:  https://doi.org/10.1080/03014460.2026.2720076
  26. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00079-6. [Epub ahead of print]191 27-59
    Blood biomarkers of oxidative stress and mitochondrial dysfunction in Parkinson's disease and Alzheimer's disease.
    Deepak Kumar, Snehasish Shee, Ashok Kumar Datusalia, Shyam Sunder Sharma.
      Parkinson's disease (PD) and Alzheimer's disease (AD) are the most prevalent neurodegenerative disorders and represent a major global health burden. Despite distinct clinical features, both diseases share key pathogenic mechanisms, particularly oxidative stress and mitochondrial dysfunction, which contribute to neuronal injury and progression. Current diagnostic approaches based on clinical evaluation, neuroimaging, and cerebrospinal fluid (CSF) biomarkers are invasive, costly, and often detect disease only after significant neuronal loss, underscoring the need for minimally invasive, pathway-relevant assays. This chapter reviews blood- and CSF-based biomarker assays reflecting oxidative stress and mitochondrial dysfunction in PD and AD, including lipid peroxidation products, antioxidant capacity, oxidative DNA damage markers, mitochondrial bioenergetic indices, and quality-control proteins. Emerging assay platforms targeting circulating cell-free mitochondrial DNA, mitochondrial-derived vesicles, extracellular vesicle cargo, and regulatory non-coding RNAs are also discussed. The mechanistic relevance of these biomarkers is examined in relation to impaired mitochondrial quality control, disrupted redox homeostasis, defective oxidative phosphorylation, and interactions with disease-defining proteins such as α-synuclein, amyloid-β, and phosphorylated tau. Collectively, these assay-based biomarkers hold promise for early detection, disease monitoring, and therapeutic stratification, although challenges related to standardization, sensitivity, and longitudinal validation remain.
    Keywords:  Alzheimer’s disease; Blood biomarkers; Cerebrospinal fluid; Extracellular vesicles; Mitochondrial DNA; Mitochondrial dysfunction; Neurodegeneration; Oxidative stress; Parkinson’s disease
    DOI:  https://doi.org/10.1016/bs.irn.2026.07.003
  27. Exp Ther Med. 2026 Oct;32(4): 291
    From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).
    Hui Liu, Yao Zhang, Ziliang Zhuo, Wei Zhong, Manyun Yan, Zhongbo Zhao.
      Neurodegenerative diseases (NDDs) are commonly accompanied by persistent low-grade neuroinflammation, yet current therapies rarely achieve durable disease modification. This review aims to systematically delineate the role of mitochondrial DNA (mtDNA) leakage in linking mitochondrial injury to innate immune activation and to explore its pathological significance in NDDs. A comprehensive review of recent literature on mitochondrial stress, mtDNA release and innate immune signaling was conducted. Evidence was integrated regarding the sources of mtDNA immunogenicity, routes of mtDNA escape, mitophagy-lysosome gating mechanisms and the modulation of leakage baseline by aging and metabolic stress. Accumulating evidence indicates that cytosolic mtDNA is sensed by cyclic GMP-AMP synthase (cGAS) and activates the stimulator of interferon (IFN) genes (STING) pathway signaling through the TANK-binding kinase 1 and IFN regulatory factor 3 axis to induce type I IFN responses and promoting NF-κB-driven inflammatory transcription, thereby enhancing NLRP3 inflammasome priming. Oxidized mtDNA, pore-forming membrane events and ionic imbalance further facilitate NLRP3 assembly and pyroptotic execution, exacerbating mitochondrial damage and mtDNA release in a self-amplifying loop. Based on these findings, a modular assessment framework was proposed across the 'input-chronicity-amplification' layers and the potential of mtDNA-cGAS/STING-NLRP3 axis-informed stratified diagnosis and treatment was discussed Central nervous system-targeted delivery, cellular heterogeneity and immune safety windows remain critical for translational research. This review provides a testable mechanistic framework and a clinical evaluation pathway for understanding mtDNA-driven persistent inflammation in NDDs.
    Keywords:  NLRP3 inflammasome; cGAS/STING; mtDNA; neuroinflammation; stratified assessment
    DOI:  https://doi.org/10.3892/etm.2026.13286
  28. Mitochondrion. 2026 Sep 25. pii: S1567-7249(26)00110-8. [Epub ahead of print] 102220
    Changes in protein markers of the mitochondrial respiratory chain and quality control in a mouse model of psychosis.
    Laura Norma, Tiziana Imbriglio, Rosamaria Orlando, Luisa Di Menna, Valeria Bruno, Giuseppe Battaglia, Milena Cannella, Ferdinando Nicoletti.
      Alterations in mitochondrial function and mitochondrial quality control (MQC) in the CNS have been consistently associated with neurological disorders, but are less investigated in psychiatric disorders. We measured levels of mitochondrial proteins involved in oxidative phosphorylation and MQC in a neurodevelopmental mouse model that recapitulates some of the features of schizophrenia. We used adult male and female mice prenatally exposed to the toxin, methylazoxymethanol (MAM, injected i.p. to pregnant dams, daily from gestational day 15 to 17, at the dose of 10 mg/kg). This treatment caused abnormalities in locomotor activity, social interaction, novel object recognition, and prepulse inhibition of acoustic startle in the adult offspring. MAM-treated mice showed sex-dimorphic changes in proteins of complex I and IV of the mitochondrial respiratory chain, as well as changes in proteins involved in mitochondrial fusion and fission (mitofusin-1 and -2 and dynamin-related protein-1, respectively), mitophagy (PTEN-induced kinase-1, Rab5 and Rab7a), and mitochondrial biogenesis (peroxisome proliferator-activated receptor γ-coactivator-1α, nuclear respiratory factors 1 and - 2, and mitochondrial transcription factor-B2). To our knowledge, this is the first extensive study of mitochondrial proteins in preclinical models of schizophrenia, and our data pave the way to a focused investigation of mitochondrial morphology and function in MAM-treated mice of both sexes.
    Keywords:  Gender difference; Methylazoxymethanol; Mitochondria; Oxidative phosphorylation; Psychotic like phenotype; Schizophrenia
    DOI:  https://doi.org/10.1016/j.mito.2026.102220
  29. bioRxiv. 2026 Sep 15. pii: 2026.09.09.750228. [Epub ahead of print]
    Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
    Wenyu Tang, Haoyu Xu, Steven Beck, Marcus T Cicerone, Sung Min Han, Wei-Wen Chen.
      Mitochondrial dysfunction is a hallmark of aging, yet how mitochondrial states are remodeled across tissues and subcellular compartments in vivo remains elusive. Progress has been limited, in part, because mitochondrial physiology is highly sensitive to experimental perturbations, underscoring the need for minimally disruptive measurement strategies. Here, we establish a tissue-resolved, in vivo framework for the quantitative analysis of mitochondrial states in live, intact Caenorhabditis elegans without confounding effects from mounting-induced hypoxia. This platform couples two-photon fluorescence lifetime imaging microscopy (2p-FLIM) with a custom segmentation pipeline, MitoSLIT, to track functional and structural features across multiple tissues and single neurons. By integrating membrane potential-associated TMRM intensity, lifetime-based microenvironmental metrics, and morphological descriptors, we uncover localized metabolic heterogeneity masked by conventional intensity analysis. Leveraging this framework, we mapped physiological aging against mitochondrial shifts induced by acute stress and fission-fusion mutations. Our analyses reveal that mitochondrial aging is highly tissue-specific, executing distinct trajectories across cell types. Extending the framework to genetically identified neurons revealed age-dependent divergence between somatic and axonal mitochondrial states, accompanied by structural remodeling and a late shift in optical redox ratio. Together, our findings demonstrate that mitochondrial populations do not converge on a uniform bioenergetic endpoint during aging, but rather follow highly compartmentalized, tissue-specific spatiotemporal trajectories in vivo .
    DOI:  https://doi.org/10.64898/2026.09.09.750228
  30. Nat Rev Nephrol. 2026 Sep 24.
    Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.
    Shen Li, E Dale Abel, Zoltan Arany, Joseph A Baur, Liming Pei, Katalin Susztak.
      Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals - including FGF21, GDF15, succinate and circulating mitochondrial DNA - enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41581-026-01127-4
  31. Anim Cells Syst (Seoul). 2026 ;30(1): 16-38
    Mitochondria-ER contact sites in neurological disorders.
    Eun Jin Jang, Jisoo Lee, Seungha Shin, Tran Diem Nghi, Sang Ki Park.
      Mitochondria-associated ER membranes (MAMs) are inter-organelle contact sites that mediate signaling between the ER and mitochondria. MAMs play crucial roles in Ca2+ transfer, lipid metabolism, mitochondrial respiration, protein homeostasis, autophagy, and ER stress. In the central nervous system (CNS), these functions are particularly important because neurons and glial cells require precise communication between ER and mitochondria to sustain various neuronal functions. Previous studies often interpreted the MAM dysfunction associated with disease as an alteration in ER-mitochondria coupling. More recently, however, MAMs are regarded as functionally specialized signaling platforms whose molecular composition is dynamic, cell type- and disease stage-dependent. Here, we discuss how MAM remodeling underlies a range of neurological diseases, including neurodegenerative and neurodevelopmental conditions, neuropsychiatric disorders, neuroinflammation, neuronal aging, and brain tumors.
    Keywords:  MAM remodeling; MAMs; Mitochondria-associated ER membranes; neurological disorders; organelle homeostasis
    DOI:  https://doi.org/10.1080/19768354.2026.2725542
  32. Mol Vis. 2026 ;32 196-208
    Assessing mitochondrial phenotypes in a cybrid model of dry age-related macular degeneration.
    Jacob Dohl, Nyan Lin Zaw, Jett Nguyen, Gordon Burns, Brandon Park, Shari Atilano, Kevin Schneider, Marilyn Chwa, Maria Cristina Kenney.
       Purpose: Dry age-related macular degeneration (DAMD) is the leading cause of vision loss in developed countries, yet there are no FDA-approved treatments currently available. Mitochondria play a significant role in the pathology of DAMD; the retinal pigment epithelium cells of patients with DAMD exhibit mitochondrial dysfunction, elevated levels of mitochondrial DNA lesions, and increased mitochondrial reactive oxygen species. Investigations into the mitochondrial contributions to DAMD are complex as human tissue is challenging to acquire, and animal models do not fully recapitulate disease phenotypes. Cytoplasmic hybrid (cybrid) cells, formed by depleting the mitochondria of an immortalized cell line and fusing with patient platelets, are a possible model for mitochondrial studies on DAMD. This study evaluates if cybrid models of DAMD recapitulate the mitochondrial hallmarks of the disease, including mitochondrial dysfunction, decreased mitochondrial protein levels, lipid accumulation, and mitochondrial DNA lesions.
    Methods: The mitochondrial functions of five healthy and five DAMD cybrid cell lines were compared based on mitochondrial oxygen consumption rates, membrane potential, and protein expression. Secondary factors of mitochondrial dysfunction, including lipid accumulation and mitochondrial DNA stress response, were also examined.
    Results: Compared to healthy control cybrid lines, we found no alterations in bioenergetics, protein levels, and lipid accumulation in DAMD cybrid lines. Mitochondrial DNA stress responses were aberrant in DAMD cybrids compared to healthy controls, suggesting some conserved mitochondrial dysfunction.
    Conclusions: Taken together, this study suggests that these DAMD cybrids do not fully recapitulate DAMD mitochondrial pathology, though this is limited to the study population of males with the H mtDNA haplogroup. However, there may be a niche for cybrid cell lines in investigating mitochondrial DNA phenotypes in patients with DAMD. This is likely because DAMD is a multifactorial disease, dependent upon an individual's genetics and the retinal microenvironment.
    DOI:  https://doi.org/10.63500/mv_v32_196
  33. J Pediatr. 2026 Sep 24. pii: S0022-3476(26)00371-9. [Epub ahead of print] 115343
    Genome Sequencing in Pediatrics: Expanded Use Requires Strong Stewardship.
    Michael Duyzend, Colby Chiang.
      
    Keywords:  genome sequencing; genomic stewardship; medical genetics; newborn sequencing; pediatric genomic medicine; rare disease; variant interpretation
    DOI:  https://doi.org/10.1016/j.jpeds.2026.115343
  34. Cell Rep Med. 2026 Sep 22. pii: S2666-3791(26)00475-1. [Epub ahead of print] 103058
    Therapeutic oligonucleotides as genetic medicines: The current state and future perspective.
    Bruno Miguel Da Cruz Godinho, Chantal M Ferguson, Annemieke Aartsma-Rus.
      Antisense therapeutic oligonucleotides are entering a transformative era in clinical development, with a total of 21 oligonucleotides approved and a robust pipeline poised for the coming years. These drugs have emerged as a cornerstone of genetic medicine, providing a programmable platform to modulate gene expression and treat otherwise untreatable disorders. This review covers the different mechanisms of action of these drugs and highlights the key advances in oligonucleotide chemistry and delivery that have supported the clinical successes witnessed in the last decade. It also provides a historical account and overview of the growing number of approvals and key phase 3 studies. Finally, it offers a perspective on the future of the field, initially focused only on rare diseases and now expanding to common disorders.
    Keywords:  ASOs; RNA interference; RNA therapeutics; antisense; genetic medicine; siRNAs
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103058
  35. Aging Cell. 2026 Oct;25(10): e70720
    Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.
    Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie.
      Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.
    Keywords:  HIF‐3α‐BNIP3 axis; aging heart; mitochondrial transplantation; mitophagy flux
    DOI:  https://doi.org/10.1111/acel.70720
  36. bioRxiv. 2026 Sep 14. pii: 2026.09.07.749965. [Epub ahead of print]
    Mitochondrial perturbation adapts the proteome from early to advanced immune responses.
    Jessica Alvarez, Sofia Rivera, Sarahbeth Roberts, Natalia Herrera, Tyron Chang, Krishna Kanth Chitta, Jeon Lee, Andrew Lemoff, Dustin C Hancks.
      Dysregulated immunity, a hallmark of many human diseases, co-occurs with mitochondrial dysfunction and is commonly associated with misprimed primary immune signaling. While transcriptionally well-characterized, the impact of mitochondria on the host response at the protein level is less clear. Using in vitro and in vivo approaches including proteotranscriptomics, our data suggest that OXPHOS promotes expression of early, cell autonomous immune proteins whereas mitochondrial perturbation favors mediators of cell extrinsic responses like inflammation. This response is independent of immune cues, time-dependent, conserved, and occurs across tissues in mouse models of mitochondrial dysfunction. These data illustrate unappreciated roles for mitochondrial state in adapting host responses at the protein level, which have implications for complex disease etiology and the ancestral origins for eukaryotic immune sensing.
    DOI:  https://doi.org/10.64898/2026.09.07.749965
  37. Res Sq. 2026 Sep 17. pii: rs.3.rs-10856264. [Epub ahead of print]
    Machine-Readable Database for Genotype-Phenotype Analyses in Rare Diseases Using FKTN-related Congenital Muscular Dystrophies as a Prototype.
    Matthew E Lefkowitz, Sofia G Eisenberg, Ruili Huang, Uma S Mudunuri, Robert Leaman, Zhiyong Lu, Svetlana Gorokhova, Sharie J Haugabook, Elizabeth A Ottinger, Ann R Knebel, Donald C Lo, Carsten G Bönnemann, A Reghan Foley.
      The FKTN -related muscular dystrophies are a subtype of highly heterogeneous, ultra-rare genetic diseases that are part of the α-dystroglycanopathies (αDGs). These disorders present with different prevalences depending on the population and cause a spectrum of severities with frequently severe phenotypes with often congenital presentation (congenital muscular dystrophy). To better understand the impact of specific FKTN variants in the affected individuals, we first comprehensively aggregated all publicly known and available data resulting in a database comprising all published literature that details FKTN variants and their associated clinical phenotypes. A machine-readable format for the database was achievedvia harmonized data conversion for genotypes and clinical phenotypes. We also developed a clinical severity scale utilizing previously existing metrics as a means of categorizing phenotypic data to facilitate effective genotype/phenotype correlation. This dataset also serves as a pilot for similar data extraction and harmonization in other muscular dystrophies and rare monogenic diseases.
    DOI:  https://doi.org/10.21203/rs.3.rs-10856264/v1
  38. medRxiv. 2026 Sep 20. pii: 2026.09.16.26363192. [Epub ahead of print]
    AlphaGenome Atlas: in silico mutagenesis of the entire human genome improves prioritization and interpretation of non-coding variants.
    Jun Cheng, Kyle R Taylor, Lauren Nicolaisen, Joshua Pan, Clare Bycroft, Matteo Perino, Tom Ward, Gareth Hawkes, Laura E Covill, Melanie Weilert, Raina W Thomas, Natasha Latysheva, Maile J Hirschmann, Xi Dawn Chen, Robin N Beaumont, V Kartik Chundru, Michael N Weedon, Simon Bourdareau, Hoyin Chu, Dhavanthi Hariharan, Thais Kagohara, Lucas Tenorio, Yosuke Ushigome, Courtney A Shearer, Barbara Ikica, Ada Fang, Mouad Naciri, Victoria Johnston, Richard Green, Lai Hong Wong, Vincent Dutordoir, Anne Mottram, Adam Gayoso, Eirini Arvaniti, Guido Novati, Heidi L Rehm, Fei Chen, Caleb A Lareau, Caroline F Wright, Anne O'Donnell-Luria, Julia Zeitlinger, Pushmeet Kohli, Ziga Avsec.
      A major challenge in genomics is deciphering the functional consequences of non-coding genetic variation. Here we present AlphaGenome Atlas, a comprehensive resource that enables the joint interpretation and prioritization of variant effects across the entire human genome. Using AlphaGenome, we predicted the regulatory effects across thousands of molecular phenotypes for every possible human single nucleotide variant and many observed indels. These predictions were then used to derive a unified and interpretable AlphaGenome Variant Impact (AVI) score and to map cis-regulatory motifs across the genome. AVI achieved state-of-the-art performance across diverse benchmarks with improved prioritization of deleterious non-coding variants. Application of the combined Atlas resource helped solve an epileptic encephalopathy rare disease case, increased the statistical power to detect rare non-coding variants driving population-level phenotypes, and enhanced the mechanistic interpretation of these variants. Thus, AlphaGenome Atlas improves the prioritization and molecular interpretation of non-coding variants with genetic and clinical significance.
    DOI:  https://doi.org/10.64898/2026.09.16.26363192
  39. Expert Rev Neurother. 2026 Sep 19. 1-15
    Epilepsy with myoclonic-atonic seizures: a comprehensive review with emphasis on current and emerging pharmacotherapies.
    Debopam Samanta.
       INTRODUCTION: Epilepsy with myoclonic-atonic seizures (EMAtS), historically termed Doose syndrome, is a developmental and epileptic encephalopathy characterized by the usually abrupt onset of multiple generalized seizure types, including myoclonic-atonic seizures, in early childhood. Advances in genetic diagnostics, antiseizure treatments, and precision therapies have reshaped understanding and management of EMAtS.
    AREAS COVERED: This review synthesizes the clinical spectrum of EMAtS, including core clinical features and diagnostic approach based on a literature search of PubMed, Embase, and OVID/MEDLINE. The genetic landscape is discussed to contextualize emerging precision therapies. Treatment is reviewed hierarchically, from valproate, clobazam, levetiracetam and ethosuximide as commonly used first- and second-line agents to the ketogenic diet, cannabidiol, felbamate, and sulthiame for drug-resistant disease. Precision approaches for key genetic etiologies, includingSLC2A1, SLC6A1, SYNGAP1, CHD2, STXBP1,andSCN2A, are also reviewed.
    EXPERT OPINION: Although approximately two-thirds of patients with EMAtS achieve seizure remission, a substantial minority experience drug-resistant seizure, intellectual disability, and behavioral comorbidities, underscoring the importance of timely diagnosis, appropriate pharmacotherapy, and early consideration of the ketogenic diet in drug-resistant cases. As precision therapeutics advance, syndrome-based care will increasingly be complemented by treatments tailored to the specific genetic etiology.
    Keywords:  DEE; Doose syndrome; children; disease-modifying; epilepsy; intractable epilepsy; precision therapy
    DOI:  https://doi.org/10.1080/14737175.2026.2735961
  40. Methods Mol Biol. 2027 ;3075 41-57
    Prime Editing: An Overview.
    Emilio M García-Tenorio, Mar Alvarez, Eva Richard, Lourdes R Desviat.
      CRISPR tools are revolutionizing the landscape of genetic therapies, with the potential to cure a range of previously untreatable diseases. Among all the available genome editing technologies, prime editing is an especially versatile tool that enables precise genetic modifications, including point mutations, insertions, and deletions, without inducing double-strand breaks or requiring a donor DNA template. Through structural modifications and the development of novel systems with additional functionalities, prime editing has expanded its applicability with improved precision, efficacy, and safety. It is already being tested in clinical trials for chronic granulomatous disease, and many preclinical studies are underway. However, significant challenges remain for its broad applicability as a potential curative therapy for human genetic diseases, mainly related to ensuring efficient and safe delivery to target tissues.
    Keywords:  CRISPR/Cas; Genome editing; Personalised medicine; Prime editing; pegRNA
    DOI:  https://doi.org/10.1007/978-1-0716-5547-4_3
  41. Cells. 2026 Sep 11. pii: 1647. [Epub ahead of print]15(18):
    Beyond Precision: A Multidimensional Framework for Selecting Genetic Medicine Platforms.
    Jared Wieland, Peyton Jackson, William Penrod, Spencer Nadauld, Jared Barrott.
      Gene therapy is undergoing continued clinical translation and technological development. This progress has been marked by regulatory approvals and broadened therapeutic indications across genetic, metabolic, and oncologic diseases and disorders. The field has evolved over decades from early viral-mediated gene addition to approaches capable of targeted editing, regulation, or replacement of genetic information. These systems include base and prime editors, epigenetic modulators, CRISPR-Cas, RNA therapeutics and programmable integration platforms. When paired with increasingly sophisticated viral and nonviral delivery strategies, these technologies enable greater control over tissue targeting, duration of activity, and therapeutic exposure. Recent clinical successes, including approved ex vivo CRISPR-based therapies for hemoglobinopathies, in vivo CRISPR editing for transthyretin amyloidosis, and emerging clinical applications of base and prime editing, provide growing clinical evidence for the feasibility of genetic medicines. However, technological advancement has also made platform selection increasingly complex. Therapeutic performance is determined not by editing efficiency alone, but by the interaction among genetic precision, temporal control, dosage tunability, delivery efficiency, durability, and disease-specific safety requirements. A molecularly efficient platform may still have limited therapeutic value if it cannot reach the disease-relevant cell population at sufficient and safe exposure. In this review, we examine recent technological and clinical advances in genetic medicine with particular emphasis on developments during the past approximately five years. We propose a multidimensional framework in which gene therapy platforms are evaluated according to three intrinsic properties-genetic precision, temporal control, and dosage tunability-while delivery, clinical maturity, and disease context act as major translational constraints. This framework highlights that no single platform is universally optimal; rather, successful therapeutic design depends on matching the biological characteristics of the intervention to the requirements of the disease and target tissue. Remaining challenges in extrahepatic delivery, genomic safety, immunogenicity, manufacturing, and long-term monitoring remain important determinants of broader clinical implementation.
    Keywords:  CRISPR-Cas; base editing; gene delivery; gene therapy; genetic medicine; genome editing; genomic safety; prime editing
    DOI:  https://doi.org/10.3390/cells15181647
  42. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2607452123
    Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
    Qing Li, Tong Shu, Chen Liu, Min Zheng, Yuanpei Li, Lei Zhang, Gao Fan, Wenbin Lu, Huiwen Zhang, Pingping Liu, Xiaoniu He, Hong Zheng, Wen Liu, Jing Ye, Zhenyu Yin, Xianming Deng, Chensong Zhang, Canhua Huang, Han You.
      PARP inhibitors (PARPis), known to elicit mitochondrial protection in nononcological diseases by elevating the cellular NAD+ pool, exhibit potent cytotoxicity in selected human cancers. The role of mitochondrial metabolism in PARPi-mediated antitumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD+ metabolism and PARPi responsiveness. In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity toward STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1. FoxO1 modulates transcriptomic signature governing mitochondrial NADPH fluxes to de novo mito-dTMP generation. Our results uncover a fundamental vulnerability that can be leveraged by cotargeting STAT3 and PARP to trigger mitochondrial dysfunction.
    Keywords:  PARPi resistance; de novo mitochondrial dTMP biosynthesis; mitochondrial NAD+ metabolism
    DOI:  https://doi.org/10.1073/pnas.2607452123
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