bims-polgdi Biomed News
on POLG disease
Issue of 2026–10–11
43 papers selected by
Luca Bolliger, lxBio
  1. Sterile inflammation in LHON: mitochondrial stress, innate immune signaling, and implications for AAV gene therapy.
  2. From heteroplasmy shift to direct base correction: mitochondrial genome editing for disease modeling and therapy.
  3. Editors' Note: Gene Therapy and Rare Diseases Through the Ages: Stories of Science and Society.
  4. Cellular Mechanisms Enabling Mitochondria Transfer and Transplantation.
  5. Genetic insights into multiple sclerosis: exploring mitochondrial DNA and nuclear POLG gene variation in a Polish single-center RRMS cohort.
  6. Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.
  7. Mitochondrial DNA damage elicits PINK1 upregulation in pontine cholinergic neurons in Parkinson's disease.
  8. Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases.
  9. Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.
  10. Rare diseases: NHS labs fail to share data vital for diagnosis and care, BMJ finds.
  11. Patient engagement in protocol development for rare disease clinical trials: a framework.
  12. The Genetic and Epigenetic Mechanisms of mtDNA in Regulation of Inflammation and Metabolism.
  13. Low-level of mitochondrial DNA alterations during direct-acting antiviral treatment in leukocytes of people who inject drugs living with HCV.
  14. Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.
  15. Inheritance and selection of the mitochondrial genome.
  16. Rare diseases, body, and stigma: a comparative analysis of people living with berardinelli syndrome and Machado-Joseph disease in Brazil.
  17. Hyperinflammatory syndromes in primary mitochondrial disease: A three-center case series and focused review.
  18. Lower mitochondrial DNA copy number in ATTRV50M Swedish carriers.
  19. Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
  20. Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.
  21. Sestrin1 Ameliorates Senescence and Mediates the Protective Effects of Exercise Against Hepatic Abnormality in C57BL/6J Mice.
  22. Paediatric biobanking in the era of precision medicine: ethical, regulatory, and scientific challenges from childhood to adulthood.
  23. Cancer-associated mitochondrial homeostasis disrupted and retrograde signaling activated.
  24. The mitochondrial Na⁺/Ca²⁺ exchanger NCLX in calcium homeostasis and disease pathophysiology: mechanisms, controversies and research perspectives
  25. Understanding barriers to quality healthcare in rare diseases.
  26. Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.
  27. Djp1 is a multifunctional Hsp40 cochaperone for mitochondrial phospholipid metabolism.
  28. Harmonizing ALS research data across multimodal data sets using the OMOP Common Data Model.
  29. Building Sustainable Patient Involvement in Rare Condition Research.
  30. Nucleotide stress in chronic inflammatory memory: Mitochondrial DNA damage and NAD+-dependent PARP1 chromatin dynamics.
  31. A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.
  32. Mapping mitochondria-associated research in inflammatory bowel disease: A bibliometric and network analysis.
  33. A Novel GNN-Bi-LSTM Framework with Attention Mechanism for Detecting Rare Genetic Disorders.
  34. Mechanistic interactions of diet, exercise, and pharmacotherapy in skeletal muscle metabolism: evidence and translational perspectives.
  35. Genetic Testing in Clinical Immunology: What to Know and How to Do It.
  36. Mitochondria affect antibacterial immunity in cross talk with innate immune response molecules coded by genes of nuclear origin.
  37. Artificial Intelligence in the Diagnosis, Treatment, and Management of Rare Diseases: Opportunities and Challenges from a Latin American Perspective.
  38. From iPSC Disease Modeling to Epigenome Editing: Toward Therapeutic Reversal of Genomic Imprinting Disorders.
  39. Plasma PINK1/Parkin ratio and ATF5 as potential biomarkers associated with dyskinesia in Parkinson's disease.
  40. Regulatory sandboxes for drug development: from uncertainty to structured evidence generation.
  41. Primary cilium as a sensory organelle and metabolic hub in health and diseases.
  42. Genomic Data Governance Challenges Between Research and Clinical Care: A Scoping Review.
  43. Coordinated mitochondrial quality control underlies oxidative stress resilience in MUSE stem cells.
  1. Front Immunol. 2026 ;17 1935135
    Sterile inflammation in LHON: mitochondrial stress, innate immune signaling, and implications for AAV gene therapy.
    Xue Zhang, Aiqin Chang, Yuan Liu, Hong Yu.
      Leber hereditary optic neuropathy (LHON) is a mitochondrial disease caused primarily by pathogenic mitochondrial DNA (mtDNA) variants that impair respiratory chain complex I function. Although bioenergetic failure, oxidative stress, and retinal ganglion cell degeneration are central features of disease pathogenesis, these mechanisms do not fully explain the incomplete penetrance, male predominance, and marked clinical heterogeneity observed in LHON. Emerging evidence suggests that mitochondrial dysfunction can also trigger sterile inflammatory responses through the release of mitochondrial damage-associated molecular patterns (DAMPs), including mtDNA and reactive oxygen species, and through impaired mitophagic clearance. These signals activate innate immune pathways, including cGAS-STING, TLR9, and the NLRP3 inflammasome, potentially contributing to neuroinflammation, glial activation, and secondary neuronal injury. The relevance of immune signaling has gained further attention with the development of AAV-based gene therapies for LHON, where treatment-associated ocular inflammation has emerged as a clinically important challenge. In this review, we examine the evidence linking mitochondrial dysfunction to innate immune activation in LHON, discuss the immunological mechanisms underlying disease progression and gene therapy-associated inflammation, and highlight emerging opportunities for biomarker development, immunomodulatory intervention, and improved therapeutic design. We propose that LHON should be viewed not only as a disorder of mitochondrial bioenergetics but also as a neuroinflammatory disease shaped by the interplay between mitochondrial stress and immune signaling.
    Keywords:  Leber hereditary optic neuropathy; adeno-associated virus; gene therapy; innate immunity; mitochondrial DNA; mitochondrial stress; sterile inflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1935135
  2. BMB Rep. 2026 Oct 07. pii: 6949. [Epub ahead of print]
    From heteroplasmy shift to direct base correction: mitochondrial genome editing for disease modeling and therapy.
    Yerin Chi, Sung-Ik Cho.
      Mitochondria are essential organelles that support cellular energy metabolism and contribute broadly to tissue homeostasis, stress responses, and disease pathophysiology. As the mitochondrial genome encodes core components of oxidative phosphorylation, genetic alterations in mitochondrial DNA (mtDNA) can profoundly affect cellular and tissue function. Nevertheless, compared with the nuclear genome, mtDNA remains difficult to interrogate and manipulate because of longstanding technical barriers to mitochondrial genome engineering. Consequently, many fundamental questions surrounding mtDNA biology remain unresolved, including the mechanisms governing heteroplasmy, mutationspecific disease phenotypes, tissue-dependent pathogenic thresholds, and long-term mtDNA population dynamics. These limitations are particularly evident in mitochondrial genetic diseases, which can cause severe neurological, muscular, cardiac, and visual phenotypes but for which only a limited number of genetically defined disease models are available. Recent advances in mitochondrial genome editing are beginning to overcome these barriers. In this review, we organize the field according to therapeutic strategy, from selective depletion of mutant genomes to direct base correction and emerging precision-editing architectures. Mitochondria-targeted zinc-finger nucleases, mitoTALENs, and mitoARCUS can selectively eliminate mutant mtDNA and shift heteroplasmy toward wild-type genomes, whereas DddAderived cytosine base editors, TALE-linked deaminases, strandselective mitochondrial base editors, and their engineered derivatives enable direct C·G-to-T·A or A·T-to-G·C conversion without programmed double-strand breaks. We evaluate these platforms in relation to mutation class, heteroplasmy level, sequence context, bystander and off-target editing, target tissue, delivery format, durability, and functional rescue. Beyond therapeutic correction, mitochondrial genome editors are opening new opportunities for disease modeling by enabling defined pathogenic variants to be introduced into cells, organoids, and animal models. Validated applications include human cell and organoid systems and genetically defined mouse rat models. Extension to larger animals and nonhuman primates remains a future direction for the disease-modeling framework discussed here. Clinical translation, however, remains constrained by cargo size, co-delivery requirements, unintended nuclear exposure, long-term mtDNA dynamics, and the need for efficient and tissue-specific delivery to clinically relevant organs and cell types. Finally, we propose a framework linking genotype, heteroplasmy, and tissue context to editor selection, with the goal of moving the field from measurements of editing efficiency toward mechanistic understanding and therapeutic relevance.
  3. Yale J Biol Med. 2026 Jun;99(2): 259-262
    Editors' Note: Gene Therapy and Rare Diseases Through the Ages: Stories of Science and Society.
    Amirreza Naderi, Anna Chriss.
      
    Keywords:  Gene Therapy; History of Medicine; Rare diseases
    DOI:  https://doi.org/10.59249/RTAW1482
  4. Adv Sci (Weinh). 2026 Oct 06. e78137
    Cellular Mechanisms Enabling Mitochondria Transfer and Transplantation.
    F Seyma Gokdemir, Yagmur Ozendi, Gokhan Burcin Kubat, Keshav K Singh.
      Mitochondrial transfer and transplantation (mitoTT) has emerged as an experimental and potentially transformative therapeutic strategy, drawing attention for its ability to modulate cellular bioenergetics, stress responses, and tissue repair. Endogenous mitochondrial transfer can occur through tunneling nanotubes, extracellular vesicles, cell fusion, gap junction-associated communication, and phagocytosis-like internalization. These routes differ substantially in distance, directionality, cargo integrity, regulatory control, and physiological relevance. Preclinical studies indicate that exogenous mitochondria may transiently improve bioenergetic function, attenuate oxidative stress, and support recovery in models of cardiac, skeletal muscle, and nervous system injury, whereas clinical evidence remains limited and heterogeneous. Broad clinical implementation remains constrained by unresolved biological and translational barriers. These include inefficient or poorly controlled uptake of extracellular mitochondria, uncertain long-term persistence, incomplete functional integration, donor-recipient incompatibility, mitochondrial-nuclear mismatch, heteroplasmy-related risks, immunogenicity, and the lack of standardized potency and delivery assays. Here, we critically synthesize the cellular mechanisms enabling mitoTT, emphasizing the checkpoints that determine whether transferred mitochondria are integrated, remodeled, immunologically sensed, or eliminated. We further discuss cristae biology and the mitochondrial contact site and cristae organizing system, mitochondrial nucleoid maintenance, mitochondrial DNA replication, organelle contact sites, and emerging bioengineering strategies required to move mitoTT from experimental rescue toward reproducible therapeutic application.
    Keywords:  cell metabolism; inter‐organelle contact sites; mitoTT; mitochondria; mitochondrial DNA; mitochondrial transfer; mitochondrial transplantation
    DOI:  https://doi.org/10.1002/advs.78137
  5. Neurol Neurochir Pol. 2026 Oct 05.
    Genetic insights into multiple sclerosis: exploring mitochondrial DNA and nuclear POLG gene variation in a Polish single-center RRMS cohort.
    Agnieszka Piotrowska-Nowak, Biruta Kierdaszuk, Ada M Dziedzicka, Magdalena Kaliszewska, Aleksandra Podlecka-Piętowska, Katarzyna Tońska.
       AIM OF THE STUDY: To evaluate the contribution of mitochondrial DNA (mtDNA) variation and four POLG mutations to disease susceptibility and course in Polish patients with relapsing-remitting multiple sclerosis (RRMS).
    CLINICAL RATIONALE FOR THE STUDY: Mitochondrial dysfunction is increasingly implicated in the pathogenesis of multiple sclerosis (MS), yet its precise role remains unclear. Determining the impact of mtDNA variation and POLG mutations may improve understanding of factors influencing disease onset and progression.
    MATERIAL AND METHODS: Whole mtDNA was sequenced in 100 RRMS patients using next-generation sequencing and compared with previously generated mtDNA data from 212 Polish individuals without MS. The presence of pathogenic variants, distribution of haplogroups, rare variants, and heteroplasmy were assessed. Absolute mtDNA copy number was measured by real-time PCR. Additionally, RRMS patients were screened for four common POLG mutations (p.Gly268Ala, p.Ala467Thr, p.Pro587Leu, and p.Trp748Ser).
    RESULTS: No pathogenic mtDNA variants or any of the four screened POLG variants were detected. No significant associations were found between major mtDNA haplogroups, copy number, heteroplasmy, or rare variants and MS risk or progression. Exploratory analyses identified nominal associations between several mtDNA variants and relapse occurrence, disability level, age at symptom onset, and sex in the RRMS cohort.
    CONCLUSIONS AND CLINICAL IMPLICATIONS: Pathogenic mtDNA variants, major haplogroups, mtDNA copy number, rare variant burden, and the four screened POLG variants do not appear to play a major role in RRMS susceptibility or clinical course in the analyzed cohort. Several associations involving individual mtDNA variants were identified, but these findings are exploratory and require independent replication in larger cohorts before their biological or clinical relevance can be established.
    Keywords:  EDSS; POLG gene; genetic variation; mitochondrial DNA; mitochondrial disorders; multiple sclerosis; relapses
    DOI:  https://doi.org/10.5603/pjnns.113007
  6. EMBO Mol Med. 2026 Oct 06.
    Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.
    Aftab Mohammed, Tavleen Kaur, Priyanka Panwar, Samanwita Ghosh, Hanif Ahmad, Sadananda Kumbhakar, Meltem Muftuoglu, Carlo Viscomi, Sagar Sengupta.
      POLGA, the catalytic subunit of the mitochondrial DNA polymerase, is essential for mitochondrial DNA (mtDNA) replication and maintenance. Mutations in POLGA cause progressive external ophthalmoplegia (PEO), but the underlying pathogenic mechanisms remain unclear. Here, we show that the mitochondrial E3 ligase MITOL hyperubiquitylates PEO-associated POLGA mutants at lysine 1060, triggering conformational changes and formation of insoluble aggregates that impair their mitochondrial import and consequently compromise mtDNA replication and mitochondrial homeostasis. To identify compounds that disrupt POLGA aggregates and restore mutant POLGA function, we screened an FDA/EMA/PMDA-approved drug library using a split-GFP system. We identified two clinically approved compounds, diltiazem hydrochloride (C1) and sulbactam (C4), that disrupted POLGA aggregates, prevented aberrant MITOL recognition, restored mitochondrial import, and rescued mtDNA replication and mitochondrial function. Importantly, treatment with either compound significantly improved motor performance in a knock-in mouse model carrying the disease-relevant A467T-equivalent POLGA mutation. These findings establish pathogenic aggregation as a previously underrecognized disease mechanism and demonstrate that disrupting POLGA aggregates with repurposed drugs can restore mitochondrial function in vivo, providing a potential therapeutic strategy for POLGA-associated mitochondrial disease.
    DOI:  https://doi.org/10.1038/s44321-026-00532-3
  7. Brain. 2026 Oct 07. pii: awag348. [Epub ahead of print]
    Mitochondrial DNA damage elicits PINK1 upregulation in pontine cholinergic neurons in Parkinson's disease.
    Huiwen Lu, Angela Pyle, Jannetta S Steyn, Conor Lawless, Rafiqul Hussain, Maria Falkenberg, Joanna L Elson, Ilse S Pienaar.
      In Parkinson's disease, cholinergic neurons of the pedunculopontine nucleus, located in the upper pons, undergo extensive degeneration, contributing to severe hypokinetic-motor and non-motor symptoms. We previously demonstrated that loss of these neurons is associated with mitochondrial dysfunction, driven by high mitochondrial DNA deletion burden. Increased mitochondrial DNA replication was also observed in these neurons, contrasting with reduced mitochondrial DNA copy number previously reported in Parkinson's-affected surviving nigral-dopaminergic neurons. Here, ultra-deep whole-genome sequencing combined with stringent quality control was used to characterise mitochondrial DNA alterations within single-cell pedunculopontine-cholinergic neurons isolated from Parkinson's-affected and neurologically-normal post-mortem specimens. Analyses included mitochondrial DNA deletion spectrum, -size distribution, genomic location, heteroplasmy levels, breakpoint classification, and point-mutation frequency. Thermodynamic modelling was used to investigate whether the stability of mitochondrial DNA secondary structures surrounding deletion breakpoints could provide insight into the mechanisms underlying mitochondrial DNA deletion formation in Parkinson's disease. In parallel, nuclear-encoded mitochondrial pathway responses were assessed using a customised single-cell multiplexed multi-target gene expression assay, comparing Parkinson's and control post-mortem neurons. Parkinson's-affected neurons exhibited substantial mitochondrial DNA damage, characterised by large-scale mitochondrial DNA deletions predominantly locating within mitochondrial DNA's major arc. Mitochondrial DNA deletions ranged ∼50-5,500 base-pairs, with most exceeding 1,000 base-pairs. Clonal expansion of large-scale mitochondrial DNA deletions, likely arising from replication-associated errors, represented the dominant mutant species. Small mitochondrial DNA deletions (<50bp) were rare, suggesting that free radical-induced strand breakage was not the primary driver of somatic mitochondrial DNA damage. Point-mutation frequency was similar between Parkinson's and control neurons but showed greater functional impact on electron transport chain complex-I subunits in Parkinsonian neurons. Thermodynamic modelling revealed reduced stability of mitochondrial DNA secondary structures flanking mitochondrial DNA deletion breakpoints in Parkinsonian post-mortem neurons, with an average decrease of ∼2 kJ/mol across two major mitochondrial DNA deletions formation models. The increased mitochondrial DNA damage was accompanied by marked upregulation of the nuclear-encoded mitophagy regulator PINK1, specifically in PD patients with extended survival, suggesting activation of a compensatory cytoprotective response. Together, these findings provide comprehensive single-cell resolution profiling of mitochondrial genomic alterations in pedunculopontine-cholinergic neurons in Parkinson's, displaying extensive mitochondrial DNA structural disruption dominated by large-scale mitochondrial DNA deletions. Our results further suggest that upregulation of mitophagy-related pathways may represent an adaptive mechanism to mitigate progressive mitochondrial genomic instability and preserve neuronal energy homeostasis.
    Keywords:  Parkinson’s disease; brainstem; cholinergic neurons; mitochondrial DNA; mitophagy; pedunculopontine nucleus
    DOI:  https://doi.org/10.1093/brain/awag348
  8. EMBO Mol Med. 2026 Oct 05.
    Ebselen restores mitochondrial function through metabolic rewiring in Barth syndrome and related mitochondrial diseases.
    Claire Almyre, Anne-Louise Cayer, Nolwenn Bounaix, Anaïs Hoarau, Marie-Alix Derieppe, Julie Martineau, Pierre Costet, Camille Charles, Mélody Dufossée, Cécile Duplaa, Jim Dompierre, Bénédicte Salin, Marc-Alexandre D'Elia, Corinne Blancard, Aurélie Massoni-Laporte, Stéphane Claverol, Caroline Tokarski, Yaser Hashem, Alexandre Favereaux, Yeranuhi Hovhannisyan, Juliette Jouhet, Cyrille Guimaraes, Jean-François Dumas, Olivier R Baris, Laetitia Dard, Jérémy Richard, Vanessa Bergeron, Naïg Gueguen, Valérie Desquiret-Dumas, Jordan Rivron, Douglas Strathdee, Carole H Sellem, Nathalie Bonnefoy, Laurent Monassier, Estelle Ayme-Dietrich, Onnik Agbulut, Stéphane Azoulay, Jean-Paul di Rago, Vincent Procaccio, François Godard, Déborah Tribouillard-Tanvier.
      Despite major advances in the genetic diagnosis of mitochondrial disorders, effective disease-modifying therapies remain scarce. Here, we identify ebselen (EBS) as a promising therapeutic candidate through a phenotypic drug screen in a yeast model of Barth syndrome, a cardiomyopathy caused by defective cardiolipin maturation. EBS improved oxidative phosphorylation-dependent growth across diverse fungal models of mitochondrial diseases, including defects in complex I, complex IV, mitochondrial DNA maintenance, mitochondrial translation, and ATP synthase. Therapeutic efficacy was further validated in patient-derived fibroblasts, iPSC-derived cardiomyocytes, and a cardiolipin-deficient mouse model. Mechanistically, EBS acts independently of its established antioxidant activity by engaging a conserved metabolic program that suppresses cytosolic translation while stimulating pyruvate dehydrogenase-dependent tricarboxylic acid cycle activity, thereby improving proteostasis and mitochondrial bioenergetic function. These effects are likely coordinated through lysosome-associated mTOR signaling, consistent with the localization of EBS to lysosomes and its colocalization with mTOR. Together, our findings identify a conserved mechanism for enhancing mitochondrial function and establish ebselen as a strong candidate for therapeutic repurposing in Barth syndrome and a broad spectrum of inherited mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s44321-026-00518-1
  9. Geroscience. 2026 Oct 09.
    Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.
    Salvatore Nesci, Cristina Algieri.
      Ageing is characterized by a progressive decline in mitochondrial integrity that extends beyond impaired energy production to include redox imbalance, defective quality control, altered organelle dynamics, and persistent inflammatory signalling. This review examines mitochondrial dysfunction as a mechanistic bridge linking bioenergetic failure to cellular senescence and inflammaging, two central features of biological ageing. We discuss how impaired oxidative phosphorylation, loss of mitochondrial membrane potential, increased electron leak, and excessive reactive oxygen species progressively damage mitochondrial DNA, proteins, and lipids, thereby amplifying organelle dysfunction and compromising cellular homeostasis. Particular emphasis is placed on the threshold effect of mitochondrial DNA mutations, whose age-dependent clonal expansion can drive respiratory chain deficiency in vulnerable tissues. We further analyze mitochondria as signalling platforms that integrate regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, and as sources of mitochondrial damage-associated molecular patterns promoting sterile inflammation. Finally, we highlight mitochondrial dysfunction-associated senescence as a central process through which persistent mitochondrial stress reshapes the senescence-associated secretory phenotype and reinforces inflammaging. Overall, the evidence supports a model in which dysfunctional mitochondria act as both initiators and amplifiers of senescence and inflammation, contributing to tissue degeneration and age-related functional decline. Understanding these interconnected mechanisms may help identify therapeutic strategies targeting mitochondrial bioenergetics, inflammatory signalling, and senescent cell burden in ageing.
    Keywords:  Ageing; Cell death; DAMPs; Inflammation; Mitochondria
    DOI:  https://doi.org/10.1007/s11357-026-02588-y
  10. BMJ. 2026 Oct 07. 395 e101004
    Rare diseases: NHS labs fail to share data vital for diagnosis and care, BMJ finds.
    Jennifer Richardson.
      
    DOI:  https://doi.org/10.1136/bmj-2026-101004
  11. Res Involv Engagem. 2026 Oct 09. pii: 167. [Epub ahead of print]12(1):
    Patient engagement in protocol development for rare disease clinical trials: a framework.
    Janella Beltran, Sarah Bolton, Pesh Patel, Rohita Sharma.
       BACKGROUND: Meaningful patient engagement requires understanding lived disease and healthcare experiences. This patient-centric approach is especially valuable when applied to the design and execution of clinical trials, as participation barriers may hinder trial recruitment, retention, and detection of meaningful outcomes. Patient engagement is particularly important in the study of treatments for rare diseases, where populations are small and geographically dispersed and there are few sites with relevant clinical expertise. Additionally, protocol amendments to address hurdles are expensive and can cause delays in trial activities, which can affect downstream regulatory approvals and access to treatments. Alexion, AstraZeneca Rare Disease, worked with patients and their stakeholders to identify points of additional trial burden and enable patient-driven changes before clinical trial protocol finalization.
    METHODS: Patients, parents of pediatric patients, and patient advocacy group representatives with diverse experiences participated in virtual, study-specific perspective exchange sessions on 4 protocols (adults with generalized myasthenia gravis, pediatric patients with generalized myasthenia gravis, adults with antibody-mediated rejection after kidney transplantation, and adults with transthyretin amyloid cardiomyopathy). Participants discussed their disease journey, the protocol, and perceived barriers to clinical trial awareness, enrollment, participation, and follow-up through semistructured interviews.
    RESULTS: Participants raised points about the eligibility criteria, study drug self-administration, visit frequency, participant mental health, and the relevance of specific outcome measures. In response, the study sponsor proactively changed the clinical trial protocols when feasible. Changes included expanding the eligibility criteria, developing an instructional video on self-administration of the study drug, and reducing the frequency of clinic visits. In addition, the sponsor created appreciation cards and trained trial sites on a standardized approach to help participants understand the goals of specific outcome measures.
    CONCLUSIONS: These insights led to demonstrable, advocate-recommended changes in rare disease clinical trial protocols before study delivery, underscoring how early patient-partnered drug development can be meaningfully applied to research in rare diseases.
    TRIAL REGISTRATION: NCT05556096, NCT06607627, NCT06744647, and NCT06183931.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Clinical trial; Patient perspective; Rare disease; Trial design
    DOI:  https://doi.org/10.1186/s40900-026-00985-3
  12. FASEB J. 2026 Oct 15. 40(19): e72346
    The Genetic and Epigenetic Mechanisms of mtDNA in Regulation of Inflammation and Metabolism.
    Yulin Zhang, Yanjiang Zheng, Hongyu Duan, Yifei Li.
      Mitochondria serve as the primary cellular powerhouses, generating ATP through oxidative phosphorylation (OXPHOS) to sustain essential cellular processes. Beyond energy production, mitochondria function as critical regulators of metabolic homeostasis, intracellular signaling networks, and programmed cell death pathways. The mitochondrial genome comprises 37 genes encoding 13 OXPHOS subunits, 22 transfer RNAs, and 2 ribosomal RNAs, all transcribed and translated within the organelle. Mitochondrial DNA integrity becomes compromised through diverse pathological stimuli, including metabolic dysregulation, oxidative stress, and inflammatory cascades, contributing to disease pathogenesis across multiple organ systems. This review synthesizes current knowledge on the multifaceted roles of mtDNA in health and disease. We propose a framework of three interconnected mechanisms through which mtDNA exerts its effects: (1) retrograde signaling to the nucleus, reprogramming nuclear gene expression; (2) cytosolic and extracellular release of mtDNA as a damage-associated molecular pattern (DAMP), activating innate immune pathways like cGAS-STING and NLRP3; and (3) intrinsic epigenetic modifications that directly modulate mitochondrial gene expression. We critically evaluate the evidence linking mtDNA alterations to a spectrum of diseases, including cancer, cardiovascular and metabolic disorders, neurodegeneration, and psychiatric conditions. We conclude that a comprehensive understanding of mtDNA's multifaceted nature, moving beyond its perception as a mere DAMP, is essential for translating mitochondrial biology into effective clinical interventions.
    Keywords:  diseases process; mitochondrial function; molecular mechanisms; mtDNA; pathophysiology
    DOI:  https://doi.org/10.1096/fj.202600927R
  13. Microbiol Spectr. 2026 Oct 09. e0194626
    Low-level of mitochondrial DNA alterations during direct-acting antiviral treatment in leukocytes of people who inject drugs living with HCV.
    Laetitia Gay, Clara Rapenne, Valérie Desquiret-Dumas, Roselyne Vallo, Quynh Bach Thi Nhu, Linh Le Thi Thuy, Huong Thi Duong, Binh Nguyen Thanh, Catherine Quillet, Hong Thi Tran, Thanh Nham Thi Tuyet, Oanh Khuat Thi Hai, Vinh Vu Hai, Khue Pham Minh, Nicolas Nagot, Didier Laureillard, Pascal Reynier, Jean-Pierre Molès.
      Direct-acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment, offering high cure rates and favorable safety profiles. However, concerns remain regarding their long-term mitochondrial safety, particularly among vulnerable populations such as people who inject drugs (PWID), who are frequently exposed to multiple mitotoxic agents. This longitudinal study investigated mitochondrial DNA (mtDNA) instability, including deletions and single-nucleotide variants, among PWID living with HCV during DAA treatment, using whole mitochondrial genome sequencing. We analyzed samples of 33 PWID living with HCV before treatment (baseline), at the end of treatment (week 12), and after long-term follow-up (week 48), in comparison with 30 HCV-seronegative PWID. Associations with clinical events were assessed during a 3-year follow-up after study completion. mtDNA deletions were detected in 9.1% of PWID living with HCV at baseline and increased to 19.2% post-treatment, whereas no mtDNA deletions were observed in HCV-seronegative PWID. Heteroplasmy levels (i.e., proportion of mutated to wild-type mtDNA) remained below 1%. Variants were widespread in both HCV-positive and HCV-seronegative PWID, predominantly in the non-coding D-loop region. A small number of low-heteroplasmy treatment-emergent variants were detected during follow-up, but none persisted at long-term follow-up. No significant associations were found between mtDNA instability and hepatic or splenic complications assessed at 3 years. These findings suggest that DAA exposure is associated with low-level mtDNA instability in blood leukocytes. Nonetheless, long-term mitochondrial surveillance is warranted, especially in post-mitotic tissues, to fully assess the implications of cumulative mitotoxic exposures in this high-risk population.
    IMPORTANCE: Direct-acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment, but their safety is still under debate. Given the nature of these regimens, mitochondrial genotoxicity could represent a potential off-target effect. We searched for mitochondrial DNA alterations in people who inject drugs living with HCV. The prevalence of HCV infection is high in this population, and any potential toxicity would be exacerbated as they are exposed to other mitotoxic drugs. We detected low-level mitochondrial DNA alterations in blood leukocytes, including a modest increase in mitochondrial DNA deletions, but these alterations remained at very low levels (below 1%) and were not associated with any clinical complications during 3 years of follow-up. These findings provide reassuring evidence regarding the short-term mitochondrial safety of DAA treatment in blood leukocytes while supporting the need for longer-term studies in post-mitotic tissues.
    CLINICAL TRIALS: This study is registered with Clinical Trial Registry as NCT03526939 and NCT03537196.
    Keywords:  HCV treatment; direct-acting antivirals; drug users; genotoxicity; mitochondria
    DOI:  https://doi.org/10.1128/spectrum.01946-26
  14. FEBS J. 2026 Oct 07.
    Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.
    Anamika Acharyya, Riddhiman Dhar.
      Mitochondrial DNA (mtDNA) copy number determines the functional state of mitochondria and thus, influences cellular energy production, growth, metabolism, and stress response. Variation in mtDNA copy number has been observed across many cancer types and has been linked to changes in gene expression. However, whether mtDNA copy number has any link to mutation accumulation in cancer is unknown. Further, how mtDNA copy number variation alters expression of cancer-associated pathways and thereby influences cancer progression remains unclear. Here, through an analysis of whole genome data in multiple cancer types, we show that mtDNA copy number increases with an increase in mutational load in cancer samples and the increase in mtDNA copy number bears a signature of compensation for mitochondrial function. We also show that the samples with low-mtDNA generally have increased expression of cancer-promoting genes, including genes involved in cell migration and epithelial-mesenchymal transition (EMT). Taken together, these results reveal a close association of mtDNA copy number with mutational load and disease progression in cancer. These findings provide a way forward toward a better understanding of the role of mtDNA copy number and mitochondrial functional state in cancer progression.
    Keywords:  MtDNA copy number; cancer progression; differential expression; epithelial–mesenchymal transition; multicancer analysis; mutational load
    DOI:  https://doi.org/10.1111/febs.70736
  15. Nat Rev Genet. 2026 Oct 05.
    Inheritance and selection of the mitochondrial genome.
    Qin Xie, Harry E Walker, Michal Minczuk, Marcos R Chiaratti, Patrick F Chinnery.
      The functioning mitochondrial genome is essential for cellular energy production. Being strictly maternally inherited and possessing limited DNA repair capacity, mitochondrial DNA (mtDNA) replication errors tend to accumulate over time. If left unchecked, these errors can accumulate through the female germline over successive generations, potentially leading to species extinction. However, this outcome is not observed in most species, including humans, which implies the existence of mechanisms that counteract the progressive accumulation of deleterious mtDNA mutations. Recent technological advances are building a deeper understanding of the processes that preserve mtDNA integrity, including the molecular and cellular basis and timing of purifying selection. This new knowledge helps to explain how mtDNA can change rapidly over just a few generations, whilst remaining compatible with the independently inherited, evolving nuclear genome.
    DOI:  https://doi.org/10.1038/s41576-026-01019-0
  16. J Community Genet. 2026 Oct 08. pii: 116. [Epub ahead of print]17(5):
    Rare diseases, body, and stigma: a comparative analysis of people living with berardinelli syndrome and Machado-Joseph disease in Brazil.
    Waleska Aureliano, Carlos Guilherme Octaviano do Valle, Jociara Nóbrega.
       OBJECTIVES: This article analyses how people living with rare diseases are stigmatised due to physical features and bodily alterations, considering the moral dimensions through which these differences are read. The analysis draws on research conducted in two regions of Brazil (Northeast and Southeast) with people affected by two hereditary rare conditions: Berardinelli Syndrome (BS) and Machado-Joseph Disease (MJD). We selected these conditions because of their significant bodily transformations: BS is present from birth, whereas MJD emerges in adulthood. This enabled us to examine how stigma is managed within families across the life course and identify who, beyond those directly affected, experiences its impacts.
    METHODS: The article draws on data from two research projects conducted at different times. Both involved ethnographic fieldwork in hospitals and public events organised by patient associations, as well as in-depth interviews with patients and family members. Materials were analysed through narrative analysis.
    RESULTS AND DISCUSSION: Our analysis was guided by three lines of inquiry concerning the construction and perception of stigma among people living with BS and MJD: (1) recognition of the first symptoms and lay interpretations of illness, leading to encounters with genetic explanations for its causation; (2) experiences of stigma through the interplay between bodily changes and gender expectations in the context of rare disease; and (3) health activism as a mechanism for coping with stigma.
    FINDINGS: Our findings reveal how the intersection of body, stigma, and identity produces moral readings of people living with rare diseases, based on the social interpretation of bodily changes brought about by these conditions.
    Keywords:  Berardinelli syndrome; Machado-Joseph Disease; Rare diseases; Stigma
    DOI:  https://doi.org/10.1007/s12687-026-00950-3
  17. Mol Genet Metab. 2026 Sep 26. pii: S1096-7192(26)00561-5. [Epub ahead of print]149(3): 110278
    Hyperinflammatory syndromes in primary mitochondrial disease: A three-center case series and focused review.
    Dan R Brooks, Eliza Gordon-Lipkin, Ibrahim Elsharkawi, Shannon Kruk, Madeleine Hesselgesser, Christine Eng, Weimin Bi, Lisa Emrick, Kristen S Fisher, Peter J McGuire, Fernando Scaglia.
       INTRODUCTION: Primary mitochondrial diseases (PMtD) are increasingly recognized to involve clinically meaningful immune dysregulation in addition to bioenergetic failure. Hyperinflammatory syndromes, including secondary hemophagocytic lymphohistiocytosis (HLH) and related cytokine-mediated inflammatory states, remain underrecognized complications of PMtD, and the mechanisms linking mitochondrial dysfunction to pathologic inflammation are incompletely understood.
    METHODS: We report three individuals with genetically confirmed PMtD evaluated at three academic medical centers who developed severe hyperinflammatory syndromes. Clinical, laboratory, treatment, and outcome data were retrospectively abstracted from the medical record using a standardized framework. We also performed a focused narrative review of the literature on hyperinflammation in mitochondrial disease.
    RESULTS: Individual 1 had pyruvate dehydrogenase complex deficiency (PDCD), due to a PDHA1 variant and developed infection-associated HLH at age 9 years, with ferritin 17,203 ng/mL and bone marrow hemophagocytosis. He met 6 of 8 HLH-2004 criteria and had an HScore of 303 (>99% probability of HLH). He survived the index episode with corticosteroid-based therapy but experienced recurrent inflammatory decompensations and later died. Individual 2 had POLG-related mitochondrial disease and developed HLH at age 8 years during presumed viral-triggered neurologic deterioration in the setting of pre-existing hepatic vulnerability. He met 6 of 8 HLH-2004 criteria, had an HScore of 233 (>98% probability of HLH), and showed an initial biomarker response to emapalumab, but ultimately died of multiorgan failure. Individual 3 had MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; due to an m.3243 A>G variant in MT-TL1 and developed a sterile interferon (IFN)-driven hyperinflammatory syndrome during a stroke-like episode (SLE), with markedly elevated serum soluble interleukin (IL)-2 receptor (sIL-2R), IL-6, IL-10, C-X-C motif chemokine ligand 9 (CXCL9), and cerebrospinal fluid (CSF) neopterin, without meeting full HLH-2004 criteria (fulfilling only 2/8 criteria). He had minimal response to intravenous immunoglobulin (IVIg) but showed sustained clinical and biomarker improvement with anakinra and is alive, age 15 years at the time of this publication.
    CONCLUSIONS: PMtD may be associated with a predisposition to a spectrum of hyperinflammatory syndromes ranging from classic secondary HLH to noncanonical sterile cytokine-mediated inflammation that falls below formal HLH thresholds. These complications may reflect mitochondrial danger signaling, inflammasome activation, engagement of the IFN pathway, and defective immunometabolic regulation. Early recognition and targeted immunomodulatory therapy may be critical to improving outcomes.
    Keywords:  Anakinra; Hemophagocytic lymphohistiocytosis; Hyperinflammation; MELAS; MT-TL1; Mitochondrial disease; PDHA1; POLG; Sterile interferon-driven hyperinflammation; cGAS-STING
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110278
  18. Orphanet J Rare Dis. 2026 Oct 06. pii: 353. [Epub ahead of print]21(1):
    Lower mitochondrial DNA copy number in ATTRV50M Swedish carriers.
    Gabriella Johannson, Malin Olsson, Marina Rubio Garcia, Anders Olofsson, Intissar Anan.
       BACKGROUND: Hereditary transthyretin (TTR) amyloidosis caused by TTR p.Val50Met (ATTRV50M) is a progressive systemic disease caused by misfolding of the protein transthyretin (TTR). The conversion of TTR into an amyloidogenic state has recently been found to be strongly influenced by a non-native disulfide bond, thus also a redox environment. Variation in mitochondrial DNA (mtDNA) copy number serves as an indirect marker of redox imbalance and mitochondrial dysfunction. MtDNA is moreover strictly maternally inherited, supporting previous findings where maternal inheritance of the pathogenic variant also results in both a more severe disease and an earlier onset. Considering these aspects, we aimed to investigate mtDNA levels in Swedish TTRp.Val50Met carriers.
    METHODS: 304 individuals were divided into three groups: symptomatic and asymptomatic TTR p.Val50Met carriers, and healthy non-carrier controls. Relative mtDNA copy number was quantified from buffy coat samples using multiplex qPCR.
    RESULTS: Symptomatic TTR p.Val50Met carriers showed a significantly lower copy number (p = 0.002) compared to the asymptomatic carriers. When stratified by sex, a significantly lower mtDNA copy number in symptomatic compared to asymptomatic carriers was observed only among males (p = 0.028). Furthermore, a significant difference in copy number (< 0.001) could be demonstrated in ≥ 50 year-olds (considered late onset in Swedish ATTRV50M population) betweensymptomatic and asymptomatic TTR p.Val50Met carriers, which could not be seen in < 50 year-olds (Swedish early onset).
    CONCLUSION: These findings indicate an association between lower mtDNA copy numbers and symptomatic disease in Swedish TTR p.Val50Met carriers, suggesting potential mitochondrial involvement in disease progression.
    Keywords:  ATTR; Amyloidosis; Hereditary; Mitochondrial DNA copy number; Oxidative stress; Sweden; Transthyretin; V30M; V50M; qPCR
    DOI:  https://doi.org/10.1186/s13023-026-04645-3
  19. bioRxiv. 2026 Aug 13. pii: 2026.08.12.744280. [Epub ahead of print]
    Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) compromise ETC activity and impair oxidative phosphorylation. Since eukaryotic cells contain multiple copies of mtDNA, the resulting phenotype depends on the proportion of mutant mitochondrial genomes (the heteroplasmy level). Using isogenic cell lines carrying similar mtDNA deletions, a linear decline in cellular respiration was observed as mitochondrial DNA heteroplasmy increased. Despite this, cellular redox imbalance did not change until heteroplasmy exceeded 50%. As heteroplasmy increased past 70%, cells also exhibited an integrated stress response (ISR) and impaired translation was observed. These defects were reversed by either addition of asparagine or overexpression of pyruvate carboxylase (PC). The dependence on exogenous asparagine in other respiration-deficient cells was found to correlate inversely with the PC expression level. For example, patient-derived thyroid tumor cells, harboring high heteroplasmy for a Complex I mtDNA mutation and low levels of PC, exhibited asparagine auxotrophy, and L-asparaginase treatment suppressed tumor growth. Together, these findings demonstrate a role for mitochondrial pyruvate carboxylase in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.64898/2026.08.12.744280
  20. Front Nutr. 2026 ;13 1865556
    Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.
    Wu Zhang.
      Aging and neurodegenerative disorders (NDDs) are intricately linked to a gradual deterioration in nicotinamide adenine dinucleotide (NAD+) metabolism, compromised mitochondrial functionality, persistent inflammation, and modified gut-brain interactions. Derivatives of vitamin B3, such as niacin, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide, have been identified as pivotal NAD+ precursors that possess the potential to support cellular bioenergetic processes and modulate pathways associated with brain aging. Evidence from preclinical studies and emerging clinical investigations suggests that NAD+-enhancing interventions may improve mitochondrial function and modulate neuroinflammatory pathways, thereby supporting cellular processes involved in synaptic plasticity and cognitive function; however, their long-term efficacy and clinical relevance in NDDs remain to be fully established. Concurrently, physical exercise serves as a robust physiological stimulus that augments NAD+ biosynthesis, modulates hypoxia-inducible factor-1α-dependent adaptive responses, fosters neurotrophic signaling, and enhances both vascular and metabolic health of the brain. Furthermore, emerging evidence suggests that the gut microbiota directly contributes to NAD+ homeostasis by regulating vitamin B3 precursor availability, tryptophan metabolism, and host metabolic signaling, while also influencing the efficacy of NAD+-enhancing interventions, thereby affecting systemic inflammation, metabolic equilibrium, and the production of neuroactive metabolites. Collectively, the interaction among vitamin B3 supplementation, physical activity, and gut microbiota may represent a promising framework for investigating strategies aimed at supporting cognitive health and brain resilience during aging, although definitive therapeutic applications require further validation. This review integrates current molecular, preclinical, and clinical evidence to establish mechanistic links between NAD+ metabolism, brain aging, cognitive dysfunction, and neurodegeneration, while emphasizing current limitations and future translational challenges associated with combining vitamin B3 metabolites, exercise, and microbiome-targeted approaches.
    Keywords:  NAD+ repletion; brain aging; exercise; gut microbiome dynamics; neurodegenerative disease; vitamin B3 metabolites
    DOI:  https://doi.org/10.3389/fnut.2026.1865556
  21. J Cell Physiol. 2026 Oct;241(10): e70241
    Sestrin1 Ameliorates Senescence and Mediates the Protective Effects of Exercise Against Hepatic Abnormality in C57BL/6J Mice.
    Xuege Yang, Yuchen Zou, Xiuru Li, Zhili Rong, Yanmei Niu, Li Fu.
      Liver aging is characterized by structural remodeling and functional decline, frequently driven by mitochondrial dysfunction and senescence-associated secretory phenotype (SASP). Sestrins (SESNs) are a family of stress-inducible proteins, among which Sestrin1 and Sestrin2 are crucial for maintaining metabolic and redox homeostasis, yet their specific involvement in hepatic senescence remains unclear. In the present study, in vivo experiments were performed using WT mice at young, middle, and old ages, together with aged Sestrin1-/- and Sestrin2-/- mice. The aged mice displayed multifaceted hepatic dysfunction, accompanied by a progressive, age-dependent decline of hepatic Sestrin1 and Sestrin2 expression. Intriguingly, hepatic cellular senescence, lipid deposition, oxidative stress and inflammation were significantly exacerbated in Sestrin1-/- mice compared to Sestrin2-/- and WT mice. To further explore the underlying mechanism, senescent AML12 cells overexpressing Sestrin1 were treated with or without mitochondrial division inhibitor-1 (Mdivi-1). Mechanistically, Sestrin1 preserved mitochondrial homeostasis by promoting mitochondrial fission via dynamin-related protein 1 (Drp1), a master regulator of mitochondrial fission, and curtailing the leakage of mitochondrial DNA (mtDNA) into the cytoplasm, profoundly suppressing the cGAS-STING pathway. However, these effects were abolished upon mitochondrial fission inhibition. Given that exercise training is a potent anti-aging strategy known to upregulate SESNs protein levels, we further demonstrated that Sestrin1 is indispensable for its hepatoprotective benefits. Collectively, our results identified that the Sestrin1/Drp1/cGAS-STING axis plays a pivotal role in liver aging and positioned Sestrin1 as a vital therapeutic target, serving as a key mediator of the anti-aging benefits of exercise training.
    Keywords:  Drp1; Sestrin1; cGAS/STING; exercise training; hepatic senescence; mitochondrial dysfunction; mtDNA
    DOI:  https://doi.org/10.1002/jcp.70241
  22. Eur J Pediatr. 2026 Oct 06. pii: 808. [Epub ahead of print]185(11):
    Paediatric biobanking in the era of precision medicine: ethical, regulatory, and scientific challenges from childhood to adulthood.
    Celeste Cagnazzo, Ivana Ferrero, Katia Mareschi, Franca Fagioli.
      Biobanks are increasingly central to precision medicine, particularly in rare diseases and paediatric oncology, where small and molecularly heterogeneous populations make access to high-quality, longitudinally annotated biological material essential. This narrative review examines the scientific value of paediatric biobanking and the ethical, regulatory, and organisational challenges that distinguish it from adult biobanking. Relevant scientific literature, European and Italian regulatory sources, international biobanking standards, and guidance on data protection and research governance were narratively reviewed, with particular attention to paediatric oncology, rare diseases, consent and assent, secondary use, interoperability, and emerging European frameworks. Paediatric biobanks can support biomarker discovery, molecular stratification, investigation of treatment resistance, and future analyses not foreseeable at the time of collection. Their governance is complicated by evolving child autonomy, the significance of dissent, transition to adulthood, future reuse of samples, and the distinction between consent to sample donation and the legal basis for processing associated personal data. Quality management, traceability, interoperable metadata, and controlled access are essential to preserve scientific utility. Emerging frameworks, including the European Health Data Space and EDPB guidance, favour a shift from one-time consent towards accountable life-cycle governance.
    CONCLUSION:  Paediatric biobanking should be conceived as a longitudinal research infrastructure rather than a storage activity. Sustainable models must integrate evolving autonomy, robust ethical oversight, data protection, quality, interoperability, and responsible secondary use while preserving irreplaceable biological resources for future research.
    WHAT IS KNOWN: • Biobanks are essential to precision medicine and are particularly valuable in rare diseases and paediatric cancer. • Paediatric biobanking raises specific issues concerning parental consent, assent, future use, and transition to adulthood.
    WHAT IS NEW: • Emerging European frameworks support a shift from static consent towards accountable life-cycle governance of samples and data. • A European paediatric sample-data continuum could connect biospecimens, longitudinal clinical information, omics data, and evolving participant preferences across infrastructures.
    Keywords:  Assent; Biobank; Informed consent; Paediatric oncology; Paediatrics; Precision medicine; Rare diseases; Secondary use
    DOI:  https://doi.org/10.1007/s00431-026-07475-4
  23. Med Oncol. 2026 Oct 08. pii: 309. [Epub ahead of print]43(11):
    Cancer-associated mitochondrial homeostasis disrupted and retrograde signaling activated.
    Pinya Liu, Zihan Wang, Shuhua Xi, Yue Wang.
      This review discusses mitochondrial homeostasis disrupted and retrograde signaling activated in oncogenesis and cancer progression. We summarize mitochondrial alterations and dysfunction in cancer, including mitochondrial DNA mutations, copy number alterations, dynamics changes and abnormalities of mitochondria enzymes in cancer. Furthermore, we discuss the findings on the main molecular mechanisms and roles of mitochondrial retrograde signaling pathways networks, such as reactive oxygen species (ROS), unfolded protein response (mtUPR), calcium and other retrograde signaling on cancer progression. Dysfunctional mitochondria induced retrograde signaling can lead to changes in gene expression. Tumor cells intimidate mitochondrial regulatory pathways to support tumor growth. Looking forward, we highlight critical knowledge gaps, including the need to decipher the spatiotemporal dynamics of retrograde signals, the context‑dependent dual roles of mitochondrial stress responses, and the integration of multi‑omics data to identify predictive biomarkers. We also discuss emerging therapeutic strategies that target mitochondrial retrograde signaling, such as small‑molecule modulators of mitochondrial calcium uniporter, ROS‑scavenging nanomedicines, and combination regimens with immune checkpoint inhibitors. Mitochondrial retrograde signaling might be served as a potential target for new therapeutic interventions in cancers, and future research should focus on translating these mechanistic insights into clinically actionable approaches.
    Keywords:  Calcium; Cancer; Mitochondrial dysfunction; Retrograde signaling; Unfolded protein response
    DOI:  https://doi.org/10.1007/s12032-026-03405-4
  24. Postepy Biochem. 2026 10 06. 72(3): 187-200
    The mitochondrial Na⁺/Ca²⁺ exchanger NCLX in calcium homeostasis and disease pathophysiology: mechanisms, controversies and research perspectives
    Katarzyna Romaniuk.
      Mitochondrial calcium homeostasis is an important regulator of bioenergetics, redox balance and cell survival. This review discusses the structure, regulation and pathophysiological significance of the mitochondrial Na⁺/Ca²⁺ exchanger NCLX, encoded by the SLC8B1 gene. Particular attention is paid to the role of NCLX in Ca²⁺ efflux from the mitochondrial matrix, integration of Na⁺–Ca²⁺–ROS signaling, and cellular responses to metabolic stress, hypoxia and mitochondrial injury. The available data indicate that NCLX dysfunction contributes to the pathophysiology of neurodegenerative, cardiovascular, metabolic, inflammatory and neoplastic diseases. However, the function of this transporter strongly depends on cell type, duration of stress and the degree of mitochondrial Ca²⁺ overload. Therefore, NCLX should be considered a regulator of mitochondrial function whose diagnostic, prognostic and therapeutic relevance requires further validation in experimental and clinical studies.
    DOI:  https://doi.org/10.18388/kyvc2c25
  25. Chronic Illn. 2026 Oct 09. 17423953261491392
    Understanding barriers to quality healthcare in rare diseases.
    Ariane Quintal, Élissa Hotte, Annie-Danielle Grenier, Caroline Hébert, Isabelle Carreau, Yves Berthiaume, Eric Racine.
      ObjectivesWe aimed to (1) understand barriers to quality healthcare and services in the context of rare diseases and (2) identify the multifaceted impacts of these barriers on rare disease patients.MethodsSemi-structured interviews exploring barriers to optimal rare disease care, the impacts of these barriers, empowerment strategies used, and recommendations. The Ten New Rules to Redesign and Improve Care Framework proposed by the Committee on Quality of Health Care in America of the US Institute of Medicine (2001) guided content analysis.ResultsTwelve individuals living with different rare diseases were interviewed. Numerous pertinent barriers were reported. For example, 'care based on continuous healing relationships' (rule 1) is impacted by very long delays in obtaining diagnoses. Patient abandonment and lack of follow-up are also experienced because of the perplexing nature of rare diseases. Regarding 'the patient as the source of control' (rule 3), the rationality of patients is questioned, including claims of malingering and misunderstandings about their unusual experiences. These barriers have multifaceted impacts such as strong negative affect and estrangement from mainstream healthcare.DiscussionThere is a clear and pressing need to improve the quality of care for people living with rare diseases, in alignment with major clinical recommendations.
    Keywords:  Rare diseases; ethics; patient preferences; qualitative research; quality of care
    DOI:  https://doi.org/10.1177/17423953261491392
  26. Biogerontology. 2026 Oct 03. pii: 171. [Epub ahead of print]27(5):
    Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.
    Yapei Zhang, Jianing Zhu, Lifan Cui, Sirong Chen, Xin Li, Liwenqin Gao, Xin Chen, Kaizhi Wen, Binbin Zeng, Yayun Qian.
      In addition to cell cycle arrest, cellular senescence is characterized by disrupted mitochondrial homeostasis, development of the senescence-associated secretory phenotype (SASP), and alterations in the immune microenvironment. Mitochondrial membrane damage, disrupted mitochondrial dynamics, and impaired mitochondrial quality control (MQC) can occur during cellular senescence. These changes may cause mitochondrial DNA (mtDNA) to leak abnormally into the cytosol. Cytosolic mtDNA can then activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Unlike the acute innate immune response elicited by pathogen-derived DNA, cGAS-STING signaling in senescent cells is mainly activated by the aberrant cytosolic accumulation of endogenous DNA. This signaling activates the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) axis and induces a type I interferon response. It also promotes nuclear factor kappaB (NF-κB)-mediated inflammatory transcription, sustains the SASP, and modulates paracrine signaling and immune cell function. This review focuses on mitochondrial structural damage, mtDNA release, and impaired MQC. It summarizes the mechanisms that activate the mtDNA-cGAS-STING axis during cellular senescence and examines its functional changes. It also discusses the potential development of senescence-associated biomarkers. Current evidence suggests that this signaling axis mainly contributes to the maintenance and amplification of the inflammatory senescence phenotype. It is unlikely to independently determine the onset of cellular senescence. Its effects are highly dependent on cell type and pathological context, while assay standards, causal relationships, and therapeutic windows require further clarification.
    Keywords:  CGAS-STING; Cellular senescence; Immunomodulation; Inflammatory senescence; Mitochondrial DNA; SASP
    DOI:  https://doi.org/10.1007/s10522-026-10515-z
  27. bioRxiv. 2026 Aug 11. pii: 2026.08.10.743968. [Epub ahead of print]
    Djp1 is a multifunctional Hsp40 cochaperone for mitochondrial phospholipid metabolism.
    Rashima Prem, Alex Maya-Romero, Chi Xie, Zach Irwin, Bradley Wagaman, Pingdewinde N Sam, Salloni Gill, Ketaki Nirbhavane, Mackenzie T Primrose, Kevin Whited, Steven M Claypool.
      Mitochondria are cellular energy hubs best known for ATP production via oxidative phosphorylation; however, they also serve as biosynthetic centers for phospholipids. Mitochondrial phospholipids are critical for various cellular processes, and their loss underlies myriad mitochondrial diseases. The critical enzymes underlying these biosynthetic cascades are encoded in the nucleus, translated in the cytosol, and imported into mitochondria. Understanding of mechanisms and factors that ensure precise targeting of proteins to mitochondria has been long overlooked but remains critical. Recently, the J-protein/Hsp40 cochaperone Djp1 has emerged as a key player in mitochondrial protein targeting by promoting the transfer of precursors from the endoplasmic reticulum (ER) surface to mitochondria in a pathway termed ER-SURF. Molecular details regarding how Djp1 recognizes clients and more broadly supports mitochondrial function remain unknown. Using biochemical approaches, proteomics, and thin layer chromatography, we demonstrate that Djp1 is a regulator of Phosphatidylserine decarboxylase 1 (Psd1), an inner mitochondrial membrane resident responsible for mitochondrial phosphatidylethanolamine (PE) production. This regulation of Psd1 biogenesis is dependent on its mitochondrial targeting signal and is specific to Djp1 compared to other members of the Hsp40 family or ER targeting factors. Intriguingly, the combined loss of Djp1 and Psd1 results in a synthetic sick phenotype that unexpectedly reflects a role(s) for Djp1 in proper mitochondrial phospholipid metabolism independent of Psd1. Taken together, these findings expand our understanding of Djp1-dependent mitochondrial protein regulation and unveil Djp1 as important for mitochondrial phospholipid metabolism by multiple mechanisms.
    DOI:  https://doi.org/10.64898/2026.08.10.743968
  28. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 08. 1-3
    Harmonizing ALS research data across multimodal data sets using the OMOP Common Data Model.
    Brandon Jernigan, Hannah L Walters, Diane Corey, Albert Garcia, Alan Premasiri, William T Roddy, Dillon Shearer, Terri G Thompson, Jason Tucker, Fernando Vieira, Danielle Boyce.
      Three nonprofit organizations-ALS Therapy Development Institute (ALS TDI), Answer ALS, and the Critical Path Institute (C-Path)-collaborated to harmonize distinct ALS research datasets using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). This effort was designed to make otherwise separate ALS resources more comparable, enabling larger and more informative cross-cohort analyses. The teams coordinated vocabulary mapping, identified OMOP vocabulary gaps, and submitted new concepts to the Observational Health Data Science and Informatics (OHDSI) community for approval. Harmonized data from ALS TDI and Answer ALS were merged in the Neuromine data portal, while their clinical and digital health technology (DHT) datasets are also available through C-Path's Rare Disease Cures Accelerator-Data Analytics Platform (RDCA-DAP). This collaboration aligns with current regulatory priorities for data sharing and offers a model for harmonizing rare disease data. A robust, public GitHub repository was established to share real-time updates with the ALS research community.
    Keywords:  ALS; Act for ALS; OMOP; data harmonization; digital health technology
    DOI:  https://doi.org/10.1080/21678421.2026.2738533
  29. Mol Genet Genomic Med. 2026 Oct;14(10): e70300
    Building Sustainable Patient Involvement in Rare Condition Research.
    Dani Bancroft, Natasha Ratcliffe, Amy Hunter.
      An overview of the structural and cultural barriers to patient and public involvement and engagement (PPIE) in academic research, which are amplified in rare condition research, with recommendations on how to address them and reflections from patient, researcher and funder perspectives.
    DOI:  https://doi.org/10.1002/mgg3.70300
  30. Free Radic Biol Med. 2026 Oct 05. pii: S0891-5849(26)01189-5. [Epub ahead of print]
    Nucleotide stress in chronic inflammatory memory: Mitochondrial DNA damage and NAD+-dependent PARP1 chromatin dynamics.
    Xie Han, Ling Wu, JiaKuo Li, WeiTing Zu, Mei Zhao.
      Chronic sterile inflammation can persist after the initiating stressor has subsided, indicating that resolution failure may involve more than continued cytokine signaling. We propose that nucleotide stress, defined here as disruption of cellular NAD+ availability together with altered dNTP/rNTP homeostasis, can couple mitochondrial damage to persistent inflammatory priming. Mitochondrial superoxide (O2•-) is converted to hydrogen peroxide (H2O2), which can support metal-catalyzed formation of hydroxyl radicals (•OH), whereas O2•- can also react with nitric oxide to form peroxynitrite. These chemistries can produce oxidative base modifications such as 8-oxo-7,8-dihydro-2'-deoxyguanosine, while abasic sites and strand discontinuities represent chemically distinct lesion classes; altered nucleotide ratios can add a separate burden through ribonucleotide incorporation into mtDNA. We emphasize that mtDNA copy number, subcellular localization, and chemical lesion burden are different variables and should not be used interchangeably. Mislocalized mtDNA can engage cGAS-STING and other DNA-sensing pathways, while NLRP3 can respond to mitochondrial damage and oxidized mtDNA in defined contexts. In the nucleus, PARP1 requires NAD+ for productive PARylation during the DNA-damage response. We hypothesize that sustained but non-catastrophic NAD+ limitation may alter the lifetime of selected DNA-bound PARP1 states and delay post-repair nucleosome restoration. This is a central, unproven kinetic prediction and is not equivalent to pharmacological PARP trapping. We position the NCI framework as a complementary resolution-failure hypothesis rather than a universal model of trained immunity. We outline analytical safeguards, evidence boundaries, and longitudinal withdrawal-rechallenge experiments that can test whether correcting nucleotide stress produces durable chromatin and inflammatory resetting rather than transient suppression.
    Keywords:  8-oxo-dG; NAD(+); NLRP3 inflammasome; PARP1; cGAS-STING; chromatin restoration; inflammatory memory; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.007
  31. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2618654123
    A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.
    Hong Wang, Eizo Marutani, Luca Zazzeron, Marissa Menard, Laura Volpicelli-Daley, Fumito Ichinose, Vamsi K Mootha.
      A growing body of preclinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for rare and common diseases. However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, "hypoxia-in-a-pill" combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2α inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis. Although this small-molecule regimen extended the lifespan of the Ndufs4 knockout (KO) mouse model of mitochondrial complex I deficiency and Leigh syndrome, its efficacy did not match chronic 11% FIO2. Here we optimize this regimen using GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, and show it rescues key neurodegenerative phenotypes in multiple models. When we initiate therapy in 50 d old Ndufs4 KO mice with advanced disease, GBT601 monotherapy alleviated neurological disease phenotypes and extended median lifespan from 62 to 105 d, while dual therapy with the GBT601/PT2399 combination extended median lifespan to 158 d. When initiated after onset of advanced disease in a mouse model of Friedreich's ataxia, the combination halted further progression of motor phenotypes. In a mouse model of Parkinson's disease due to α-synuclein toxicity, initiating the GBT601/PT2399 combination after onset of motor dysfunction attenuates brain hyperoxia and lipid peroxidation and reverses motor phenotypes. Importantly, the combination maintained body weight without inducing any signs of pulmonary hypertension. Our findings motivate further preclinical and clinical evaluation of our "hypoxia in a pill" approach for diseases with high unmet need.
    Keywords:  HIF-2α; hemoglobin; hyperoxia; hypoxia; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.2618654123
  32. Medicine (Baltimore). 2026 Oct 09. 105(41): e51103
    Mapping mitochondria-associated research in inflammatory bowel disease: A bibliometric and network analysis.
    Houshu Tu, Menglin Chen, Panpan Zhu, Jing Hong, Ling He.
       BACKGROUND: Mitochondria-associated research has become increasingly prominent in inflammatory bowel disease (IBD), but its publication growth, collaboration structure, knowledge base, and thematic evolution have not been comprehensively quantified.
    METHODS: Web of Science Core Collection records published from 2010 through 2025 were retrieved on September 19, 2025. Of 215 candidate records, 112 met prespecified eligibility criteria. The 111 records with complete Full Record and Cited References metadata were used for primary analyses; 1 additional eligible record was included only in an annual-output sensitivity analysis. Bibliometrix/Biblioshiny, VOSviewer 1.6.20, and R were used for descriptive, network, temporal, and robustness analyses.
    RESULTS: Annual output increased significantly (Kendall τ = 0.638, P = .0009; Sen slope = 1.20 publications/year, 95% confidence interval 0.50-1.71), whereas annualized citation impact showed no significant monotonic trend after exclusion of 2025 (Spearman ρ = 0.093, P = .742). China led corresponding-author output (39 articles), while the United States had the highest aggregate citation count (985). Multi-country publications accounted for 35 of 111 articles (31.5%). The largest institutional collaboration component contained 53 organizations in 8 clusters, and the author component contained 15 authors in 2 clusters. The primary author-keyword network included 22 terms, 6 clusters, 90 links, and a total link strength of 181. Mitophagy, mitochondrial dynamics, and machine learning were positioned toward the recent end of the temporal spectrum. Cited-source and cited-reference networks were densely interconnected, indicating a shared multidisciplinary knowledge base.
    CONCLUSION: Mitochondria-associated IBD research expanded substantially during 2010 to 2025, with concentrated geographic leadership, recurrent but uneven international collaboration, and overlapping themes spanning inflammation, epithelial biology, metabolism, mitochondrial quality control, and host-microbiome interactions. The findings provide a reproducible map of the literature but should not be interpreted as evidence of biological causality or discrete mechanistic pathways.
    Keywords:  bibliometric analysis; inflammatory bowel disease; mitochondria; mitochondrial dysfunction; mitophagy; research collaboration; science mapping
    DOI:  https://doi.org/10.1097/MD.0000000000051103
  33. Clin Lab. 2026 Oct 01. 72(10): 2164-2178
    A Novel GNN-Bi-LSTM Framework with Attention Mechanism for Detecting Rare Genetic Disorders.
    Osama R Shahin, Raed N Alabdali, Mohamed N Ibrahim, Wael Alzahrani, Eman Fawzy El Azab, Eman Elsayed Bauomey Mohamed.
       BACKGROUND: The growing population in the world and inadequate health care guidelines have caused the onset of sporadic genetic disorders that need effective diagnostic and prognostic methods. However, the existing systems cannot handle the multisystem nature of genetic information resulting in delays of formal identification and therapeutic procedures.
    METHODS: The proposed study aims at proposing a more reliable model, GNN-Bi-LSTM-AM, that incorporates Graph Neural Networks (GNN), Bi-LSTM, and attention module to improve the process of identifying and diagnosing rare genetic disorders (RGDs). In this model, GNN is used to describe the genetic factors' associations with other factors, whereas Bi-LSTM models the health data over time. The attention mechanism puts emphasis on sig-nificant genetic markers, which improves predictive ability and minimizes interpretation challenges. The framework makes use of complex data such as maternal health history and parental genetic inheritance. In particular, the GNN learns the association between patients on the basis of genetic similarities, and Bi-LSTM computes temporal details of health information, and the attention module is applied to pay attention to important elements.
    RESULTS: The results of the experiment show that the proposed GNN-Bi-LSTM-AM model predicts the accuracy of 98.5, precision of 96, recall of 96, and an F1-score of 96, which is much better than traditional machine learning methods. The framework has also good efficiency in that the processing time was 7.85 seconds.
    CONCLUSIONS: The GNN-Bi-LSTM-AM framework suggested is a great step towards predictive analytics of rare genetic diseases. The model can be used to provide promising applications in early detection and clinical diagnosis by combining genetic relationships, sequential health data, and feature relevancy. Therefore, it is practical in enhancing treatment interventions and patient outcomes in genetic medicine.
    DOI:  https://doi.org/10.7754/Clin.Lab.2025.250934
  34. Front Physiol. 2026 ;17 1957316
    Mechanistic interactions of diet, exercise, and pharmacotherapy in skeletal muscle metabolism: evidence and translational perspectives.
    Yan Wang, Mengran Qin, Xuezhi Liu, Jianxiong Ma.
      Skeletal muscle plays a central role in whole-body energy homeostasis, metabolic flexibility, and insulin sensitivity, acting as a key integrator of nutritional, mechanical, and pharmacological signals. Although diet, exercise, and pharmacotherapy are often investigated as separate interventions, they converge on shared regulatory pathways in skeletal muscle, including nutrient sensing, mechanotransduction, mitochondrial quality control, inflammatory remodeling, and anabolic-catabolic balance. Through core signaling networks such as AMPK-mTOR, SIRT1/PGC-1α, and insulin/AKT pathways, these interventions may interact in additive, complementary, synergistic, or antagonistic manners depending on physiological status, disease context, baseline metabolic condition, and intervention timing. This Review critically integrates current evidence on how diet, exercise, and pharmacotherapy regulate skeletal muscle metabolism across aging, metabolic disease, and adaptive physiological states. We propose a muscle-centered integrative framework organized around five major regulatory domains: substrate utilization and metabolic flexibility, mitochondrial remodeling, protein turnover, inflammatory control, and regenerative capacity. Within this framework, we highlight how intervention responses are shaped by key biological and clinical modulators, including age, disease state, muscle fiber composition, training status, nutritional background, and baseline metabolic health. Importantly, we distinguish findings supported by human studies from those derived primarily from preclinical or mechanistic models, thereby emphasizing differences in translational reliability. Finally, we discuss current limitations in interpreting combined interventions and outline future directions for precision-oriented strategies that integrate nutrition, exercise, and pharmacotherapy to optimize skeletal muscle function and systemic metabolic health.
    Keywords:  dietary intervention; exercise; mechanism integration; pharmacotherapy; skeletal muscle metabolism
    DOI:  https://doi.org/10.3389/fphys.2026.1957316
  35. J Allergy Clin Immunol Pract. 2026 Oct;pii: S2213-2198(26)00532-5. [Epub ahead of print]14(10): 2200-2208.e6
    Genetic Testing in Clinical Immunology: What to Know and How to Do It.
    Rui Yang, Ivan K Chinn, Jordan S Orange, Xiao P Peng.
      Genetically driven immune diseases are immune-mediated disorders involving germline and/or somatic host genetic changes that make a major contribution to disease pathogenesis. These conditions, which include the inborn errors of immunity, may predispose patients to the development of immunodeficiency, immune dysregulation, atopy, autoinflammation or hyperinflammation, and malignancy. Since the development of massively parallel sequencing, also known as next-generation sequencing, and its introduction into clinical use, clinical genetic testing has expanded exponentially across medical specialties, including clinical immunology, with approximately 28% of patients with suspected genetically driven immune diseases undergoing genetic testing in the United States. Despite rapid uptake, knowledge gaps persist regarding when to order genetic testing, how to choose the appropriate assay, and how to interpret the results in clinical context. In this review, we provide a practical framework for genetic testing strategy and interpretation and discuss current limitations, as well as emerging advances that may help further enhance diagnostic yield and clinical impact.
    Keywords:  Gene panel; Genetic testing; Immune dysregulation; Immunodeficiency; Sequencing; Somatic mosaicism; Variant of uncertain significance
    DOI:  https://doi.org/10.1016/j.jaip.2026.06.034
  36. Front Immunol. 2026 ;17 1918926
    Mitochondria affect antibacterial immunity in cross talk with innate immune response molecules coded by genes of nuclear origin.
    Argha Chakraborty, Aruna Pal, Manti Debnath, Jyoti Sahu, Abantika Pal, Joydeep Mukherjee, Rajarshi Samanta, Paresh Nath Chatterjee.
       Introduction: Mitochondria are dynamic, semi-autonomous organelles that, in addition to their central role in ATP production, regulate calcium homeostasis, iron metabolism, apoptosis, and innate immune signalling. Although the mitochondrial genome encodes only 37 genes, mitochondrial architecture, bioenergetic function, and dynamics are governed predominantly by nuclear-encoded proteins, necessitating highly coordinated communication between mitochondrial DNA (mtDNA) and the nuclear genome. Disruption of this bidirectional mitochondrial-nuclear crosstalk has been increasingly implicated in the pathogenesis of numerous diseases across species; however, the molecular mechanisms underlying this communication remain incompletely understood.
    Materials and method: In the present study, we used Anas platyrhynchos as a model of duck pasteurellosis to investigate mitochondrial-nuclear interactions in the regulation of innate immune responses during Pasteurella multocida infection. We characterized the mitochondrial (cytochrome b and cytochrome c) and nuclear genes (NLRP3, IL-18, and STING) of duck, in silico molecular docking, PHYRE 2 for PDB structure prediction, pymol visualization, and experimental validation with differential mRNA expression profiling.
    Result and discussion: Our findings demonstrate that the mitochondrially encoded proteins cytochrome b and cytochrome c functionally interact with the nuclear-encoded immune regulators NLRP3, IL-18, and STING through the NOD-like receptor signalling pathway, phagocytic pathways, and the cytosolic DNA-sensing pathway. Furthermore, molecular docking analyses identified putative interaction sites between IL-18 and P. multocida, providing additional support for the functional relevance of these immune pathways during bacterial infection. To our knowledge, this study provides the first evidence in an animal model that mitochondrial retrograde signalling influences the regulation of nuclear immune genes during bacterial infection. These findings reveal a previously unrecognized mechanism through which mitochondrial gene products modulate host innate immune responses, thereby advancing our understanding of mitochondrial-nuclear communication in host-pathogen interactions.
    Keywords:  Anas platyrhnchos; antibacterial immunity; duck pasteurellosis; mitochondrial genome; nuclear gene
    DOI:  https://doi.org/10.3389/fimmu.2026.1918926
  37. Arch Med Res. 2026 Oct 07. pii: S0188-4409(26)00140-2. [Epub ahead of print]57(8): 103518
    Artificial Intelligence in the Diagnosis, Treatment, and Management of Rare Diseases: Opportunities and Challenges from a Latin American Perspective.
    Mario A Parra-Vilchis, Asbiel F Garibaldi-Ríos, Martha P Gallegos-Arreola, Adriana Alonzo-Rojo, Gildardo Sánchez-Ante, José Elías García-Ortiz.
      Rare diseases collectively affect between 3.5 and 5.9% of the global population. Yet, patients still endure an average diagnostic interval of five to seven years before receiving an accurate explanation of their condition. Approximately 80% of these disorders have a genetic origin, and nearly 95% lack approved disease-modifying therapies that alter the disease course. This combination places enormous pressure on healthcare systems and affected families. In the last decade, artificial intelligence (AI), particularly machine learning, deep learning, and natural language processing, has emerged as a credible response to these gaps. This narrative review summarizes recent AI contributions across four interrelated dimensions: differential diagnosis and pattern recognition; prognosis and risk stratification; therapeutic discovery and drug repositioning; and the operational organization of rare disease care. Available evidence indicates that AI-based approaches can shorten diagnostic intervals, reduce unnecessary testing, and increase therapeutic options for orphan conditions. Despite these global advances, implementation remains highly unequal. This review foregrounds the Latin American perspective, setting itself apart from broader overviews. The region presents a scenario in which rich genetic diversity and growing collaborative networks coexist with infrastructural bottlenecks and underrepresentation in genomic databases. The integration of AI into rare disease care will depend on federated data infrastructures, transparent and interpretable models, harmonized regulatory frameworks, and sustained investment in workforce training. Patient organizations are essential partners, particularly in emerging economies.
    Keywords:  Artificial intelligence; Deep learning; Diagnosis; Machine learning; Precision medicine; Rare diseases
    DOI:  https://doi.org/10.1016/j.arcmed.2026.103518
  38. Neurosci Res. 2026 Oct 09. pii: S0168-0102(26)00124-0. [Epub ahead of print] 105137
    From iPSC Disease Modeling to Epigenome Editing: Toward Therapeutic Reversal of Genomic Imprinting Disorders.
    Akisa Nemoto, Hideyuki Okano.
      Human induced pluripotent stem cells (iPSCs) and organoids are increasingly important components of new approach methodologies because they provide experimentally accessible human systems that preserve patient-specific genetic backgrounds and can be differentiated into disease-relevant cell types. Genomic imprinting disorders are particularly attractive targets for this approach because their pathogenesis depends not only on DNA sequence but also on parent-of-origin-specific epigenetic regulation. Prader-Willi syndrome (PWS) and Angelman syndrome (AS), which arise from distinct disruptions within the same imprinted domain on chromosome 15q11.2-q13, illustrate both the opportunities and the complexity of therapeutic epigenetic manipulation. Recent studies using PWS patient-derived iPSCs have shown that disease-associated imprinting states are largely retained after reprogramming and can be experimentally reversed by locus-specific epigenome editing. Targeted demethylation of the PWS imprinting control region restored multiple paternally expressed genes, and the corrected state persisted after differentiation into hypothalamic organoids, partially normalizing disease-associated transcriptomic and functional phenotypes. Here, we discuss how iPSC-based disease modeling is evolving from a platform for mechanism discovery toward a test bed for therapeutic epigenome engineering and outline the major challenges that must be addressed before epigenome editing can be translated to patients with imprinting disorders.
    Keywords:  Angelman syndrome; CRISPR; Prader–Willi syndrome; epigenome editing; genomic imprinting; hypothalamic organoid; induced pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.neures.2026.105137
  39. Neurobiol Dis. 2026 Oct 05. pii: S0969-9961(26)00384-0. [Epub ahead of print]230 107638
    Plasma PINK1/Parkin ratio and ATF5 as potential biomarkers associated with dyskinesia in Parkinson's disease.
    Shuangjie Qian, Weiqi Xiang, Keke Chen, Yishu Du, Binbing Xu, Qi Duan, Xi Xiong, Jialong Hou, Tao Jiang, Dewei Xie, Jingjing Qian, Chenglong Xie, Jia Li.
       BACKGROUND: Motor complications (MCs), particularly dyskinesia (DYS), affect many PD patients within years of levodopa therapy, yet reliable biomarkers for MC subtypes remain elusive. Mitochondrial quality control (MQC) pathways, including mitophagy and the mitochondrial unfolded protein response (UPRmt), are central to PD pathogenesis; however, their association with MCs remains to be clarified.
    METHODS: In this cross-sectional study, a total of 247 PD patients were enrolled and analyzed in a mitophagy discovery set (n = 174), a UPRmt discovery set (n = 179), and an overlap subset (n = 106) with complete data for both biomarker panels, which was used for internal consistency analyses. Plasma levels of PINK1, Parkin, PGAM5, ATF4, ATF5, and CHOP were measured by ELISA. Patients were classified as MC, further subtyped as wearing-off (WO) or DYS, or NMC. Univariate analysis identified candidate biomarkers; multivariable logistic regression and LASSO regression evaluated associations after covariate adjustment; and ROC analysis exploratorily assessed discriminative accuracy, with bootstrap resampling used to evaluate model stability.
    RESULTS: Neither mitophagy nor UPRmt markers distinguished MC from NMC. However, after batch correction and covariate adjustment, the PINK1/Parkin ratio (OR = 2.06, p = 0.044) and ATF5 (OR = 2.27, p = 0.010) remained associated with DYS. A three-biomarker panel comprising PINK1, the PINK1/Parkin ratio, and ATF5 achieved an AUC of 0.82 (95% CI: 0.68-0.93) in the overlap subset. Nonlinear associations with DYS status were observed, following a DYS > dyskinesia with wearing-off (DYSWO) > WO pattern.
    CONCLUSIONS: Circulating MQC biomarkers, particularly the PINK1/Parkin ratio and ATF5, are associated with prevalent DYS in PD, suggesting that MQC-related pathways may be involved in DYS pathophysiology.
    Keywords:  Dyskinesia; Mitophagy; Motor complications; Parkinson's disease; UPR(mt)
    DOI:  https://doi.org/10.1016/j.nbd.2026.107638
  40. Drug Discov Today. 2026 Oct 05. pii: S1359-6446(26)00226-6. [Epub ahead of print] 104821
    Regulatory sandboxes for drug development: from uncertainty to structured evidence generation.
    Pedro Franco, Maximilian Otte, Gökhan Ertaylan, Mika Naumanen.
      Regulatory sandboxes for drug development offer a framework to address regulatory and legal uncertainty associated with novel sciences and technologies without compromising efficacy, safety, or quality. Here, we explore how regulatory sandboxes support structured evidence generation when existing regulatory and legal mechanisms are insufficient to address innovation. We synthesize concepts about when a sandbox is warranted, what evidence should be generated in a controlled setting, and how governance should be structured to protect patients and data while enabling responsible innovation. Our analysis highlights that sandbox value depends on explicitly managing uncertainty, conducting controlled experimentation, maintaining safeguards and oversight, and defining clear exit criteria linked to regulatory learning. A practical governance model is presented, together with a readiness framework covering regulatory knowability, value trade-offs, institutional capacity, infrastructure, and responsibility. When appropriately designed, regulatory sandboxes enable responsible innovation, credible learning, and better-informed regulatory decision-making while preserving regulatory standards.
    Keywords:  artificial intelligence; drug development; evidence generation; innovation; lifecycle evidence; pharmaceutical regulation; regulatory decision-making; regulatory sandbox; regulatory science; regulatory uncertainty
    DOI:  https://doi.org/10.1016/j.drudis.2026.104821
  41. J Biomed Sci. 2026 Oct 07. pii: 92. [Epub ahead of print]33(1):
    Primary cilium as a sensory organelle and metabolic hub in health and diseases.
    Huan-Tzu Hou, Yu-Ying Chao, Jie-Ning Li, I-Chen Peng, Tzu-Chien Lin, Wen-Tai Chiu, Chia-Yih Wang, Shaw-Jenq Tsai.
      Primary cilia are microtubule-based organelles protruding from the cell surface, which are conventionally understood as passive cellular antennae that detect extracellular stimuli. However, emerging evidence redefines these microtubule-based organelles as dynamic, bidirectional hubs that integrate environmental sensing with cellular metabolic adaptation. By selectively compartmentalizing receptors, ion channels, transporters, and signaling components, they function as specialized signal-processing compartments that receive, integrate, amplify, and relay information to coordinate cellular metabolism, adaptation, and cell-fate determination. Cilia-dependent signaling pathways regulate glucose and lipid metabolism, Ca2⁺ and second-messenger dynamics, and mitochondrial homeostasis. Conversely, environmental and metabolic changes remodel ciliary structure, molecular composition, and signaling competence. In this review, we present primary cilia as a bidirectional interface between environmental sensing and metabolic adaptation. We discuss how cilia respond to nutrient availability, mechanical forces, and oxygen tension, and how disruption of this sensory-metabolic interface contributes to metabolic, cardiovascular, reproductive, neurodegenerative, and cancer-related diseases. Defining the cellular and environmental contexts in which ciliary remodeling is protective or pathogenic will be essential for translating cilia biology into therapeutic strategies.
    Keywords:  Ciliopathies; Glucose and lipid metabolism; Human disease; Mechanotransduction; Metabolic signaling; Mitochondrial homeostasis; Nutrient sensing; Primary cilia
    DOI:  https://doi.org/10.1186/s12929-026-01291-6
  42. Health Expect. 2026 Oct;29(5): e70889
    Genomic Data Governance Challenges Between Research and Clinical Care: A Scoping Review.
    Alice Kim, Bronwen Merner, Mark Taylor, Yingyi Luo, Fabian Cannizzo, Alan Petersen, Clara Gaff, Ainsley J Newson, Kate Marchant, Louse Keogh.
       INTRODUCTION: The translational nature of genomics highlights the importance of developing a robust genomic data governance framework. To inform the development of such a framework for Australia, we conducted a scoping review to identify genomic data governance and management differences between research and clinical care.
    METHODS: For this scoping review, four databases were searched and 9528 relevant articles published between January 2013 and October 2024 were identified. After screening, 43 empirical, legal and theoretical/commentary articles were included. The differences reported to affect genomic data governance and management practices across clinical and research settings were extracted and synthesised.
    RESULTS: Fifteen empirical articles revealed that the 'community' and the 'workforce' reported different consent priorities and differing understandings of the expected benefits of providing genomic data for research. Three legal articles reiterated the influence of regulatory regimes on genomic data practices and rights. Lastly, all twenty-five theoretical/commentary articles were authored by researchers; none by community representatives. While 3/25 articles described the genomic data practices of rare and undiagnosed disease patient populations, 22/25 examined the ethical, legal and social implications arising from genomic data. Among the latter, 14/22 proposed 'solutions' to address identified genomic data challenges associated with consent, returning research genomic data to patients and advancing precision medicine.
    CONCLUSION: Differences in understanding, expectations and regulatory regimes can challenge genomic data governance and management practices and perceptions. Considering the implications of these challenges, meaningful community involvement will be critical in developing a governance framework that responsibly leverages genomic data to deliver more equitable health care.
    LIVED EXPERIENCE OR PUBLIC CONTRIBUTION: Members of the Genetic, Undiagnosed and Rare Disease (GUARD) Collaborative - the LINEAGE Consortium's Community Advisory Group partner - Emma Bonser, Monica Ferrie, Alex Fulton, Caroline Kiefer, Kate Marchant, Tony Neilson, Maya Pinn, Tania Prior-Smith, Heather Renton, Susie Roczo-Farkas and Joel Taggart contributed community perspectives and critical reflections during discussions of early findings, informing the development of this manuscript. Kate Marchant, a LINEAGE-GUARD member, is an author of this manuscript, contributing critical revisions and approving the final manuscript.
    Keywords:  ELSI; community involvement; data governance; genomic data; health equity; informed consent; management; translational sciences
    DOI:  https://doi.org/10.1111/hex.70889
  43. Redox Rep. 2026 Dec 31. 31(1): 2698189
    Coordinated mitochondrial quality control underlies oxidative stress resilience in MUSE stem cells.
    Domenico Aprile, Sura Hilal Ahmed Al-Sammarraie, Alessia Ambrosino, Mohd Shahzaib, Yesuf Siraj, Afshin Samiminemati, Nicola Alessio, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi.
       BACKGROUND: Reactive oxygen species (ROS) regulate stem-cell function, but sustained exposure causes oxidative damage, mitochondrial dysfunction and exhaustion. Multilineage-differentiating Stress-Enduring (MUSE) cells, a rare SSEA-3⁺ MSC subset, tolerate ROS-rich environments, although the mechanisms remain unclear.
    METHODS: We compared MUSE, Non-MUSE (SSEA-3⁻) and MSCs after H₂O₂ exposure, assessing ROS clearance, mtDNA integrity, 8-oxo-dG, antioxidant and BER responses, mitochondrial morphology/function, mitophagy and biogenesis, with focus on the PGC-1α/NRF2 axis. Three independent biological replicates were analyzed by imaging, qPCR, flow cytometry and biochemical assays.
    RESULTS: MUSE cells showed greater resistance to oxidative stress than MSCs and Non-MUSE cells. After H₂O₂, they displayed lower ROS accumulation (~15-25%), preserved mtDNA integrity, reduced 8-oxo-dG, rapid induction of antioxidant and BER-related genes, and maintenance of mitochondrial morphology, membrane potential and respiratory activity. MUSE cells also showed enhanced mitophagy, with >2-fold increased LAMP1-MitoTracker colocalization and induction of PINK1/phospho-Ub-S65, together with increased biogenesis, including ~45% higher COX-I/SDHA ratio, TFAM induction and PGC-1α activation at 48 h.
    CONCLUSION: MUSE cells coordinate antioxidant defense, DNA repair, mitophagy and biogenesis through a remove-and-replace program that preserves mitochondrial function during oxidative stress.
    Keywords:  MUSE stem cells; NRF2; PGC-1α; mitochondrial DNA damage; mitochondrial biogenesis; mitochondrial quality control; mitophagy; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1080/13510002.2026.2698189
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