bims-polgdi Biomed News
on POLG disease
Issue of 2026–03–29
forty-two papers selected by
Luca Bolliger, lxBio



  1. Int J Mol Sci. 2026 Mar 23. pii: 2890. [Epub ahead of print]27(6):
      Mitochondria play a fundamental role in human reproduction by supplying the energy required for key early reproductive processes. As mitochondrial Deoxyribonucleic acid (mtDNA) is maternally inherited, pathogenic mutations can lead to multisystem disorders that are transmitted to offspring. Mitochondrial replacement therapy (MRT) has emerged as a promising assisted reproductive approach to prevent the transmission of pathogenic mtDNA by replacing defective mitochondria with healthy donor mitochondria. There have been recent reports of successful MRT in humans. However, MRT remains a relatively new procedure and needs further experiments to establish its long-term safety and effectiveness. Overall, mitochondrial replacement therapy holds significant promise in helping families build healthier futures. This review explores the evolution of mitochondrial DNA modification in reproductive cells and addresses the associated ethical considerations, including acceptable clinical indications, reproductive choices, and long-term considerations for affected children.
    Keywords:  DNA modification; assisted reproductive technique; mitochondria; mitochondrial diseases; mitochondrial replacement therapy
    DOI:  https://doi.org/10.3390/ijms27062890
  2. Cell Death Dis. 2026 Mar 26.
      Defects in nucleotide metabolism and imbalances in deoxynucleotide triphosphate (dNTP) pools are associated with several human diseases, including cancer and mitochondrial disorders. In non-replicative cells, while DNA synthesis is reduced, a continuous supply of nucleotides is essential to sustain mitochondrial DNA (mtDNA) replication and repair. Human all-α dCTP pyrophosphatase 1 (DCTPP1), a nucleotido hydrolase with high specificity for dCTP, plays a critical role in maintaining nucleotide homeostasis, however its participation in mtDNA stability remains unexplored. In this study we performed a detailed analysis of pyrimidine metabolism enzymes in non-dividing cells. We found that during quiescence, DCTPP1 is predominantly localized to mitochondria. Depletion of the enzyme leads to upregulation of the de novo thymidylate synthesis pathway and expansion of both the dCTP and dGTP pools, highlighting its pivotal role in regulating the dNTP balance. To explore the potential therapeutic relevance of these observations, we used an in vitro model of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare mitochondrial disorder caused by thymidine phosphorylase (TP) deficiency and characterized by dCTP depletion and mtDNA loss. Long-term thymidine overloading in quiescent cells (a model mimicking TP deficiency) led to reduced dCTP levels and the depletion of mtDNA, effects that were reversed upon DCTPP1 knockdown. Hence, reduced DCTPP1 levels restored dCTP availability and increased mtDNA copy number. These findings suggest that DCTPP1 plays a critical role in regulating mitochondrial dNTP pools and that down-regulation of the enzyme may serve as a compensatory mechanism in disorders marked by secondary dCTP depletion. DCTPP1 may therefore represent a promising therapeutic target for mitochondrial DNA depletion syndromes such as MNGIE.
    DOI:  https://doi.org/10.1038/s41419-026-08632-1
  3. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00166-1. [Epub ahead of print]36(6): R259-R261
      Mitochondria contain their own DNA (mtDNA), which can be released via multiple routes and cause inflammation and disease. A recent study revealed the unexpected role of a mitochondrial nuclease, present in the intermembrane space, in preventing mtDNA escape via mitophagy.
    DOI:  https://doi.org/10.1016/j.cub.2026.02.016
  4. Genes (Basel). 2026 Mar 18. pii: 338. [Epub ahead of print]17(3):
      Background/Objectives: Mitochondrial DNA (mtDNA) is an important resource for understanding human ancestry, population diversity, and the molecular mechanisms of mitochondrial diseases. However, analyzing mtDNA thoroughly often requires advanced bioinformatics skills and command-line knowledge. To address this challenge, we created Mitochondrial Genome Explorer (MitoGEx), a user-friendly computational pipeline optimized for human mtDNA analysis that combines multiple mtDNA analysis modules within a single graphical user interface. Methods: The platform simplifies key analytical steps, such as quality control, sequence alignment, alignment quality assessment, variant detection, haplogroup classification, and phylogenetic reconstruction. Users can choose between Quick and Advanced modes, which offer default settings or customizable options based on their analysis needs. To demonstrate its effectiveness, we analyzed 15 whole-exome sequencing (WES) samples from Songklanagarind Hospital using MitoGEx. Results: The sequencing data were of high quality, with over 92 percent of bases scoring above a Phred score and consistent GC content across all samples. Variant detection using the GATK mitochondrial pipeline and annotation with ANNOVAR and the MitImpact database revealed multiple high-confidence variants. Haplogroup classification with Haplogrep 3 and phylogenetic analysis with IQ-TREE 2 confirmed diverse maternal lineages within the cohort. Conclusions: Taken together, MitoGEx facilitates mitochondrial genome analysis in a reproducible and accessible manner for both research and clinical bioinformatics applications. The analytical results produced by MitoGEx are concordant with those obtained using standalone bioinformatic tools, demonstrating analytical correctness. By integrating all analysis steps into a single automated workflow, MitoGEx reduces execution time and limits human error inherent to manual, multi-step pipelines.
    Keywords:  MitoGEx; bioinformatics; computational tools; mitochondrial DNA; mitochondrial diseases; mitochondrial genome analysis
    DOI:  https://doi.org/10.3390/genes17030338
  5. bioRxiv. 2026 Mar 20. pii: 2026.03.19.713005. [Epub ahead of print]
      Maternal inheritance of mitochondrial DNA (mtDNA) is a near-universal feature of eukaryotes 1 , yet the mechanisms that ensure this by preventing paternal mtDNA inheritance have remained unclear. In both Drosophila and humans, mtDNA is actively eliminated from sperm during spermatogenesis, producing mature sperm whose mitochondria lack their genomes 2-5 . Here we identify Hotaru, a previously uncharacterized, testis-specific GIY-YIG endonuclease, as a central player in this process. We find that Hotaru is expressed in elongated spermatids, localizes to the mitochondrial matrix, and is required for paternal mtDNA elimination. In hotaru mutants, sperm retain mtDNA at levels comparable to those present before the elimination process. Genetic and biochemical analyses show that Hotaru selectively recognizes and cleaves cruciform DNA structures within the mtDNA control region. Together, these findings identify a dedicated nuclease that enforces mitochondrial genome elimination in the animal male germline and reveal that an unexpected structural feature of mtDNA serves as the molecular determinant of its destruction. By recognizing DNA structure rather than specific sequence motifs, this mechanism is inherently robust to the high mutation rate of mitochondrial genomes.
    DOI:  https://doi.org/10.64898/2026.03.19.713005
  6. Eur J Immunol. 2026 Apr;56(4): e70176
      Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon-stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease-causing genes. Control fibroblasts showed a strong expression of interferon-stimulated genes in response to interferon, but only 43% of patients' fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients' fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.
    DOI:  https://doi.org/10.1002/eji.70176
  7. Genes (Basel). 2026 Feb 25. pii: 255. [Epub ahead of print]17(3):
      Genome stability is the cornerstone of cellular health, and imbalances can cause a number of outcomes, including aging, cancer, and other pathologies. DNA damage is a strong driver of both cellular senescence and mitochondrial dysfunction, two other key hallmarks of aging. Both nuclear and mitochondrial genome instability have been shown to drive aging in the hematopoietic system, which then propagates to non-lymphoid tissues, enhancing morbidity and mortality. The loss of TFAM, a key regulator of mitochondrial DNA replication and nucleoid stability, in T cells has been shown to cause mitochondrial dysfunction, leading to premature immune aging and eventual systemic aging. We sought to investigate whether the loss of TFAM in all immune cells would have a comparable or stronger effect on both the immune system and parenchyma. To address this, we attempted to generate Vav-iCre+/-; Tfamfl/fl mice, which are deficient in TFAM in all immune cells. However, this genotype was unrecoverable as no mutant pups were born, suggesting embryonic lethality. Conversely, we generated mice lacking SIRT6, a nuclear DNA repair enzyme that also regulates mitochondrial homeostasis, in all immune cells and found them to be viable and born at expected Mendelian frequencies. Our findings demonstrate the necessity of mitochondrial genome maintenance and homeostasis repair in immunity.
    Keywords:  aging; genomic instability; immunology; immunosenescence; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/genes17030255
  8. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261427023
      The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs) worldwide. The Task Force members interviewed 23 key opinion leaders (KOLs), providing perspectives from experts in the use of TH for the diagnosis, treatment, and prevention of RDs (10 KOLs); for research and evaluation in RDs (7); and for the continuing education of health care providers (HCPs) in RDs (6). The KOLs represented a broad array of diverse perspectives with regard to both geographic regions, including Europe, United States, Sub-Saharan Africa, and Asia, and professional expertise, including rare disease patients and family members, RD association spokespersons, TH association representatives, physicians, researchers, and regulatory authorities. The Task Force solicited KOL opinions to identify factors that influence TH in improving access to diagnosis, care, prevention, and research experiences for RD patients and providers as well as continuing education and peer mentoring for HCPs. This manuscript represents a synthesis of those interviews and some common themes that emerged, along with identification of evidence and knowledge gaps that will benefit from future research efforts to help advance and expand the use of TH for RD care, research, and education. KOLs agreed on the unique elements of RD medical care that could benefit from TH approaches and recognized the increasing role that remote assessments can play in supporting RD research. They identified models for health care provider education afforded by TH that can enhance care for RD patients and broaden the pool of experts in these conditions. While recognizing that barriers to broad implementation exist, they agreed that TH provides a unique tool to provide greater access to care for RD patients worldwide.
    Keywords:  IRDiRC; decentralized clinical trial; eHealth; key opinion leader; peer mentoring; rare disease; rare disease care; rare disease education; rare disease research; teleconsultation; telehealth; telemedicine
    DOI:  https://doi.org/10.1177/26330040261427023
  9. J Adv Res. 2026 Mar 20. pii: S2090-1232(26)00257-2. [Epub ahead of print]
       BACKGROUND: Current therapeutic models for ischemic stroke (IS) are shifting from a narrow focus on neuroprotection to a broader concept of cytoprotection. This new paradigm emphasizes rescuing damaged brain cells and maintaining their structural and functional integrity through organelle transfer between healthy and damaged cells. Mounting evidence have supported that intracellular mitochondrial transfer is an intrinsic response to IS, playing a critical role in mitigating neural damage. Consequently, mitochondrial transplantation from stem cell is emerging as a therapeutic avenue for IS.
    AIM OF REVIEW: This article reviews the IS-induced mitochondrial dysfunction, the modes and mechanisms of endogenous intracellular mitochondrial transfer, and recent advances in using stem cell-derived mitochondrial transplantation to treat IS.
    KEY SCIENTIFIC CONCEPTS: This review emphasizes the dual roles of mitochondrial transfer in determining neural cells fate and neurological function recovery following IS. On one hand, health cells can donate intact mitochondria to damaged cells, to revitalize them by restoring cell metabolic function. On the other hand, damaged cell may expel dysfunction mitochondria, which can be cleared by healthy neighbors or, alternatively propagate injury. We discuss the current challenges in this field and propose that enhancing healthy mitochondrial transfer or preventing damaged mitochondrial release may hold great potential for alleviating IS injury.
    Keywords:  Cell to cell communication; Ischemic stroke; Mitochondrial transfer; Preserving neuronal function; Stem cell therapy
    DOI:  https://doi.org/10.1016/j.jare.2026.03.037
  10. medRxiv. 2026 Mar 02. pii: 2026.02.26.26347219. [Epub ahead of print]
       Objective: Systematic clinical phenotyping using Human Phenotype Ontology (HPO) is central to rare disease diagnosis. However, current disease prioritization (ranking candidate diseases from HPO for a patient) methods face key challenges: they often fail to account for the hierarchical structure of HPO terms, ignore dependencies among correlated terms, and do not adjust for batch effects arising from systematic differences in phenotype documentation across cohorts, institutions, or clinicians. We aim to develop a scalable and statistically principled framework to address these limitations for rare disease prediction and patient stratification.
    Methods: We developed PhenoSS, a Gaussian copula-based framework that models disease-specific marginal prevalence of HPO terms while capturing their joint dependencies through a multivariate normal distribution. Phenotype frequencies were estimated using external curated resources, including OARD (Open Annotations for Rare Diseases) and HPO annotations. PhenoSS supports both pair-wise phenotype similarity calculation for patient clustering and posterior odds estimation for patient-specific disease prioritization. A batch-effect correction module mitigates systematic phenotyping differences across datasets.
    Results: Across diverse simulation scenarios, PhenoSS demonstrated robust disease-prediction performance and consistently improved accuracy after batch-effect correction. In real electronic health record (EHR) data, PhenoSS identified clinically meaningful patient clusters and effectively distinguished patients with different rare diseases. In disease prioritization tasks, PhenoSS achieved competitive performance with existing methods, particularly for patients exhibiting sparse or noisy phenotype annotations.
    Conclusion: PhenoSS provides a statistically interpretable framework for modeling phenotypic heterogeneity in rare disease research and is adaptable to other structured clinical vocabularies such as SNOMED-CT and ICD codes.
    DOI:  https://doi.org/10.64898/2026.02.26.26347219
  11. Cells. 2026 Mar 12. pii: 504. [Epub ahead of print]15(6):
      A rare disease is a condition that affects only a small portion of the population [...].
    DOI:  https://doi.org/10.3390/cells15060504
  12. Toxics. 2026 Mar 12. pii: 248. [Epub ahead of print]14(3):
      Ground-level ozone is widely acknowledged as one of the primary air pollutants, capable of inducing adverse health effects across multiple human systems, including asthma, cardiovascular events, and central nervous system dysfunction. Epidemiological and toxicological studies indicate that the onset of related systemic diseases is often attributed to ozone-mediated inflammatory responses. However, since O3 itself lacks antigenic properties to trigger innate immune responses, an intermediary substance induced by ozone exposure likely activates subsequent inflammatory pathways. Multiple ozone exposure studies have identified mitochondrial DNA (mtDNA) as a potential biomarker released during ozone-induced mitochondrial dysfunction. mtDNA may serve as a damage-related molecular pattern that activates innate immune responses, potentially acting as a crucial link between ozone and inflammatory reactions. This review therefore examines the structure and function of mitochondrial DNA, along with potential mediating mechanisms underlying inflammation associated with ozone exposure.
    Keywords:  innate inflammation; mtDNA; mtDNA release; ozone exposure
    DOI:  https://doi.org/10.3390/toxics14030248
  13. Eur J Neurol. 2026 Mar;33(3): e70554
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (TYMP), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP.
    METHODS: We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo-obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP-related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo-obstruction. This patient later suffered from a catastrophic stroke-like episode, resulting in massive cerebral edema and brain death at the age of 38.
    RESULTS: Next-generation sequencing (NGS) using a custom-targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis, and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real-time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long-range PCR and Nanopore sequencing.
    CONCLUSIONS: These cases showed a very distinctive POLG phenotype, with some MNGIE-like features, expanding the clinical and genetic spectrum of the POLG-related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.
    Keywords:  central nervous system diseases; malabsorption syndromes; mitochondrial diseases; mitochondrial encephalomyopathies
    DOI:  https://doi.org/10.1111/ene.70554
  14. medRxiv. 2026 Mar 03. pii: 2026.03.02.26347469. [Epub ahead of print]
      Rare diseases affect over 300 million people worldwide, yet patients often endure years-long diagnostic delays that limit timely intervention and trial opportunities. Computational rare disease recognition (RDR) remains constrained by knowledge resources that are often incomplete, heterogeneous, and dependent on extensive multi-disciplinary expert curation that cannot scale. Large language models (LLMs) applied directly for end-to-end diagnosis or disease discrimination face similar knowledge bottlenecks while also raising concerns around cost, reproducibility, and data governance. Here, we introduce GEN-KnowRD, a knowledge-layer-first framework that leverages LLMs to generate schema-guided rare disease profiles, systematically assesses their quality, and constructs a computable knowledge base (PheMAP-RD) for local deployment. GEN-KnowRD integrates this knowledge into lightweight inference pipelines for both general-purpose disease screening and specialized early discrimination from longitudinal electronic health records. Across six public benchmarks for general-purpose screen (9,290 patients spanning 798 rare diseases), GEN-KnowRD significantly improves disease ranking compared to a state-of-the-art, HPO-centered diagnostic framework (up to 345.8% improvement in top-1 success), advanced end-to-end LLM reasoning (up to 129.1% improvement), and a variant of GEN-KnowRD instantiated with expert-curated knowledge rather than LLM-generated profiles. In two real-world cohorts for early diagnosis of idiopathic pulmonary fibrosis (511 patients) as a use case, GEN-KnowRD also demonstrates robust discrimination performance gains, supporting effective RDR during the pre-diagnostic window. These findings demonstrate that repositioning LLMs from diagnostic reasoning to the knowledge layer-decoupling knowledge construction from patient-level inference-yields stronger RDR, while providing scalable, continuously updatable, and reusable infrastructure for diagnosis, screening, and clinical research across the rare disease landscape.
    DOI:  https://doi.org/10.64898/2026.03.02.26347469
  15. Trends Mol Med. 2026 Mar 24. pii: S1471-4914(26)00033-X. [Epub ahead of print]
      Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, many tumours exhibit metabolic plasticity and retain oxidative phosphorylation capacity. Mitochondrial DNA (mtDNA) mutations are common across cancers, yet their roles in carcinogenesis and therapy response remain unclear. Emerging base-editing technologies now enable modelling of these mutations, allowing the exploration of their impact on tumourigenesis, which may differ depending on mutation type, heteroplasmy, and tissue origin. mtDNA alterations also shape immune responses within the tumour microenvironment and therefore may influence treatment sensitivity. This review integrates recent advances on mtDNA's role in cancer biology and explores therapeutic opportunities for targeting mitochondrial metabolism.
    Keywords:  DNA, mitochondrial; genes, neoplasm; neoplasms; oxidative phosphorylation; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2026.02.003
  16. Biotechniques. 2026 Jan-Dec;78(1-12):78(1-12): 1-11
      Mitochondria, with their own DNA, Represent a potential target for nucleic acid-based precision therapies. However, effective delivery of therapeutic oligonucleotides remains challenging due to the dual mitochondrial membranes and the localization of mitochondrial DNA within nucleoid complexes in the matrix. To understand the delivery process and assess the delivery efficiency of potential vectors, such as dendrimers, it is essential to effectively quantify the oligonucleotides that are successfully delivered to and remain within mitochondria. Currently, there are only limited yet inconvenient methods available for this purpose. Here, we describe a method for quantifying the delivery of fluorescent oligonucleotide cargos in isolated mitochondria using a microfiltration apparatus for reliable fluorescent analysis. By working within a range of dilutions, we are able to safeguard the concentration limits. The quantification protocol also enables the visualization of specific localization within mitochondria, allowing for the determination of whether delivery can occur across both membranes. This is particularly useful, as it offers a key insight into improving vectors as they must deliver the cargoes within the mitochondrial matrix. We validate this method in this proof-of-concept study, providing biological data to assess the difference between two amphiphilic dendrimer vectors for oligonucleotide delivery in mitochondria.
    Keywords:  Oligonucleotide delivery; dendrimers; microfiltration; mitochondria; subcellular localization
    DOI:  https://doi.org/10.1080/07366205.2026.2635461
  17. Antioxidants (Basel). 2026 Mar 11. pii: 353. [Epub ahead of print]15(3):
      Cuproptosis is a copper-dependent form of regulated cell death that is triggered when intracellular copper handling is perturbed and mitochondrial metabolism becomes the primary site of damage. Aging provides a biological context for this process because copper trafficking shifts, mitochondrial quality control and proteostasis decline, and immune function is remodeled toward immunosenescence with persistent low-grade inflammation. These age-associated changes can weaken antioxidant buffering, reshape labile copper pools, and lower the threshold at which copper stress is converted into mitochondrial proteotoxic injury. In parallel, inflammaging-related cytokines and NF-κB programs can alter copper import, export, and sequestration, while impaired efferocytosis prolongs danger signaling, creating feedforward loops that sustain tissue injury. In this review, we summarize the molecular features that distinguish cuproptosis from other death programs and discuss how redox buffering capacity, copper transport machinery, and mitochondrial metabolic state jointly determine cuproptosis sensitivity during aging. We then examine disease contexts in which these pathways are plausibly relevant, including hereditary copper-handling disorders and age-related neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders. Finally, we discuss key knowledge gaps and experimental priorities for interpreting cuproptosis-related signals in aged tissues, with emphasis on how copper handling, mitochondrial state, and immune remodeling jointly shape disease phenotypes.
    Keywords:  copper homeostasis; cuproptosis; glutathione; immunosenescence; inflammaging; iron sulfur clusters; mitochondrial metabolism; oxidative stress; protein lipoylation; redox buffering
    DOI:  https://doi.org/10.3390/antiox15030353
  18. Commun Med (Lond). 2026 Mar 23.
       BACKGROUND: As the population ages, a rising mortality burden is attributed to deaths in older adults, particularly deaths from inflammation-related chronic non-communicable diseases. The synergism between aging and inflammation remains unclear. Here, we conducted a study to examine whether a decrease in leukocyte mitochondrial DNA copy number (mtDNACN) with age modifies the association between inflammation and the mortality risk in older adults.
    METHODS: A total of 3520 adults (mean [SD] age, 67.6 [7.4] years) underwent serial leukocyte mtDNACN and serum high-sensitivity C-reactive protein (hs-CRP) measurements and ascertainment of subsequent all-cause and cardiovascular diseases (CVD) deaths. Mortality risks were estimated using Cox proportional hazards models.
    RESULTS: Compared to participants with both a sustainedly low serum hs-CRP and change in leukocyte mtDNACN at the highest tertile, the adjusted hazard ratios (95% CI) of all-cause and CVD death are 3.20 (2.20-4.66) and 5.77 (2.72-12.21) for those with both increased serum hs-CRP and change in leukocyte mtDNACN at the lowest tertile, 1.48 (0.93-2.38) and 1.24 (0.44-3.53) for those with increased serum hs-CRP alone, and 1.29 (0.93-1.81) and 1.44 (0.70-2.97) for those with a change in leukocyte mtDNACN at the lowest tertile alone. The relative excess risks due to interaction (95% CI) for all-cause and CVD death are 1.42 (0.19-2.65) and 4.08 (0.21-7.96). Similar results are observed for those with a change in leukocyte mtDNACN at the middle tertile and in sensitivity analyses.
    CONCLUSIONS: We demonstrate super-additive interactions between decreases in leukocyte mtDNACN and inflammation on the mortality risk in older adults, indicating underlying synergism.
    DOI:  https://doi.org/10.1038/s43856-026-01531-8
  19. Cells. 2026 Mar 13. pii: 517. [Epub ahead of print]15(6):
      Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC.
    Keywords:  T-cell exhaustion; immune evasion; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15060517
  20. Front Immunol. 2026 ;17 1750974
      Chronic inflammatory and autoimmune conditions frequently manifest as multi-organ dysfunction without a single explanatory lens that integrates metabolic stress, innate immune activation, transcriptional control, and autonomic regulation. Here, we propose the Bio-Intelligence Circuit (BIC) as a hypothesis-generating systems framework connecting mitochondrial dysfunction, LPS-TLR4-NF-κB innate immune signaling, nuclear receptor dysregulation, and vagal reflex imbalance as interacting regulatory failure patterns that may sustain chronic inflammatory states. The central hypothesis is that loss of coordinated energetic, immune-sensing, and neuro-autonomic regulation sustains a self-reinforcing dysregulation loop that amplifies inflammatory signaling, impairs regulatory restraint, and limits recovery potential. Within this framework, we introduce Informational Bio-Recalibration (IBR) as a hypothesis-generating transition sequence in which improvement of mitochondrial bioenergetics and redox buffering, attenuation of excessive TLR4 signaling, restoration of nuclear receptor transcriptional coordination, and rebalancing of autonomic tone may together shift the system toward resolution-permissive physiology. This article does not report interventional outcomes; rather, it provides a structured conceptual model and testable predictions to guide future experimental validation across inflammatory and immune-mediated phenotypes.
    Keywords:  bio-intelligence circuit; chronic inflammation; hypothesis-generating framework; immune dysregulation; informational bio-recalibration; mitochondrial bioenergetics; nuclear receptor coordination; systems biology
    DOI:  https://doi.org/10.3389/fimmu.2026.1750974
  21. Genes (Basel). 2026 Mar 15. pii: 318. [Epub ahead of print]17(3):
      Next-generation sequencing (NGS) and antisense oligonucleotide (ASO) technologies are converging to transform the diagnosis and treatment of rare monogenic disorders. NGS enables comprehensive, single-test molecular diagnoses through targeted panels, whole-exome sequencing, and whole-genome sequencing, which together reveal pathogenic variants across coding, intronic, and structural domains. Integration with transcriptomic analyses, including RNA sequencing, further refines genotype-phenotype correlations and identifies splicing aberrations amenable to correction by ASOs. Therapeutic advances now span RNase H1-dependent gapmers for transcript knockdown, splice-modulating phosphorodiamidate morpholino oligomers (PMOs), and peptide/antibody-conjugated PMOs that enhance muscle and cardiac delivery. These platforms underpin the rise in N-of-1 ASO therapies-customized drugs developed for individual patients with unique pathogenic variants. Landmark cases such as Milasen and Atipeksen illustrate the clinical feasibility and ethical complexities of personalized RNA therapeutics, while updated FDA guidance supports expedited, patient-specific investigational pathways. Despite progress, challenges persist in delivery efficiency, long-term efficacy, and equitable access. Emerging approaches-including long-read sequencing, AI-driven oligo design, and improved delivery-promise to extend ASO precision and reach. This review synthesizes current advances linking genomic diagnosis to individualized RNA-targeted interventions, outlining how integrated NGS-ASO pipelines are reshaping the therapeutic landscape for rare genetic diseases.
    Keywords:  N-of-1; antisense oligonucleotides; next-generation sequencing; rare genetic diseases
    DOI:  https://doi.org/10.3390/genes17030318
  22. Autophagy. 2026 Mar 22. 1-2
      Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
    Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2646238
  23. Med Sci (Basel). 2026 Mar 06. pii: 124. [Epub ahead of print]14(1):
      Background: Obesity is a multifactorial, chronic disease characterised by excessive fat accumulation, low-grade inflammation, and metabolic dysfunction. Emerging evidence suggests that the gut microbiome-mitochondria axis may play a significant role in the pathophysiology of obesity, particularly in regulating energy metabolism, inflammatory responses, and mitochondrial function. However, most mechanistic insights into this axis derive from preclinical animal studies, while human evidence remains limited and largely associative. Mitochondrial dysfunction disrupts cellular energy balance, increases reactive oxygen species production, and may exacerbate gut dysbiosis, further contributing to metabolic disturbances. In addition, factors such as micronutrient deficiencies also play a relevant role in obesity development and progression. Objectives: This review aims to examine the bidirectional interactions between the gut microbiome and mitochondrial systems in obesity, with a focus on the underlying molecular mechanisms and their potential as therapeutic targets. Methods: Evidence from experimental models and clinical studies was analysed to evaluate how modulation of the microbiome-mitochondria axis through probiotics, prebiotics, dietary strategies, and faecal microbiota transplantation influences mitochondrial function, inflammation, and metabolic regulation. Results: Preclinical studies indicate that the gut microbiome modulates mitochondrial activity through the production of bioactive metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived compounds, which influence mitochondrial efficiency, lipid metabolism, and glucose regulation. Dysbiosis reduces these beneficial metabolites, impairing mitochondrial signalling and promoting adiposity and insulin resistance. Interventions targeting this axis have shown potential in restoring metabolic balance, improving mitochondrial function, and mitigating obesity-related complications such as hyperlipidaemia and glucose intolerance. Conclusions: Targeting the microbiome-mitochondria axis represents a promising therapeutic strategy for obesity, with the evidence based largely on preclinical findings. However, further well-designed human studies are required to clarify causality, optimise interventions, assess long-term safety and efficacy, and establish standardised clinical protocols for implementation.
    Keywords:  microbiome-mitochondria axis; microbiota; mitochondria; obesity; treatment
    DOI:  https://doi.org/10.3390/medsci14010124
  24. Biomedicines. 2026 Mar 16. pii: 682. [Epub ahead of print]14(3):
      Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.
    Keywords:  inflammation; mitochondrial dysfunction; oxidative stress; respiratory complexes
    DOI:  https://doi.org/10.3390/biomedicines14030682
  25. Nutrients. 2026 Mar 22. pii: 1007. [Epub ahead of print]18(6):
      Chronic non-communicable diseases rarely occur in isolation; cardiovascular, metabolic, neurodegenerative, malignant, and age-associated disorders share upstream drivers including oxidative stress, chronic inflammation, mitochondrial dysfunction, and metabolic imbalance. This narrative review synthesizes epidemiological, interventional, and mechanistic studies identified through targeted literature searches to examine redox biology as a shared mechanistic hub linking these conditions. We evaluate antioxidant-rich dietary patterns, selected nutraceuticals, myocardial ischemia-reperfusion injury as a clinical exemplar, rare redox-imbalance disorders as mechanistic stress models, and emerging gene-based reinforcement of endogenous antioxidant systems. Rather than proposing clinical targets, we present an integrative, hypothesis-generating framework illustrating how coordinated lifestyle-driven modulation of redox balance may simultaneously influence multiple disease trajectories. Collectively, the evidence supports a unified redox framework for multi-disease prevention for multi-disease prevention and future intervention design.
    Keywords:  AMPK; SASP; TMAO; antioxidants; cardiovascular aging; gene therapy; inflammation; lifestyle medicine; longevity; mTOR; microbiome; nutraceuticals; orphan diseases; oxidative stress; senescence
    DOI:  https://doi.org/10.3390/nu18061007
  26. J Cell Biol. 2026 Apr 06. pii: e202603036. [Epub ahead of print]225(4):
      In this issue, Yan et al. show that mitochondrial targeting signals (presequences) vary widely in import strength. Using the quantitative MitoLuc and PotLuc assays, they dissect multiple parameters of protein import and reveal how presequence features influence mitochondrial targeting efficiency and stress sensitivity.
    DOI:  https://doi.org/10.1083/jcb.202603036
  27. Sci Adv. 2026 Mar 27. 12(13): eaeb1174
      Mitochondrial dysfunction and dysregulated proteolysis drive Huntington's disease (HD), tauopathy, and related neurodegenerative disorders. Calpain-2, a Ca2+-activated protease restrained by calpastatin (CAST), is pathologically overactivated, yet no therapies directly target this axis. We identify A36, a brain-penetrant small molecule derived from CHIR99021 that selectively stabilizes the CAST-calpain-2 complex without inhibiting GSK3. A36 acts as a protein-protein interaction stabilizer, enhancing CAST-calpain-2 binding, preventing CAST degradation, and thereby limiting calpain-2 activation and mitochondrial damage. In patients with HD induced pluripotent stem cell-derived neurons and mutant mouse striatal neurons, A36 normalized mitochondrial morphology and membrane potential, reduced oxidative stress, and improved survival. In vivo, A36 displayed favorable pharmacokinetics and central nervous system exposure; treatment reduced striatal neurodegeneration, mutant huntingtin aggregation, and motor deficits in HD R6/2 mice, and lowered phosphorylated tau, neuroinflammation, and cognitive decline in tauopathy PS19 mice. These findings establish pharmacological stabilization of CAST-calpain-2 as a therapeutic strategy and position A36 as a mechanism-selective modulator with broad neurodegenerative disease potential.
    DOI:  https://doi.org/10.1126/sciadv.aeb1174
  28. Molecules. 2026 Mar 22. pii: 1050. [Epub ahead of print]31(6):
       BACKGROUND: Main risk factors associated with the development of sarcopenia (coexistence of muscle mass loss and dysfunction) are a sedentary lifestyle coupled with obesity. Associated mitochondrial dysfunction leads to energy deficits and perturbations in the balance between protein synthesis and degradation, thereby triggering muscle dysfunction or atrophy. Aside from exercise, which is challenging to implement and maintain, particularly in women, treatments for diminishing sarcopenia are scarce. The objective of the present study was to evaluate the effect of the flavanol (-)-epicatechin (EC) in a hypercaloric diet-induced obese female rat model. Muscle strength and endurance, as well as relative mitochondrial DNA content in skeletal muscle, were assessed.
    METHODS: Female rats were fed a hypercaloric diet to induce obesity, as evidenced by increases in body weight, Lee index, and lipid profile alterations, and by abdominal fat accumulation, and to promote a sarcopenic phenotype. Functional tests of grip strength and mobility (treadmill) were performed. Mitochondrial relative content was evaluated by measuring the ratio of mtDNA/nuclear DNA, and the expression of genes related to mitochondrial biogenesis (Pgc1-α, Tfam), fusion (Mfn1 and Opa1), fission (Drp1 and Fis1), and mitophagy (Pink1 and Pkn), and function; citrate synthase and Ucp3 were also evaluated.
    RESULTS: A significant decrease in mobility and strength was observed in obese female rats, accompanied by reduced mitochondrial numbers, activity, and dynamics, but not by changes in muscle size or weight. Treatment with EC induced mitochondrial biogenesis and positive changes in mitochondrial dynamics (fission and fusion) and activity, as measured indirectly by changes in citrate synthase and Ucp3 expression.
    DISCUSSION: Results reinforce the potential of EC as a modulator of mitochondrial function in dysfunctional conditions associated with obesity, thereby attenuating the mechanisms underlying sarcopenia.
    Keywords:  epicatechin; females; obesity; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/molecules31061050
  29. J Mark Access Health Policy. 2026 Mar 06. pii: 14. [Epub ahead of print]14(1):
      Population-adjusted indirect comparisons (PAICs), including Matching-Adjusted Indirect Comparison and Simulated Treatment Comparison, are increasingly used to inform health technology assessments. These methods offer a pragmatic approach to generating comparative evidence between treatments when head-to-head trial data are unavailable and standard indirect treatment comparison methods are unfeasible. In rare diseases, however, PAICs often face substantial methodological challenges arising from small sample sizes, limited covariate overlap, and the frequent use of unanchored comparisons that rely on unverifiable assumptions. These limitations can lead to unstable estimates, reduced precision, and bias that may undermine the reliability of findings. Methodological refinements-such as optimized weighting, Bayesian approaches, and doubly robust estimators-provide some improvements but do not resolve these fundamental issues. Current European Joint Clinical Assessment guidance recommends that anchored PAICs be applied with great caution, while unanchored PAICs are considered highly problematic, and other methods should be used instead. We argue that PAICs can play a supportive role within a multidimensional and deliberative HTA process, contributing to comparative assessment alongside other evidence sources when available data are limited. However, their results require careful interpretation and transparent communication of uncertainty. Future research should prioritize the further development of formal frameworks to quantify bias and systematically assess robustness, thereby preventing overstatement of the credibility of PAIC-derived evidence in rare disease contexts.
    Keywords:  matching-adjusted indirect comparison; rare diseases; simulated treatment comparison
    DOI:  https://doi.org/10.3390/jmahp14010014
  30. Int J Mol Sci. 2026 Mar 11. pii: 2579. [Epub ahead of print]27(6):
      Multiple sclerosis (MS) is a highly disabling chronic autoimmune disease of the central nervous system with neuroinflammatory and neurodegenerative alterations found in the white and grey matter of the brain. The pathogenesis of MS is complex and not fully understood. Mitochondrial dysfunctions are suspected to play an important role. The visual system is often affected in MS. Optic neuritis is a frequent symptom, but also the retina itself, including retinal synapses appear compromised in MS independent from demyelination of the optic nerve. A previous study demonstrated synapse-specific alterations of mitochondria in photoreceptor synapses in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS at day 9 after injection, an early time point in pre-clinical EAE. In the present study, we analysed even earlier stages of pre-clinical EAE for possible alterations of synaptic mitochondria. For this purpose, we performed qualitative and quantitative immunolabelling analyses of the mitochondrial cristae organising protein MIC60 at retinal synapses and functional analyses by measuring synaptic mitochondrial membrane potential (during rest and depolarisation-induced exocytosis) and visually guided behaviour (optometry analyses). At day 3 after injection, morphological and functional data were indistinguishable between MOG/CFA-injected EAE mice and CFA-injected control mice. But already on day 5 after injection, we observed a decreased expression of the mitochondrial MIC60 protein at synaptic mitochondria, a decreased synaptic mitochondrial membrane potential at rest, an enhanced drop of mitochondrial membrane potential during stimulated exocytosis and a decreased visual performance of the respective EAE mice. These data argue that synaptic pathology in the EAE retina begins as early as day 5 after injection. Our data propose that dysfunctions of mitochondria play an important role already at the very early stages of synaptic pathology in EAE.
    Keywords:  EAE; MIC60; mitochondria; mitochondrial membrane potential; multiple sclerosis; retina; ribbon synapse
    DOI:  https://doi.org/10.3390/ijms27062579
  31. Genes (Basel). 2026 Mar 23. pii: 359. [Epub ahead of print]17(3):
      To comprehend the current state and future of newborn screening (NBS), it is essential to understand its history. Over the past six decades, this well-established and exemplary population-based screening program has been guided by screening principles dating back more than half a century. Advances in laboratory and point-of-care testing, diagnostic methods, and a surge of available treatments and even cures have made it challenging to balance screening criteria that have not kept pace with the current landscape. The availability to screen as well as the demand from parents and stakeholders to screen for more and increasingly complex conditions while limiting the retention of NBS specimens and genetic material has been both exciting and challenging. This paper shares the history of NBS in the United States, followed by the development and integration of genomic sequencing as a complement to current practice. It explores evidence supporting the concomitant use of biomarker- and DNA-sequencing-based approaches for NBS, how disorders are selected for inclusion, and available treatments, and offers recommendations regarding what to consider and how to proceed in this ever-changing NBS landscape.
    Keywords:  genetic disorders; genome sequencing; newborn screening
    DOI:  https://doi.org/10.3390/genes17030359
  32. PLOS Glob Public Health. 2026 ;6(3): e0003516
      Rare diseases (RD) are not rare collectively, affecting around 300 million people globally and 96 million in India. These diseases have not been prioritized in most low- and middle-income countries' health policies. India launched its first functional RD policy in 2021. Successful policy implementation requires the active participation of diverse stakeholders. In the context of rare diseases, such collaboration has been particularly instrumental in driving policy execution and systemic transformation. RDs are not well researched in India and there are no studies on mapping and analysis of RD stakeholders. Thus, this study aims to comprehensively map all stakeholders in the RD ecosystem in India, to understand their power, positions, influence, and needs. In-depth analysis of stakeholder perspective was done through semi structured interviews and news-media analysis. This is an exploratory study aimed to map all RD stakeholders and present their perspectives without drawing conclusive inferences. We found that stakeholders such as local and international patient organizations, think tanks, research communities, policymakers, local and multinational companies engage extensively with RD activities. However, high influence is limited largely to policymakers, and a few rare disease specialist physicians, with some participation of other groups. A significant lack of awareness and knowledge about RDs was found among general healthcare professionals and allied health professionals. This places a disproportionate burden on a limited pool of specialized doctors, predominantly concentrated in a few cities. Thus, for better implementation of RD policy it is crucial to encourage diverse stakeholder engagement and participation. The study highlighted stakeholders with high and low engagement. Highly engaged stakeholders should be leveraged for policy implementation, while awareness and training programs need to be targeted towards low engagement groups.
    DOI:  https://doi.org/10.1371/journal.pgph.0003516
  33. Chem Res Toxicol. 2026 Mar 24.
      We revealed in this study that prolonged aristolochic acid I (AA-I) exposure leads to an increase in oxidative stress level, and decreases in mitochondrial DNA (mtDNA) copy numbers and ATP levels in the heart, kidneys, and liver of exposed mice. The most significant decreases in ATP levels were observed in the heart and kidneys, both of which are high-energy-consuming organs. Additionally, high levels of AA-DNA adducts were detected in the mtDNA isolated from the kidneys. These combined observations of AA-induced mitochondrial dysfunction in key energy-consuming organs may help explain previous observations of rapidly progressive renal failure and the later onset of milder hypertension in patients with aristolochic acid nephropathy.
    DOI:  https://doi.org/10.1021/acs.chemrestox.6c00060
  34. Life (Basel). 2026 Mar 16. pii: 478. [Epub ahead of print]16(3):
      The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native physiological substrates remains elusive. Here, we present the high-resolution cryo-EM structure of the human LonP1 hexamer actively engaging its native substrate, TFAM. The reconstruction reveals a distinct bipartite search-and-shred mechanism. Unlike its bacterial homologs, the human N-terminal domain (NTD) adopts a compact architecture acting as a selective vestibule to recruit and initially unfold the substrate tertiary structure. Subsequently, the polypeptide is threaded through the central channel via a hand-over-hand mechanism driven by a spiral array of aromatic pore-loops. This structural framework provides a mechanistic rationale for the spatial segregation of LonP1 and offers a template for targeting mitochondrial proteostasis in human diseases.
    Keywords:  Lon protease; cryo-EM; native substrate
    DOI:  https://doi.org/10.3390/life16030478
  35. Trends Endocrinol Metab. 2026 Mar 25. pii: S1043-2760(25)00267-X. [Epub ahead of print]
      The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.
    Keywords:  NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox
    DOI:  https://doi.org/10.1016/j.tem.2025.12.003
  36. Metabolites. 2026 Feb 24. pii: 148. [Epub ahead of print]16(3):
      Small extracellular vesicles (sEVs; commonly referred to as "exosomes" in many studies) are nanoscopic messengers released by healthy and diseased cells that mediate intercellular communication by transferring proteins, lipids, and nucleic acids to local or distant recipient cells. In this narrative review, we synthesize recent evidence linking tissue-derived sEVs to neurological disorders (including neurodegeneration and traumatic brain injury), metabolic syndrome, cardiovascular diseases, cancers, and bone diseases, with a particular emphasis on CNS-periphery crosstalk across the blood-brain barrier. Compared with prior reviews that focus on single organ systems, we highlight cross-disease, cross-tissue mechanisms and summarize candidate biomarker cargos and therapeutic strategies in dedicated tables. While accumulating data support brain-body communication via sEVs, the concept of CNS-derived sEVs acting as a "third central efferent pathway" is presented here as an emerging hypothesis that complements-rather than replaces-neuronal and endocrine signaling. Overall, tissue-derived sEVs represent a promising but still evolving platform for diagnostic and therapeutic innovation, warranting standardized isolation/characterization and further clinical validation.
    Keywords:  biomarker; extracellular vesicles (EVs); inter-organ crosstalk; small extracellular vesicles (sEVs); therapeutic delivery
    DOI:  https://doi.org/10.3390/metabo16030148
  37. Mol Neurobiol. 2026 Mar 26. pii: 525. [Epub ahead of print]63(1):
      Mitochondrial dysfunction is central to Parkinson's disease (PD), but assessing it in vivo remains challenging. Plasma L1CAM-immunocaptured putative neuron-derived exosomes (NDEs) offer minimally invasive access to brain molecular signatures. This study investigated whether mitochondrial complex (MC) proteins in NDEs are altered in PD and explored their association with clinical features. Plasma putative NDEs were isolated from 28 patients with PD and 33 normal controls (NCs) by L1CAM immunocapture. Levels of mitochondrial subunits-NDUFS3 (Complex I), UQCRC2 (Complex III), MT-CO1 (Complex IV), and ATP5F1A (Complex V)-and the antioxidant enzyme SOD1 were quantified by ELISA. Correlations with clinical severity and diagnostic performance were analyzed. Compared with NCs, PD patients exhibited significantly lower levels of NDUFS3 and UQCRC2 in NDEs (p < 0.05, after FDR correction). NDUFS3, UQCRC2, and SOD1 showed modest inverse correlations with motor symptom severity (R = -0.26). The NDUFS3/UQCRC2 combination yielded an AUC of 0.763 (95% CI: 0.638-0.862) with 100% sensitivity and 51.5% specificity in this exploratory cohort, indicating limited discriminative capacity. These exploratory findings suggest that mitochondrial proteins within plasma putative NDEs may reflect neuronal mitochondrial alterations in PD. The NDUFS3/UQCRC2 combination represents a candidate signature warranting validation in larger cohorts.
    Keywords:  Biomarkers; Mitochondrial complex; Mitochondrial dysfunction ; Neuron-derived exosomes; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-026-05817-9
  38. Stem Cell Rev Rep. 2026 Mar 24.
      Cell therapy for neurodegenerative diseases (NDs) is considered a promising strategy to halt disease progression. Currently, most clinically applied cells are derived from two-dimensional (2D) cultures. However, 2D-cultured mesenchymal stem cells (MSCs) are prone to aging and functional deterioration after multiple passages, and the availability of neural precursor cells for cell replacement therapy remains limited. In contrast, three-dimensional (3D) cell cultures have garnered significant attention due to their unique 3D spatial interactions. The unique spatial architecture of 3D culture not only enhances cell-cell and cell-extracellular matrix (ECM) interactions in MSC spheroids, thereby preserving MSCs properties, but also facilitates developmental processes of brain organoids derived from pluripotent stem cells, including embryogenesis, morphogenesis, and organogenesis. This review highlights the therapeutic ability of 3D-cultured MSC spheroids and brain organoids for NDs and summarizes advanced engineering platforms for their production. Future research should integrate the strengths of both technologies by establishing standardized quality control systems and scalable production processes to harness the microenvironmental modulation capacity of MSC spheroids and the precise cell replacement ability of brain organoids, ultimately advancing personalized therapies for NDs.
    Keywords:  3D cell culture; Microfluidic; Neurodegenerative diseases; Organoids; Stem cell spheroids
    DOI:  https://doi.org/10.1007/s12015-026-11101-z
  39. Cells. 2026 Mar 19. pii: 551. [Epub ahead of print]15(6):
      Cellular senescence, including replicative senescence (RS) and stress-induced premature senescence (SIPS), is a state of the permanent arrest of cell growth, which can occur in proliferative cells and post-mitotic cells. Cellular senescence is believed to contribute importantly to aging and aging-related diseases. Although several hypotheses, including telomere shortening, oncogene activation, oxidative stress, DNA damage, and mitochondrial dysfunction, have been proposed, the mechanisms underlying cellular senescence in either physiological or pathological conditions remain poorly understood. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue type and urokinase type of plasminogen activators (tPA and uPA), has multiple functions. PAI-1 expression increases with age and in many aging-related diseases. Importantly, increased PAI-1 expression is not only a marker but also a mediator of cell senescence induced by different stimuli in vitro and in vivo. This review focuses on the recent advance in the role of PAI-1 in cell senescence during aging and in aging-related diseases as well as the potential mechanisms by which PAI-1 promotes cell senescence.
    Keywords:  PAI-1; aging; aging-related diseases; cell senescence
    DOI:  https://doi.org/10.3390/cells15060551
  40. Regen Ther. 2026 Jun;32 101102
       Background: This study aimed to summarize the current practices and mechanisms of market access, pricing and reimbursements for gene therapy products (GTPs) in major jurisdictions, and to identify the key barriers and facilitators affecting the translation of GTPs from regulatory approval to market access across the countries.
    Methods: An integrated scoping review was conducted to identify publicly available literature and documents on the marketing access, pricing and reimbursement of GTPs under the PRISMA-ScR guidelines. Key barriers and potential enablers were identified and thematically analyzed using the Consolidated Framework for Implementation Research (CFIR).
    Results: Thirty-four studies published between 2020 and May 2025 were included in this study. A total of 21 GTPs had received market authorization from the FDA, EMA, PMDA, or NMPA, targeting four major disease areas: genetic diseases (n = 8), hematologic disorders (n = 7), cancer-related indications (n = 5), and vascular diseases (n = 1). Despite growing approvals, substantial variation exists across jurisdictions in terms of access, pricing, and reimbursement pathways. Commonly reported challenges include concerns over budget impact and affordability (n = 25), uncertainty in clinical evidence (n = 24), limited value assessment frameworks (n = 17), lack of clearly defined reimbursement pathways (n = 17), misalignment between regulatory requirements and real-world implementation capacity (n = 15), and insufficient delivery infrastructure (n = 12). To address these barriers, 15 studies proposed potential solutions involving five areas: cross-country regulatory alignment and processes streaming (n = 3), pricing and reimbursement reform including budget caps, annuity payments and patent buyouts (n = 12), enhanced evidence generation through RWE and adaptive trial designs (n = 5), institutional infrastructure and workforce capacity building (n = 4), and early multi-stakeholder engagement among regulators, HTA bodies, payers, healthcare providers, and patients to align expectations and accelerate access (n = 7).
    Conclusion: By adopting the CFIR framework, this study has systematically identified the key challenges and potential solutions in translating GTPs from regulatory approval to patient access. To ensure effective access, it is essential to adopt context-adapted value assessment models, diversified payment mechanisms, and coordinated policy strategies to guide the implementation processes. Building on international experiences, advancing localized implementation strategies encompassing tailored value frameworks, innovative payment models, regional pilots and institutional readiness offer actionable pathways for developing forward-looking access and reimbursement systems for GTPs.
    Keywords:  Advanced therapy medicinal products; Gene therapy products; Market access; Market entry agreements; Payment; Reimbursement
    DOI:  https://doi.org/10.1016/j.reth.2026.101102
  41. Front Cell Dev Biol. 2026 ;14 1761278
       Introduction: The decline of mitochondrial homeostasis and proteostasis, the two key cell quality control mechanisms, is the hallmark of aging and age-related diseases. One of the most notable examples is the age-related progressive loss of muscle mass, quality, and strength --a condition known as sarcopenia. In atrophic muscle, mitochondrial dysfunction and proteostasis impairment frequently occur together, indicating a potential association between the decline of mitochondrial homeostasis and proteostasis. However, the mechanism by which these two modes of cell quality control are coordinated remains poorly understood.
    Methods: We employed dexamethasone-induced muscle atrophy models in both larval and adult zebrafish to investigate the role of cell stress responses in muscle maintenance. Mitochondrial stress was assessed by measuring the mitochondrial unfolded protein response (UPRmt) activity using qRT-PCR and reporter analyses. Proteostasis impairment was evaluated by detecting insoluble polyubiquitinated protein aggregates via Western blotting. Muscle integrity was examined histologically in larval and adult tissues. We performed these assays in sirt1 loss of function conditions (genetic mutation and pharmacological inhibition). Furthermore, to elucidate the mechanism by which Sirt1 regulates proteostasis and muscle preservation, we inhibited the mitochondrial fatty acid oxidation (mFAO) using etomoxir.
    Results: Inhibition of Sirt1 markedly exacerbated muscle deterioration and proteostasis impairment under dexamethasone-induced muscle atrophy in zebrafish. Mechanistically, Sirt1 is required for activation of the UPRmt, which in turn promotes expression of the mFAO gene cpt1b. Pharmacological inhibition of Cpt1 using etomoxir phenocopied the defects in muscle integrity and proteotoxic stress observed following Sirt1 inhibition. Importantly, enhancement of proteostasis via hormetic heat shock partially rescued the etomoxir-induced muscle defects.
    Discussion: We have demonstrated that muscle atrophic stress induced by dexamethasone treatment activates the UPRmt in zebrafish. The UPRmt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Notably, suppressing the UPRmt via Sirt1 inhibition leads to protein aggregation and the ultimate loss of muscle mass, indicating a link between mitochondrial function and proteostasis. We have further shown that mitochondrial metabolism plays a role in proteostasis regulation, as pharmacological inhibition of the mFAO exacerbates dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking UPRmt signaling to myocellular proteostasis, and highlight the activity of Sirt1, which coordinates these two key cell quality control mechanisms, in muscle preservation during muscle atrophy.
    Keywords:  SIRT1; UPRmt; mitochondrial dysfunction; mitochondrial homeostasis; muscle atrophy; myocellular proteostasis; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2026.1761278