bims-polgdi Biomed News
on POLG disease
Issue of 2026–08–23
fifty papers selected by
Luca Bolliger, lxBio
  1. Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
  2. Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.
  3. Recurrent Single-Nucleotide Insertions in the Mitochondrial Second Light-Strand Promoter Cause Tubulointerstitial Kidney Disease.
  4. Anesthetic management of patient with myoclonic epilepsy with ragged red fibers, a mitochondrial disease - A case report.
  5. The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
  6. Allosteric rewiring of mitochondrial stress signaling through Miro1.
  7. Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.
  8. Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
  9. Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).
  10. Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
  11. Urolithins in clinical translation: from gut microbial metabolites to precision interventions.
  12. Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
  13. Giant panda sign: an adult case of single large-scale mitochondrial DNA deletion syndrome.
  14. Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
  15. Cell-Free Circulating Mitochondrial DNA: A Biomarker of Physiological Stress and Adaptation in Athletes.
  16. Sirtuins in mitochondrial physiology and energy homeostasis.
  17. When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.
  18. ArchSpiral: An iPad-Based Digital Archimedean Spiral Assessment for Objective Motor Evaluation in Rare Diseases.
  19. Artificial intelligence agents and agentic artificial intelligence applied to precision medicine.
  20. Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.
  21. Mitochondrial dysfunction in schizophrenia and psychotic disorders: Implications for antipsychotic drug mechanisms.
  22. A Heterozygous Pathogenic Variant in POLG Associated With Isolated Neuropathic Pain and Rhabdomyolysis.
  23. Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.
  24. A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.
  25. Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences.
  26. MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide.
  27. Real-Time, Noninvasive Evaluation of Mitochondrial Function Using Resonance Raman Spectroscopy.
  28. Application of Exosome Derived from Mesenchymal Stem Cells after Cerebral Stroke: The Role of Exosomes on Mitochondrial Dysfunction.
  29. Human-induced pluripotent stem cells in psychiatric disorders: An inflammatory perspective.
  30. Crisis readiness for rare disease populations: learnings and recommendations by the European Reference Networks.
  31. Mitochondrial Dysfunction in Ifosfamide-Induced Nephrotoxicity: Mechanisms and Possible Interventions.
  32. Mitochondrial dynamics in Huntington's disease.
  33. Recommendations for generating real-world evidence with regulatory-grade relevance and reliability.
  34. Restoring mitochondria and associated chaperone function: New therapeutic strategies for neurodegenerative diseases.
  35. Harnessing neuromodulation to target microglial activity in neurodegenerative diseases.
  36. Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.
  37. Targeting cellular senescence through nutritional senotherapeutics in brain aging and neurodegenerative diseases.
  38. Patient experience data as a methodological and strategic innovation in clinical trial design.
  39. Nonequilibrium temperature fluctuations as modulators of mitochondrial elastocapillary stability.
  40. A human cytokine response atlas to reconstruct underlying gene regulatory networks.
  41. Mitochondrial-centric regulatory networks in MASLD: integrating quality control, organelle interactions, and gut-liver communication.
  42. Enhancing Parents' Experiences of Paediatric Genomic Testing in Usual Outpatient Care: Insights From a Multi-Perspective Qualitative Study.
  43. Diagnostic delay, care needs, and trust in healthcare among persons with rare disease and their next of kin living in Sweden.
  44. Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
  45. Stem cell-based therapies in pediatric disorders: translational advances, unresolved challenges, and future horizons.
  46. Mitochondrial dysfunction in neurodegenerative diseases: Mechanisms and therapeutic advances.
  47. Severe mitochondrial cardiomyopathy with m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene: A study of large family analysis.
  48. Multi-Omics Integration in Clinical Practice for the Identification of Genetic Variants in Rare Diseases.
  49. The GLP-1-Mitochondria Axis in Metabolic Aging.
  50. Evaluating Test Accuracy Study Designs for Rare and Ultra-rare Conditions: Application to Newborn Blood Spot Screening.
  1. WIREs Mech Dis. 2026 Jul-Aug;18(4):18(4): e70014
    Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
    Rosa Di Lorenzo, Rola S Zeidan, Riccardo Calvani, Vito Pesce, Emanuele Marzetti, Anna Picca.
      Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.
    DOI:  https://doi.org/10.1002/wsbm.70014
  2. Metabolomics. 2026 Aug 20. pii: 140. [Epub ahead of print]22(5):
    Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.
    Marianne Venter, Karin Terburgh, Jeremie Z Lindeque, Emi Ogasawara, Mirian C H Janssen, Jan A M Smeitink, Kazuto Nakada, Roan Louw.
      Pathogenic mitochondrial DNA (mtDNA) mutations contribute to a broad spectrum of both common and rare metabolic diseases. However, clinical presentation is highly variable and only partially explained by the proportion of mutant mtDNA or heteroplasmy. With the relationship between mutation burden and clinical manifestation poorly defined, controlled models are required to uncover underlying mechanisms. Here, we explore the metabolic consequences of increasing heteroplasmy in a well-characterised mouse model harbouring a pathogenic mtDNA deletion. Untargeted urinary metabolomics reveals distinct mutation load-dependent metabolic shifts with some metabolites declining early on, while others exhibit threshold-like increases beyond ~ 60% mutation load - the level at which lactic acidemia and OXPHOS defects become apparent in this model. To assess translational relevance, we examined these heteroplasmy-associated metabolites in urine from patients carrying the most common mtDNA mutation, m.3243 A > G. Several of these metabolites were differentially expressed in patients relative to controls, with conserved directionality across species. Among these, 2-hydroxyisovalerate (2-HIVA), which was most strongly affected in the mouse model, also emerged as the top discriminator in patients. Receiver operating characteristic analysis indicated that urinary 2-HIVA has strong discriminatory power, supporting its potential utility as a biomarker for mtDNA-based disorders. These findings enhance our understanding of mtDNA-related disease pathophysiology and establish a foundation for further validation studies.
    Keywords:  2-Hydroxyisovalerate; Heteroplasmy; M.3243A > G; Metabolomics; Mito-mice; Mitochondrial disease; MtDNA
    DOI:  https://doi.org/10.1007/s11306-026-02518-1
  3. medRxiv. 2026 Aug 03. pii: 2026.07.31.26359118. [Epub ahead of print]
    Recurrent Single-Nucleotide Insertions in the Mitochondrial Second Light-Strand Promoter Cause Tubulointerstitial Kidney Disease.
    Klára Svojšová, Kendrah O Kidd, Dita Mušálková, Tereza Kmochová, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Veronika Barešová, Helena Trešlová, Martin Radina, Lea Pavlovičová, Jakub Sikora, Abbigail Taylor, Lauren Martin, Antonio Sanchez, Nelson Weller, Thomas Pinder, Megan E Astley, Xiangling Wang, Abhijit Dixit, Stephen M Korbet, Colm Rowan, Peter J Conlon, Karina Soto, Afonso Santos, Marek Mysliveček, Jiří Zeman, Hana Štufková, Hana Hansíková, Kateřina Tauchmannová, Petr Pecina, Vilma Kaplanová, Marek Vrbacký, Tomáš Mráček, Örjan Persson, Claes M Gustafsson, Maria Falkenberg, Martina Živná, Anthony J Bleyer, Stanislav Kmoch.
       Introduction: Mitochondrial DNA (mtDNA) is not routinely analyzed in inherited kidney disease. We evaluated mtDNA variation in families who remained genetically unresolved despite extensive testing.
    Methods: We reviewed pedigrees from the Wake Forest-Charles University Rare Inherited Kidney Disease Registry to identify genetically unresolved families with suspected maternal inheritance, performed mtDNA genotyping, clinically characterized variant carriers, and functionally evaluated disease-associated mitochondrial variants.
    Results: Among 33 families with evidence of maternal inheritance, 18 (55%) carried one of seven disease-associated mtDNA variant types, including homoplasmic recurrent single-nucleotide insertions in the second light-strand promoter (LSP2; 9 families), novel MT-TW and MT-TL2 variants (2 and 1 families, respectively), and previously reported MT-TF and heteroplasmic MT-ND5 variant (5 and 1 families, respectively). In 16 families, variants occurred on distinct haplotypes, consistent with independent mutational events and rapid enrichment to homoplasmy across generations. Maternal transmission was strongly supported, with below-normal kidney function observed in 54/60 (90%) offspring of affected mothers versus 1/17 (6%) offspring of affected fathers (p = 1.23 × 10 ⁻11 ). Pathogenicity was further supported by predicted deleterious structural effects and functional evidence of impaired mitochondrial transcription and translation, respiratory chain deficiency, and CoQ10 depletion. Affected individuals predominantly presented with chronic tubulointerstitial kidney disease, occasionally accompanied by gout and only sporadically with extrarenal manifestations. The rate of kidney disease progression appeared to vary both between and within families. Overall, 109/119 genetically affected individuals or obligate at-risk carriers were clinically affected; most unaffected carriers were younger than 45 years of age. Clinical status was unavailable for an additional 66 obligate at-risk carriers.
    Conclusions: These findings establish the physiological relevance of the LSP2 promoter, support routine assessment of the mitochondrial genome in inherited kidney disease, and highlight mtDNA variants as an important cause of familial and sporadic tubulointerstitial kidney disease of previously unexplained etiology.
    Lay Summary: Many inherited kidney diseases remain unexplained because routine genetic testing focuses on genes in the cell nucleus and does not examine mitochondrial DNA-the small genome in the cell's energy-providing mitochondria, inherited only from the mother. We studied 33 families with chronic kidney disease whose family histories suggested maternal inheritance and identified disease-causing mitochondrial DNA variants in 18 (55%). Nine families carried variants in LSP2, a recently discovered mitochondrial regulatory element, highlighting its importance in normal mitochondrial function and disease. Others carried pathogenic variants in mitochondrial tRNA genes required for mitochondrial protein synthesis. Laboratory studies showed that these variants impair mitochondrial energy conversion. In all families, the predominant manifestation was slowly progressive kidney disease, sometimes leading to dialysis or kidney transplantation. These findings identify pathogenic mitochondrial DNA variants as an underrecognized cause of inherited kidney disease and support the inclusion of mitochondrial DNA analysis in routine genetic testing.
    DOI:  https://doi.org/10.64898/2026.07.31.26359118
  4. Anesth Pain Med (Seoul). 2026 Aug 19.
    Anesthetic management of patient with myoclonic epilepsy with ragged red fibers, a mitochondrial disease - A case report.
    Yunho Kang, Bo-Eun Kim, Ji Hyeon Kim, Se Hun Park.
       Background: Myoclonic epilepsy with ragged red fibers (MERRF) is a rare mitochondrial disorder caused by pathogenic mutations in mitochondrial DNA. Anesthetic management in these patients is challenging because, commonly used anesthetic agents may exacerbate mitochondrial dysfunction and increase the risk of perioperative respiratory, cardiac, and metabolic complications.
    Case: A 44-year-old woman with MERRF underwent a unilateral salpingo-oophorectomy. General anesthesia was induced applying low-dose midazolam, remifentanil and rocuronium, and maintained with desflurane and remifentanil. Perioperative management focused on minimizing metabolic stress through the maintenance of normothermia, avoidance of lactate-containing solutions, and close hemodynamic and respiratory monitoring. The intraoperative and immediate postoperative courses were uneventful.
    Conclusions: This case highlights that safe anesthetic care in patients with MERRF can be achieved through comprehensive preoperative evaluation, cautious selection and dosing of anesthetic agents, strict metabolic control, and perioperative monitoring. Hence, individualized anesthetic strategies are essential to optimize perioperative outcomes in patients with mitochondrial disorders.
    Keywords:  Anesthesia, general; DNA, mitochondrial; Mitochondrial complex; Mitochondrial myopathies; Myoclonic epilepsy with ragged red fibers; Oxidative phosphorylation
    DOI:  https://doi.org/10.17085/apm.26610
  5. Hum Reprod Update. 2026 Aug 19. pii: dmag022. [Epub ahead of print]
    The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
    Brianna L Kline, Alison G Compton, Ann E Frazier, Svenja Pachernegg, Andrew H Sinclair, Katie L Ayers, Elena J Tucker.
       BACKGROUND: Female infertility occurs in ∼37% of infertile couples, while premature ovarian insufficiency (POI) impacts 1-3.7% of women under the age of 40. POI is clinically heterogeneous, with various genetic pathways associated with its pathogenesis. Mitochondrial diseases (MDs) are a broad group of clinically heterogeneous genetic conditions characterized by aberrantly functioning mitochondria. MDs have a disproportionate burden on organs and tissues with increased aerobic/energy demands, such as the heart, skeletal muscles, brain, and ovaries. The role of mitochondria in female fertility and ovarian reserve is increasingly being recognized.
    OBJECTIVE AND RATIONALE: A comprehensive understanding of the role of mitochondria in the maintenance of female fertility is pertinent to better understanding female reproductive potential. In a world with increasing demand for assisted reproductive technologies (ART), due to a considerable rate of global infertility, there is a need to better understand the genes and pathways involved in female reproduction. This review summarizes, evaluates, and explores the current knowledge of mitochondria-associated genes and variants that are implicated in POI, including their function and dysfunction in female reproduction.
    SEARCH METHODS: We searched articles in the PubMed database, containing the following key words: premature ovarian insufficiency, mitochondria, mitochondrial, premature ovarian failure, genetics, mitochondrial DNA, mtDNA, mitochondrial protein, infertility, premature menopause, mitochondrial donation, assisted reproductive technologies, electron transport chain, oxidative phosphorylation (OXPHOS), mitochondrial disease, oocyte, oogenesis, meiosis, in vitro fertilization, mitoribosome, Perrault syndrome, and ovarioleukodystrophy, in the English-language literature until March 2026.
    OUTCOMES: Genetic variants that affect mitochondrial genes/proteins can negatively impact ovarian function. Various mitochondrial pathways are associated with female infertility, reflecting the broad sensitivity of ovarian reserve to mitochondrial dysfunction. Mitochondrial dysfunction and infertility can present in isolation or as part of a syndrome. Infertility in women may be the first clinical sign of a MD. Conversely, POI may be an underappreciated symptom of MDs.
    WIDER IMPLICATIONS: This review draws attention to the fact that females with MDs should be monitored for POI so it can be detected early for prompt and appropriate therapeutic interventions, such as hormone replacement therapy. This is known to mitigate the risk of comorbidities such as cardiovascular and bone disease and will optimize long-term health outcomes. Of equal importance, our review highlights the potential for girls and women presenting with apparently 'isolated' POI to harbour pathogenic variants in MD-associated genes, therefore putting these individuals at risk of developing further clinical manifestations of MDs. We emphasize the need for surveillance in these cases for hearing loss, vision disturbance, cardiomyopathy, muscle weakness and neurodegeneration, depending on the genetic cause. Given that mitochondrial function is essential to female fertility, future therapies for mitochondria-associated infertility could involve mitochondrial supplementation to improve the mitochondrial fraction or mitochondrial donation to optimize the likelihood of reproductive success. Finally, we also discuss the current landscape of biomarkers as potential early diagnostic tools for POI. Whilst currently rudimentary in their clinical utility, the further development of early screening methods will be invaluable for the detection, diagnosis, and early intervention of POI.
    REGISTRATION NUMBER: N/A.
    Keywords:  POI; genetics; infertility; mitochondria; mitochondrial disease; premature ovarian insufficiency
    DOI:  https://doi.org/10.1093/humupd/dmag022
  6. Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073
    Allosteric rewiring of mitochondrial stress signaling through Miro1.
    Layla Drwesh, Julia C Fitzgerald.
      In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.011
  7. Gerontology. 2026 Aug 17. 1-21
    Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.
    Chaodong Han, Zilian Zhang, Yafeng Song.
      : Background: Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades. Summary: This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming. Crucially, we examine how mitochondria act as signaling hubs for inter-organ crosstalk. Through the secretion of mitokines (e.g., FGF21, GDF15) and the release of damage-associated molecular patterns (DAMPs), dysfunctional mitochondria trigger chronic inflammation via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 inflammasome (NLRP3) pathways, actively driving systemic aging within the skeletal muscle-brain and adipose/liver-cardiovascular axes. Additionally, this paper synthesizes current therapeutic interventions, ranging from lifestyle modifications and nicotinamide adenine dinucleotide (NAD+) precursors to frontier technologies like mitochondrial transplantation and gene editing. Key Messages: While promising in animal models, clinical translation of these interventions is currently hindered by limited long-term safety data and evidence gaps. Therefore, mitochondria-targeted studies incorporating integrated multi-organ phenotyping are urgently required to establish robust strategies for extending human healthspan.
    DOI:  https://doi.org/10.1159/000553430
  8. Sci Adv. 2026 Aug 21. 12(34): eaed6318
    Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
    Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.
      Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.
    DOI:  https://doi.org/10.1126/sciadv.aed6318
  9. Neurotherapeutics. 2026 Aug 18. pii: S1878-7479(26)00218-7. [Epub ahead of print] e01048
    Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).
    Michio Hirano, Andres Berardo, Emanuele Barca, Valentina Emmanuele, Austin Larson, Antonella Spinazzola, Amel Karaa.
      
    Keywords:  Nucleoside therapy, POLG, Thymidine, deoxycytidine, Thymidine kinase 2, TK2d
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01048
  10. Life Sci. 2026 Aug 20. pii: S0024-3205(26)00451-0. [Epub ahead of print]403 124642
    Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
    Ilitch A Marcondes-de-Castro, Thamyres Alves Sales, Thatiany Souza Marinho, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.
      Mitochondrial quality control (QC) preserves cellular homeostasis by coordinating mitochondrial structure, turnover, and bioenergetic function. Rather than operating through isolated pathways, QC is increasingly recognized as an integrated, redox-sensitive network in which reactive oxygen species (ROS), nicotinamide adenine dinucleotide (NAD+), and calcium (Ca2+) signaling regulate mitochondrial dynamics, mitophagy, biogenesis, and, ultimately, cell fate. In this narrative review, we propose a hierarchical framework in which these signaling systems function as interconnected sensors and transducers that determine whether mitochondria undergo repair, adaptive remodeling, or elimination. Under physiological conditions, controlled ROS production, adequate NAD+ availability, and tightly regulated Ca2+ flux promote a balanced mitochondrial fusion and fission, efficient mitophagic turnover, and mitochondrial biogenesis, thereby preserving bioenergetic competence and metabolic flexibility. Mitochondria-associated membranes (MAMs) emerge as key spatial platforms that integrate redox signaling, Ca2+ transfer, and lipid exchange, synchronizing communication between the endoplasmic reticulum and mitochondria. Conversely, persistent redox imbalance, characterized by excessive ROS, NAD+ depletion, and Ca2+ dysregulation, disrupts the coordination of QC pathways, resulting in mitochondrial fragmentation, defective turnover, impaired biogenesis, bioenergetic failure, and activation of apoptotic signaling. We critically discuss the mechanistic interplay among these pathways across metabolic disorders, cardiovascular disease, neurodegeneration, cancer, and aging, highlighting context-dependent adaptive and maladaptive responses. Finally, we identify unresolved questions regarding the spatiotemporal integration of redox signals, tissue-specific regulation of mitochondrial QC, and therapeutic targeting of network-level regulatory nodes. This framework provides a systems-level perspective for understanding how coordinated redox signaling governs mitochondrial adaptation and contributes to disease pathogenesis.
    Keywords:  Mitochondria-associated membranes; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Redox signaling
    DOI:  https://doi.org/10.1016/j.lfs.2026.124642
  11. Front Nutr. 2026 ;13 1854240
    Urolithins in clinical translation: from gut microbial metabolites to precision interventions.
    Lingmin Hu, Yingchun Ling, Weifeng Jin.
      Urolithins are gut microbiota-derived metabolites generated from ellagitannins and ellagic acid, and have emerged as promising mediators at the diet-microbiota-host interface. Interest in this metabolite family has increased substantially owing to growing evidence that urolithins, particularly urolithin A, influence mitochondrial quality control, autophagy, inflammatory signaling, and metabolic homeostasis across multiple tissues. These mechanistic properties have positioned urolithins as candidate interventions for aging-related functional decline, cardiometabolic disorders, neuroinflammatory conditions, and other chronic diseases characterized by impaired cellular resilience. However, their path to clinical application remains incompletely defined. In this Review, we synthesize current knowledge on the origin, microbial biotransformation, metabotypes, pharmacokinetics, and exposure biology of urolithins, with particular attention to the determinants of interindividual variability and the unresolved question of which molecular species are truly active in vivo. We then examine the core mechanisms of urolithin action and evaluate evidence across major disease contexts, integrating pre-clinical findings with available human data. Particular emphasis is placed on the current clinical literature on urolithin A, including safety, tolerability, dosing, target-engagement biomarkers, and functional endpoints. We further analyze the major factors underlying the translational gap between experimental promise and clinical outcomes, including differences in microbial production capacity, free vs. conjugated molecular forms, exposure-response uncertainty, responder heterogeneity, and limitations in trial design. Finally, we discuss how metabotype-guided stratification, microbiome-targeted strategies, improved formulations, and standardized biomarkers may support the development of urolithins within precision nutrition and translational medicine. Collectively, urolithins represent a compelling yet still evolving class of diet-derived microbial metabolites whose clinical utility will depend on resolving key mechanistic, pharmacological, and methodological uncertainties.
    Keywords:  clinical translation; ellagitannins; gut microbiota; metabotype; mitochondrial quality control; precision nutrition; urolithin A; urolithins
    DOI:  https://doi.org/10.3389/fnut.2026.1854240
  12. IUBMB Life. 2026 Aug;78(8): e70127
    Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
    Peng Ran, Lifang Yang.
      Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.
    Keywords:  aging; exercise; healthspan; mitochondrial quality control; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1002/iub.70127
  13. Neurol Sci. 2026 Aug 20. pii: 719. [Epub ahead of print]47(9):
    Giant panda sign: an adult case of single large-scale mitochondrial DNA deletion syndrome.
    Li-Ping Zhao, Qi-Dong Tang, Qu Li.
      A 38-year-old man presented with long-standing bilateral ptosis and new-onset paroxysmal limb weakness, which improved transiently after steroid treatment. He developed lethargy after self-discontinuation of medication. Brain MRI revealed the classic giant panda sign in the midbrain. Elevated plasma lactate and lactate peak on MRS were detected. Genetic testing identified a 7424 bp large-scale mitochondrial DNA deletion, confirming the diagnosis of single large-scale mitochondrial DNA deletion syndrome. Although the giant panda sign is classically associated with Wilson's disease, this case highlights that this characteristic imaging finding warrants mitochondrial genetic screening in adults with ophthalmoplegia and hyperlactatemia.
    Keywords:  Giant panda sign; Magnetic resonance imaging; Single Large-Scale Mitochondrial DNA Deletion Syndrome
    DOI:  https://doi.org/10.1007/s10072-026-09325-5
  14. Aging Cell. 2026 Sep;25(9): e70678
    Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
    Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed, Helya Rostamkhani, Brady E Hanson, Jesse C Craig, Shelby C Osburn, Allison M Manuel, Paul A Stewart, Jonathan Wanagat, Ryan M Broxterman, Joel D Trinity.
      Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.
    Keywords:  aging; exercise; mitochondrial DNA; oxidative stress; redox proteomics
    DOI:  https://doi.org/10.1111/acel.70678
  15. Int J Sports Med. 2026 Aug 19.
    Cell-Free Circulating Mitochondrial DNA: A Biomarker of Physiological Stress and Adaptation in Athletes.
    Arpan Chattopadhyay, Patrick Diel, Hemanth Naick B.
       Abstract: Circulating cell-free mitochondrial DNA has recently gained attention as a sensitive biomarker of physiological stress and adaptation in athletes. Intense exercise challenges mitochondrial function and can lead to the release of circulating cell-free mitochondrial DNA into the circulation, where it acts as a mitochondrial damage-associated molecular pattern. These fragments, recognized by the innate immune system due to their bacterial-like CpG motifs, trigger inflammatory responses and reflect cellular strain. Acute bouts of high-intensity exercise, mechanical stress, or trauma are associated with sharp increases in circulating cell-free mitochondrial DNA levels, while consistent training and regular recovery help maintain lower baseline concentrations, suggesting a role in adaptive regulation. Elevated circulating cell-free mitochondrial DNA levels in athletes have been linked to impaired recovery, increased inflammatory burden, and potential overtraining, whereas controlled exercise appears to facilitate its clearance and contribute to systemic resilience. Beyond physical performance, emerging evidence suggests that circulating cell-free mitochondrial DNA is also linked to psychobiological stress, offering an insight into both the physical and mental demands placed on athletes. Monitoring circulating cell-free mitochondrial DNA dynamics alongside traditional physiological measures such as cortisol, maximal oxygen uptake, and haematological markers could therefore provide a more comprehensive assessment of training load, recovery status, and susceptibility to stress-related disorders. As sports science advances toward precision monitoring, circulating cell-free mitochondrial DNA represents a promising molecular tool for guiding individualized training programs, preventing overtraining, and safeguarding long-term athlete health.
    DOI:  https://doi.org/10.1055/a-2929-9682
  16. Methods Enzymol. 2026 ;pii: S0076-6879(26)00157-6. [Epub ahead of print]733 111-142
    Sirtuins in mitochondrial physiology and energy homeostasis.
    Arshdeep Kaur, Ullas Kolthur Seetharam.
      Mitochondrial sirtuins integrate cellular metabolic and energetic state with post-translational regulation of mitochondrial proteins, thereby influencing bioenergetics, redox homeostasis, and metabolic flexibility. Despite extensive study of individual sirtuins, a comprehensive understanding of their function remains limited by methodological and conceptual challenges. These arise from the complex metabolic environment in which mitochondrial sirtuins act, including compartmentalized NAD+ pools, metabolite-driven non-enzymatic acylation, overlapping substrate specificities, and limited tools to accurately characterize enzyme-specific activity, particularly for SIRT4. This review aims to highlight current experimental approaches used to study mitochondrial sirtuins, and the need to integrate enzymatic measurements with metabolic and physiological readouts. We discuss the importance of considering mitochondrial spatial heterogeneity within cells, tissue-specific metabolic context, and temporal dynamics of metabolic state when interpreting sirtuin activity. Recent advances in quantitative proteomics, metabolite profiling, and mitochondria-specific analyses provide new opportunities to resolve these complexities. Moving forward, integrating these approaches with a systems-level and quantitative framework will be critical to fully understand how mitochondrial sirtuins orchestrate metabolic regulation across cellular and organismal scales.
    Keywords:  Enzyme kinetics; NAD(+) metabolism; Sirtuin activity; Spatio-temporal
    DOI:  https://doi.org/10.1016/bs.mie.2026.05.029
  17. ASN Neuro. 2026 ;18(1): 2717255
    When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.
    Aradhika Vijeev, Shaik Basha, Spandana S Nadig, Kripa Agarwal, Vibhuti Meharchandani, Aparna Ramakrishna Pai, Krishna Kishore Mahato.
      Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically heterogeneous group of rare movement disorders characterized by progressive neurodegeneration and selective basal ganglia iron deposition. Recent discoveries have fundamentally reshaped the understanding of NBIA, indicating that defects in coenzyme A metabolism, mitochondrial bioenergetics, lipid remodeling, autophagy-lysosomal pathways, and ferroptosis precede and promote secondary iron dyshomeostasis rather than resulting from primary abnormalities in iron metabolism. This review integrates recent mechanistic and translational evidence (2020-2026) across both common and underrepresented NBIA subtypes, including pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, COASY protein-associated neurodegeneration, mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, mitochondrial membrane protein-associated neurodegeneration, β-propeller protein-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, neuroferritinopathy, and mitochondrial DNA-associated forms. Unlike previous reviews, this synthesis consolidates findings from patient-derived induced pluripotent stem cell neuronal and glial models, compartment-specific iron localization, advanced neuroimaging biomarkers, and emerging therapeutic strategies within a unified mechanistic framework. Collectively, the evidence supports a paradigm in which mitochondrial dysfunction and lipid metabolic failure initiate disease progression, whereas iron accumulation amplifies oxidative injury and lipid peroxidation, thereby increasing ferroptotic cell death and neuronal degeneration, providing an updated foundation for biomarker discovery, mechanistically informed therapeutic development, and precision medicine approaches in NBIA.
    Keywords:  Coenzyme A metabolism; ferroptosis; mitochondrial dysfunction; neurodegeneration with brain iron accumulation (NBIA); precision medicine
    DOI:  https://doi.org/10.1080/17590914.2026.2717255
  18. medRxiv. 2026 Jul 30. pii: 2026.07.27.26358872. [Epub ahead of print]
    ArchSpiral: An iPad-Based Digital Archimedean Spiral Assessment for Objective Motor Evaluation in Rare Diseases.
    Daniel R Schecter, Rory J Tinker, Matteo Danieletto, Georgia MacDonald, Tamas Kozicz, Eva Morava, Benjamin S Glicksberg.
       Objectives: We developed and evaluated ArchSpiral, an iPad application that digitizes the International Cooperative Ataxia Rating Scale (ICARS) spiral tracing task to address the need for portable rare disease assessment while preserving clinical scoring and generating quantitative digital biomarkers.
    Materials and Methods: ArchSpiral (Swift/SwiftUI/PencilKit) captures Apple Pencil or finger tracings and computes tracing accuracy, root mean squared error, duration, average speed, pen lifts, pauses, steadiness, and an automated ICARS-compatible morphology score. Twelve participants with congenital disorders of glycosylation completed paired paper-digital assessments.
    Results: Digital ICARS scores spanned the scoring range (1-4). Paper and digital scores agreed exactly in 11 of 12 assessments (linear weighted κ = 0.91). Steadiness showed the strongest association with paper-based ICARS scores (ρ = -0.82, FDR-adjusted P = 0.008).
    Discussion: ArchSpiral enables standardized digital spiral assessment, while preserving compatibility with conventional ICARS scoring and adding objective quantitative measures for longitudinal rare disease research and clinical care.
    DOI:  https://doi.org/10.64898/2026.07.27.26358872
  19. Drug Discov Today. 2026 Aug 19. pii: S1359-6446(26)00186-8. [Epub ahead of print] 104781
    Artificial intelligence agents and agentic artificial intelligence applied to precision medicine.
    Fabricio F Costa.
      Precision medicine seeks to individualise care by integrating multimodal biomedical data, yet most deployed clinical artificial intelligence (AI) remains assistive, providing predictions without managing workflows or adapting autonomously. Agentic AI, built on large language models (LLMs), has emerged as a paradigm characterised by autonomy, goal-directed reasoning, memory, planning and tool use. This review synthesises evidence on agentic AI and LLMs applied to precision medicine, encompassing drug discovery, genomics, oncology, rare disease diagnostics and clinical pharmacology. This review also examines architectural components, recent validation milestones and emerging challenges, including hallucination, sociodemographic bias and evolving regulatory frameworks across the FDA, the EU AI Act and the WHO.
    Keywords:  agentic AI; clinical decision support; drug discovery; genomic foundation models; large language models; multiagent systems; precision medicine
    DOI:  https://doi.org/10.1016/j.drudis.2026.104781
  20. Adv Healthc Mater. 2026 Aug 19. e71594
    Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.
    Dnyandev G Gadhave, Ashish B Jadhav, Nitin B Waghamode, Shubham Khot, Rajiya Khan, Ravi Hole, Shankar M Dhobale, Manoj Aswar, Keshav Raj Paudel.
      Aging is a significant risk factor of neurodegenerative disorders (NDs) such as Huntington's, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Although several clinical, neuroimaging, and biomarker-based diagnostic approaches are available for NDs, their limited sensitivity for early-stage detection, disease specificity, and prediction of disease progression continue to present significant clinical challenges, often resulting in delayed diagnosis and therapeutic intervention. According to previously published works, the preliminary pathological feature of such disorders is mitochondrial dysfunction. This may lead to elevated oxidative stress, impaired mitophagy, unbalanced mitochondrial function, and bioenergetic failure. This review examines how mitochondria-targeted nanotherapeutic approaches can overcome these pathological barriers and improve therapeutic outcomes in aging-associated neurodegeneration. Targeted delivery of drug-loaded nanocarriers, such as gene-delivery, lipid-based, metallic, and polymeric nanoparticles, has emerged as a potential platform to deliver medication directly to defective mitochondria. It may increase mitochondrial biogenesis, maintain redox balance, and protect against neuronal degeneration. This work incorporates disease-specific mitochondrial pathology with current progress in targeted nanotherapeutics, age-associated delivery barriers, clinical revolution, and emerging artificial intelligence (AI)-enabled precision therapeutic approaches. Mitochondria-targeted nanotherapeutics depict a potential disease-modifying strategy for aging-related NDs. However, further advancements in targeting efficacy, scalable production, long-term safety, and clinical validation can facilitate a successful clinical revolution.
    Keywords:  blood–brain barrier; clinical insights; mechanistic insights; mitochondrial dysfunction; nanotechnology; neurodegenerative disorders
    DOI:  https://doi.org/10.1002/adhm.71594
  21. Psychiatr Danub. 2026 04;38(2): 147-154
    Mitochondrial dysfunction in schizophrenia and psychotic disorders: Implications for antipsychotic drug mechanisms.
    Svjetlana Loga-Zec, Aleksandra Klobučar, Orhan Lepara, Gorana Sulejmanpašić, Amra Memić-Serdarević, Nataša Loga-Andrijić.
       BACKGROUND: Schizophrenia (SCH) is a severe neuropsychiatric disorder associated with complex neurobiological alterations and suboptimal therapeutic outcomes. Increasing evidence indicates that mitochondrial dysfunction may contribute to SCH pathophysiology through impaired energy metabolism, oxidative stress, altered calcium homeostasis, and dysregulation of neuronal function. This review aims to summarize current knowledge regarding mitochondrial abnormalities in schizophrenia and to explore their potential involvement in the mechanisms of action of antipsychotic drugs.
    SUBJECTS AND METHODS: A comprehensive review of the current literature was performed, focusing on human studies, cellular and animal models investigating mitochondrial alterations in schizophrenia, as well as studies evaluating the effects of antipsychotic medications on mitochondrial structure and function.
    RESULTS: Available evidence demonstrates structural, molecular, and functional mitochondrial abnormalities in schizophrenia, including alterations in mitochondrial density, respiratory chain activity, oxidative phosphorylation, ATP production, and redox regulation. Antipsychotic drugs influence mitochondrial pathways in a complex and drug-specific manner. Some antipsychotics may impair mitochondrial respiration and increase oxidative stress, whereas others may exert compensatory or protective effects. Mitochondrial alterations may also contribute to cognitive impairment, negative symptoms, treatment response variability, and metabolic adverse effects associated with antipsychotic therapy.
    CONCLUSIONS: Mitochondrial dysfunction represents an important component of schizophrenia pathophysiology and a potential therapeutic target. The interaction between mitochondrial pathways and antipsychotic drug effects highlights mitochondria as a possible pharmacodynamic interface for personalized treatment strategies. Further in vivo studies and biomarker-based approaches are required to clarify drug-mitochondria interactions and improve therapeutic outcomes in schizophrenia.
    Keywords:  Schizophrenia; antipsychotic drugs; energy metabolism; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.24869/psyd.2026.147
  22. Pediatr Neurol. 2026 Jul 31. pii: S0887-8994(26)00243-2. [Epub ahead of print]184 9-10
    A Heterozygous Pathogenic Variant in POLG Associated With Isolated Neuropathic Pain and Rhabdomyolysis.
    Phan Q Duy, Weilai Dong, Avram Bukhbinder, Danielle B Pier.
      
    Keywords:  Mitochondrial disease; Neuropathy; POLG; Rhabdomyolysis
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.07.033
  23. Extracell Vesicle. 2026 Jun;pii: 100100. [Epub ahead of print]7
    Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.
    Paromita Paul Pinky, Zhong-Min Wang, Purva Khare, Jhanvi R Jhaveri, Abigail Sullivan, Vivek Basudkar, Krithika S Rao, Audrey Lawrence, Adithri Pingali, Kandarp M Dave, Donna B Stolz, Ming Sun, Si-Yang Zheng, Sruti S Shiva, Carol Milligan, Osvaldo Delbono, Devika S Manickam.
      Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1G93A transgenic mouse model of ALS.
    Keywords:  ALS; EVs; extracellular vesicles; large EVs; mitochondria; motor neurons; small EVs; spinal cord
    DOI:  https://doi.org/10.1016/j.vesic.2025.100100
  24. Alzheimers Dement. 2026 Aug;22(8): e71680
    A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.
    Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang.
       INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
    METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
    RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
    DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.
    Keywords:  AD; ALS; HD; NAD+; PD; PandaOmics; aging; artificial intelligence; machine learning; mitophagy
    DOI:  https://doi.org/10.1002/alz.71680
  25. Front Cell Neurosci. 2026 ;20 1913984
    Mitochondrial dysfunction in intracerebral hemorrhage: molecular mechanisms and pathological consequences.
    Tong Chen, Xu Gao, Yuhao Chang, Bin Wang, Zhouying Shi, Haiyue Xu, Yue Yuan, Fan Li, Ping Li.
      Intracerebral hemorrhage (ICH) carries high rates of disability and mortality, with a poor prognosis largely attributable to secondary brain injury (SBI). Mitochondria, a central hub for cellular redox regulation and energy metabolism, are not only affected by SBI but can also, once dysfunctional, initiate and exacerbate SBI. In this review, we classify post-ICH mitochondrial dysfunction into three major categories: excessive accumulation of mitochondrial reactive oxygen species, dysregulation of energy metabolism, and dysregulation of mitochondrial quantity and quality control. We delineate the molecular mechanisms and pathological consequences of each. Furthermore, given the extensive crosstalk between mitochondrial dysfunction and diverse forms of cell death in ICH (e.g., apoptosis, necrosis, necroptosis, ferroptosis, and pyroptosis), we discuss their mechanistic links. Overall, this review proposes a mitochondria-centered framework and emphasizes crosstalk between different types of dysfunction, thereby advancing our understanding of SBI pathophysiology after ICH and providing a systematic perspective on therapeutic strategies aimed at restoring mitochondrial homeostasis.
    Keywords:  cell death; intracerebral hemorrhage; mitochondrial dysfunction; mitochondrial quality control; mitochondrial reactive oxygen species; secondary brain injury; stroke
    DOI:  https://doi.org/10.3389/fncel.2026.1913984
  26. Elife. 2026 Aug 18. pii: RP87615. [Epub ahead of print]12
    MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide.
    Michelle C Rice, Maria Imun, Sang Wun Jung, Chan Yoon Park, Jessica S Kim, Rochelle W Lai, Casey R Barr, Jyung Mean Son, Kathleen Tor, Emmeline Kim, Ryan J Lu, Ilana Cohen, Bérénice A Benayoun, Changhan Lee.
      The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a host defense peptide (HDP) encoded in the human mitochondrial genome that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the 12 S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity. In human monocytes, interferon gamma (IFNγ), lipopolysaccharides (LPS), and differentiation signals each induced the expression of endogenous MOTS-c. Notably, exogenous MOTS-c, applied during primary mouse monocyte differentiation, reprogrammed the cells into macrophages with distinct transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicate that our immune system is not only encoded by the nuclear genome but also by the co-evolved mitochondrial genome.
    Keywords:  MOTS-c; cell biology; host defense peptide; human; immunology; inflammation; macrophage; microprotein; mitochondria; mitochondrial immunity; mouse
    DOI:  https://doi.org/10.7554/eLife.87615
  27. J Vis Exp. 2026 Aug 07.
    Real-Time, Noninvasive Evaluation of Mitochondrial Function Using Resonance Raman Spectroscopy.
    Yasemin Altug, Rohil Jain, Khanh T Nguyen, Padraic Romfh, Shannon N Tessier.
      Although mitochondria are central to pathogenesis and disease progression, mechanistic insight into mitochondrial health dynamics remains costly and inaccessible. To address this gap, this study employs Resonance Raman Spectroscopy (RRS) to assess mitochondrial function, using a portable system that delivers real-time, noninvasive, and quantitative measurements of mitochondrial cytochrome redox states in rat livers. In this protocol, we demonstrate the use of this technology, including setup, data acquisition, and data processing. This study presents a proof-of-concept experiment that highlights RRS's ability to measure real-time changes in mitochondrial redox state- and, by extension, mitochondrial function. Briefly, the RRS device was connected to a laser pump as well as a data acquisition computer and placed 1 cm away from the rat liver.  Acquisition parameters were selected in accordance with the rat liver protocol; redox states were measured in oxygenated and ischemic conditions utilizing an oxygen stress test. Changes in mitochondrial redox states were tracked throughout the oxygen stress test.
    DOI:  https://doi.org/10.3791/71290
  28. Stem Cells Dev. 2026 Sep;35(17-18): 339-347
    Application of Exosome Derived from Mesenchymal Stem Cells after Cerebral Stroke: The Role of Exosomes on Mitochondrial Dysfunction.
    Nasibeh Ghandy, Motahare Gholami Moghadam, Fatemeh Imanikhah, Aida Navaei Feyzabady, Mehrdad Hajinejad.
      Stroke is a major cerebrovascular event leading to high rates of disability and mortality around the world. Fundamental research has elucidated the pathological processes of stroke to inform effective therapeutic strategies. Mitochondria, as the primary energy source for neurons, play a pivotal role in maintaining nervous tissue homeostasis, and disruptions in their function contribute to mitochondrial dysfunction, neuronal injury, and apoptosis. Exosomes, particularly those derived from mesenchymal stem cells (MSCs), exhibit remarkable potential as an ideal therapeutic modality. Owing to their nanoscale dimensions and bioactive cargo, exosomes can traverse the blood-brain barrier and modulate injury outcomes in the central nervous system (CNS). This review synthesizes prior studies to delineate the current status and therapeutic promise of MSC-derived exosomes as a cell-free approach for stroke management.
    Keywords:  cerebral stroke; exosome; mesenchymal stem cell; mitochondrial dysfunction
    DOI:  https://doi.org/10.1177/15473287261466353
  29. Adv Immunol. 2026 ;pii: S0065-2776(26)00017-9. [Epub ahead of print]171 109-146
    Human-induced pluripotent stem cells in psychiatric disorders: An inflammatory perspective.
    Varsha Vishnu, Ashitha Siddappa Niranjana Murthy, Biju Viswanath.
      Psychiatric disorders have long been associated with inflammation- either as prolonged mental illnesses leading to immune dysregulations or as psychiatric conditions arising from systemic inflammation. Physiologically, inflammation is one of the responses to bodily stress, however, the degree of inflammation depends on the type and duration of the stressor. Here, we focus on understanding both- inflammation-induced brain cellular response alterations and neuroinflammation caused by an underlying psychiatric condition. Apart from post-mortem brains, the closest approach by which one can recreate both these phenomena are by using patient-derived induced pluripotent stem cells (IPSCs), as the brain tissue is inaccessible. Therefore, we focus on studies using IPSC-derived brain cells from patients to model inflammation across psychiatric conditions. Unlike any other available model system, IPSCs hold a major advantage of carrying patients' genetic background that is crucial to understand disorders as complex and enigmatic as psychiatric disorders. When knowledge on patients' genetic risks and environmental exposures are integrated into patient iPSC-derived brain cellular models, it holds enormous potential to delineate psychiatry related pathophysiology from other comorbidities. Therefore, understanding the cellular responses to inflammation and treatment helps us refine the existing therapeutic strategies and initiate early interventions to better manage psychiatric disorders.
    Keywords:  Autism; Bipolar disorder; Inflammation; Patient IPSC models; Psychiatry; Schizophrenia
    DOI:  https://doi.org/10.1016/bs.ai.2026.04.004
  30. Lancet Reg Health Eur. 2026 Oct;69 101801
    Crisis readiness for rare disease populations: learnings and recommendations by the European Reference Networks.
    Hélène Dollfus, Alexis Arzimanoglou, Teresinha Evangelista, Holm Graessner, Marta Mosca, Luca Sangiorgi, Jean-Yves Blay, Christine Bodemer, Pierre Fenaux, Francisco Hernández, Guillaume Jondeau, Marjolijn J L Ligtenberg, Ansgar W Lohse, Irene M J Mathijssen, Peter Mulders, Alberto M Pereira, Franz Schaefer, Joost F Swart, Alain Verloes, Thomas O F Wagner, René M H Wijnen, Arthur A M Wilde, María Del Mar Mañú Pereira, Ruth Ladenstein, Maurizio Scarpa.
      Patients with rare diseases are particularly vulnerable during emergencies due to dependence on specialised care pathways, medicines, and expertise. European Reference Networks (ERNs) for rare and complex diseases have operated since 2017 and were confronted with two major crises: the COVID-19 pandemic and the war in Ukraine. To assess ERN experiences, responses, and preparedness for crisis and disaster situations, we conducted a cross-sectional survey of all 24 ERN coordinators between July and September 2025. Only 2 (8·3%) ERNs reported pre-existing preparedness plans, while 70% lack structured frameworks. Major bottlenecks included patient access to healthcare facilities, drug and device shortages, bed shortage, staff unavailability, and diagnostic service interruption. Our findings highlight the need to formally integrate and mandate ERNs into European health emergency preparedness and response mechanisms. We propose a 10-point global crisis preparedness plan for rare diseases emphasizing cross-border coordination, digital infrastructure, patient education, and integration with national emergency services and non-governmental organizations.
    Keywords:  Climate change; Continuity of care; Crisis preparedness; Cross-border healthcare; European Reference Networks; Health emergency response; Health system resilience; Healthcare pathways; Pandemics; Rare diseases
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101801
  31. Eur J Pharmacol. 2026 Aug 19. pii: S0014-2999(26)00751-X. [Epub ahead of print] 179269
    Mitochondrial Dysfunction in Ifosfamide-Induced Nephrotoxicity: Mechanisms and Possible Interventions.
    Kate Liang, Jolita Ciapaite, Rosalinde Masereeuw, Marianne C Verhaar, Marry M van den Heuvel-Eibrink, Gisela G Slaats, Gerrit van den Berg.
      Ifosfamide is a chemotherapeutic agent used to treat aggressive solid tumors, but nephrotoxicity is a serious adverse effect and a risk factor for chronic kidney disease. Isophosphoramide mustard is the therapeutically active metabolite, whereas chloroacetaldehyde (CAA) is considered the nephrotoxic metabolite. The kidney injury predominantly affects the proximal tubule and has been linked to mitochondrial defects, although the cellular mechanisms remain incompletely understood. Here, we review the evidence for mitochondrial involvement and discuss potential therapeutic interventions. CAA is thought to disrupt oxidative phosphorylation, leading to ATP depletion and increased reactive oxygen species formation, which ultimately contributes to mitochondrial dysfunction. Additionally, CAA has been shown to interact with essential thiols such as glutathione and coenzyme A, and has been reported to impair lipid, protein metabolism and glucose synthesis. Collectively, these processes might contribute to tubulointerstitial nephritis, cellular senescence, and necrosis. Preclinical therapeutic interventions to prevent ifosfamide-induced nephrotoxicity have focused on protecting mitochondrial function and mitigating oxidative stress. These data indicate that antioxidants and glutathione precursors may reduce toxicity markers and preserve kidney histological structure. Ifosfamide-induced nephrotoxicity remains a clinical challenge as its mitochondrial mechanisms are not fully understood. To address this, we recommend investigating genetic susceptibility, and determining mitochondrial pathways, such as disrupted mitochondrial dynamics, mitochondrial DNA damage, and dysregulated energy signaling, through integrated molecular, functional, and metabolomic analyses in human-derived in vitro models. Additionally, we recommend evaluating nephroprotective strategies, including antioxidants, mitochondrial transplantation, and therapies that stimulate mitochondrial biogenesis, to identify interventions that prevent kidney injury while preserving antitumor efficacy.
    Keywords:  Ifosfamide; chloroacetaldehyde; kidney injury; mitochondria; nephrotoxicity; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179269
  32. J Huntingtons Dis. 2026 Aug 17. 18796397261478163
    Mitochondrial dynamics in Huntington's disease.
    Beatriz Paiva, Ana Cristina Rego.
      Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.
    Keywords:  mitochondria; mitophagy; neurotoxicity; pathogenic mechanisms; preclinical models
    DOI:  https://doi.org/10.1177/18796397261478163
  33. Int J Clin Oncol. 2026 Aug 20.
    Recommendations for generating real-world evidence with regulatory-grade relevance and reliability.
    Yasutoshi Sakamoto, Hideaki Bando, Yoshihiro Aoyagi, Hiroki Sokuoka, Toshihiro Misumi, Koji Oba, Yukiko Mori, Jun Okui, Makoto Miyazaki, Yasunari Sadatsuki, Kazuma Koizumi, Rie Otake, Akinori Yuri, Eri Tajima, Taro Ueno, Takayuki Nakamura, Hiroki Yoshihara, Keisuke Itoya, Ryosuke Annaka, Harumasa Nakamura, Natsuko Okita, Hideaki Takahashi, Tomohiro Kuroda, Kenichi Nakamura, Takayuki Yoshino, Atsushi Ohtsu.
      Real-world data (RWD) and real-world evidence (RWE) are increasingly incorporated into regulatory decision-making to complement randomized controlled trials (RCTs), particularly in settings where conventional trial designs are infeasible, such as rare diseases, rare molecular subtypes, and post-marketing evaluation. Across regulatory authorities, the use of RWD/RWE is consistently framed by the fit-for-purpose principle, centered on two foundational concepts: relevance and reliability. However, the absence of operational guidance has created uncertainty regarding how academic registries and healthcare databases can be designed or upgraded to meet regulatory expectations. Drawing on practical experience with disease registries in Japan and their regulatory applications, this review proposes a purpose-oriented framework clarifying the levels of relevance and reliability required according to specific regulatory objectives. We categorize considerations into three use cases: (1) drug development for rare diseases and rare molecular subtypes; (2) Pharmacovigilance; and (3) evidence generation for clinical questions that cannot be sufficiently evaluated through randomized controlled trials (RCTs). For each category, we outline essential requirements related to study design, data elements, quality management, governance, statistical planning, and operational feasibility. We further compare regulatory expectations across the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency (PMDA), and the International Council for Harmonisation (ICH). While international convergence is evident at the level of principles, operational thresholds and implementation frameworks differ. By articulating relevance and reliability as a shared regulatory language and emphasizing purpose-driven design and early regulatory engagement, this review provides practical recommendations for generating regulatory-grade RWE that meaningfully informs regulatory decision-making while complementing conventional clinical trials.
    Keywords:  Pharmacovigilance; Real-World Data; Relevance; Reliability
    DOI:  https://doi.org/10.1007/s10147-026-03160-6
  34. Pharmacol Ther. 2026 Aug 21. pii: S0163-7258(26)00128-2. [Epub ahead of print] 109101
    Restoring mitochondria and associated chaperone function: New therapeutic strategies for neurodegenerative diseases.
    Xue Xia, JiaBo Zhang, Xingyu Lin, Xinhui Zhao, Chun Mao, Ziyu Wu, Mimi Wan.
      Neurodegenerative diseases have emerged as a significant global health challenge, with existing treatments merely providing symptomatic relief and failing to halt disease progression. Mitochondrial dysfunction and an imbalance in the molecular chaperone network constitute the core common pathological mechanisms underlying various neurodegenerative diseases (NDDs). These two factors collaboratively induce energy metabolism disorders, oxidative stress, calcium homeostasis imbalance, and protein homeostasis collapse, collectively driving neuronal degeneration. This article systematically elucidates the core characteristics of mitochondrial dysfunction in NDDs, dissects the molecular mechanisms by which the mitochondrial molecular chaperone network maintains mitochondrial homeostasis, summarizes therapeutic strategies for NDDs aimed at restoring mitochondrial and related molecular chaperone functions, discusses the current challenges faced in research, such as targeted delivery and clinical translation, and also proposes potential development directions for future.
    Keywords:  Mitochondrial dysfunction; Mitochondrial molecular chaperone; Neurodegenerative disease; Treatment strategy
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109101
  35. Adv Immunol. 2026 ;pii: S0065-2776(26)00033-7. [Epub ahead of print]171 205-214
    Harnessing neuromodulation to target microglial activity in neurodegenerative diseases.
    Venkata Chaitanya Chirumamilla, Muthuraman Muthuraman.
      Neurodegenerative diseases are increasingly understood as conditions of disrupted neuroimmune homeostasis in which microglia play an important, dynamic, and state-dependent role. Beyond their immune functions, microglia continuously monitor neuronal activity, participate in synaptic remodeling, and contribute to neural circuit regulation in ways that vary across brain regions, disease types, and stages of neurodegeneration. In parallel, neuromodulation can modify neural activity patterns, thereby influencing downstream cellular responses and immune-related signaling within the central nervous system. Accumulating experimental evidence suggests that neuromodulatory interventions can influence microglial state, morphology, and function through activity-dependent neuron-microglia interactions and modulation of inflammatory signaling pathways. By synthesizing findings from both experimental animal models and translational human studies, this chapter presents a mechanistic framework for examining how neuromodulation may be leveraged to modulate microglial activity in neurodegenerative diseases. This approach integrates current understanding of microglial heterogeneity, neuromodulation mechanisms, biomarker strategies, and key translational challenges, with the goal of positioning microglia as measurable and biologically grounded therapeutic targets.
    Keywords:  Microglia; Neurodegenerative diseases; Neuroinflammation; Neuromodulation
    DOI:  https://doi.org/10.1016/bs.ai.2026.06.002
  36. Ophthalmology. 2026 Aug 18. pii: S0161-6420(26)00586-5. [Epub ahead of print]
    Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.
    Marco Battista, Michele Carbonelli, Luigi Brotto, Giulia Amore, Catarina P Coutinho, Martina Romagnoli, Alice Galzignato, Paolo Nucci, Leonardo Caporali, Maria Lucia Cascavilla, Claudio Fiorini, Chiara La Morgia, Francesco Bandello, Valerio Carelli, Piero Barboni.
       PURPOSE: To characterize the clinical and genetic features, investigate disease triggers, and explore factors associated with visual recovery in late-onset Leber Hereditary Optic Neuropathy (LHON).
    DESIGN: Retrospective cohort study.
    SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Seventy-seven patients with late-onset LHON (onset ≥ 40 years of age) were identified from a larger cohort of 398 Italian LHON patients. Full clinical and genetic analyses were performed on 67 of these patients, while an internal control group of 562 healthy individuals was utilized for mitochondrial haplogroup comparisons.
    METHODS, INTERVENTION, OR TESTING: Patient medical records were retrospectively reviewed to assess demographics, environmental exposures (smoking history), hormonal status (menopause, hormonal therapy), systemic comorbidities, and idebenone treatment data. Genetic testing evaluated primary mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroups, and NQO1 polymorphisms. Statistical relationships were investigated using an exploratory chi-square automatic interaction detection (CHAID) analysis to generate hypothesis-generating decision tree models.
    MAIN OUTCOME MEASURES: The primary outcome measures were the identification of precipitating factors (disease triggers) for LHON conversion and the rate of visual recovery, which was defined as an improvement of at least 0.3 LogMAR or a change from off-chart to on-chart visual acuity.
    RESULTS: The m.11778G>A variant was the predominant mtDNA mutation (62.7%), and the male-to-female ratio was lower than in canonical LHON (1.48:1). Smoking history was present in 58.2% of patients, and 85.2% of women were postmenopausal. Other relevant factors included primary open-angle glaucoma (6%) and the LHON 'plus' phenotype (7.5%). The overall visual recovery rate was 38.8%. Exploratory CHAID analysis suggested that idebenone treatment at a dosage of ≥900 mg/day and the presence of a J or T mitochondrial haplogroup were associated with a higher probability of visual recovery.
    CONCLUSIONS: Late-onset LHON represents a clinically relevant subset in which environmental and hormonal factors may contribute to disease conversion. In this retrospective cohort, high-dose idebenone treatment was associated with a higher probability of visual recovery, particularly among patients with a J or T haplogroup background. These exploratory findings should be considered hypothesis-generating and warrant confirmation in prospective studies.
    Keywords:  Leber Hereditary Optic Neuropathy; haplogroups; idebenone; late-onset disease; mitochondria
    DOI:  https://doi.org/10.1016/j.ophtha.2026.08.017
  37. Front Nutr. 2026 ;13 1824908
    Targeting cellular senescence through nutritional senotherapeutics in brain aging and neurodegenerative diseases.
    Verónica Salas-Venegas, Norma E López-Diazguerrero, Ricardo J Ramírez-Carreto, Mina Konigsberg, Anahí Chavarría.
      Cellular senescence has emerged as a key contributor to brain aging and neurodegenerative diseases, which are increasing in prevalence as life expectancy rises. Senescent cells accumulate in multiple brain cell populations and secrete the senescence-associated secretory phenotype (SASP), promoting chronic neuroinflammation, mitochondrial dysfunction, blood-brain barrier disruption, and progressive neuronal damage. This review examines the role of cellular senescence in brain aging and neurodegenerative diseases and discusses senotherapeutic strategies aimed at either eliminating senescent cells (senolytics) or modulating the SASP (senomorphics). Particular emphasis is placed on nutritional senotherapeutics, naturally occurring bioactive compounds derived from dietary sources that target molecular pathways involved in cellular senescence. Senomorphic compounds such as sulforaphane, curcumin, and resveratrol primarily attenuate oxidative stress and inflammatory signaling, whereas senolytic agents including quercetin and fisetin selectively promote the elimination of senescent cells by disrupting pro-survival pathways. Current evidence from experimental models and emerging clinical studies suggests that nutritional senotherapeutics represent promising complementary strategies for modulating cellular senescence and promoting brain health. However, their clinical translation remains constrained by limited human evidence, low bioavailability, and unresolved challenges related to optimal dosing and blood-brain barrier penetration, highlighting the need for well-designed clinical trials before their therapeutic potential can be fully established.
    Keywords:  brain; neurodegenerative disease; nutritional senotherapeutic; senescence; senolytic; senomorphic
    DOI:  https://doi.org/10.3389/fnut.2026.1824908
  38. Drug Discov Today. 2026 Aug 18. pii: S1359-6446(26)00180-7. [Epub ahead of print] 104775
    Patient experience data as a methodological and strategic innovation in clinical trial design.
    Alice Vanneste, Axelle Jankelevitch, Linda Lukeba, Peter Sinnaeve, Isabelle Huys, Tom Adriaenssens.
      Patient experience data (PED) are increasingly recognised as a methodological and strategic innovation in drug development, yet their implementation in clinical trial design remains inconsistent. Drawing on a structured literature review and multistakeholder interviews, this analysis examines how PED inform endpoint decision-making. Although clinical development is shifting towards more patient-informed measures, challenges persist due to limited standardisation, validation, methodological gaps and operational constraints. Opportunities include early patient involvement, validated disease-specific measures, consensus-based core outcome sets and clearer regulatory guidance, enabling meaningful and structured PED implementation that strengthens evidence generation, reduces development risk and improves trial efficiency and real-world relevance.
    Keywords:  clinical trial design; endpoint science; literature review; patient experience data; patient input; patient-reported outcomes; semi-structured interviews
    DOI:  https://doi.org/10.1016/j.drudis.2026.104775
  39. Phys Biol. 2026 Aug 17. 23(4):
    Nonequilibrium temperature fluctuations as modulators of mitochondrial elastocapillary stability.
    Peyman Fahimi.
      Recent studies have suggested that under high or near-maximal mitochondrial respiratory activity, ion-translocating proteins within the inner mitochondrial membrane may generate transient nonequilibrium temperature fluctuations in the adjacent mitochondrial matrix and intermembrane space. Such nonequilibrium temperature fluctuations may, in principle, influence mitochondrial mechanics and morphology. Building on elastocapillary models of mitochondrial dynamics, we investigate whether these nonequilibrium temperature fluctuations can modulate the stability of mitochondrial tubules through temperature-dependent changes in effective membrane tension and elasticity. Our numerical analysis predicts that this effect is strongly threshold-dependent: in deeply unstable states, thermal modulation remains insufficient to restore stability, whereas closer to the threshold, temperature-dependent reduction of effective membrane tension can overcome temperature-dependent elastic softening, thereby increasing the elastocapillary number, suppressing unstable modes, and shifting mitochondria toward mechanically more stable tubular states. In other words, when mitochondria begin shifting toward fission-promoting states, elevated respiratory activity, which increases the magnitude and cumulative temporal occupancy of transient thermal perturbations, tends to shift the system back toward mechanical stability. However, when mitochondria are already far within the mechanically unstable regime, transient thermal activity is no longer sufficient to restore stability. This stabilizing regime is qualitatively consistent with experimental observations linking elevated oxidative phosphorylation to mitochondrial elongation, fusion, or hyperfusion rather than fragmentation.
    Keywords:  elastocapillary stability; membrane tension and elasticity; nonequilibrium thermodynamics; temperature fluctuations
    DOI:  https://doi.org/10.1088/1478-3975/ae934f
  40. bioRxiv. 2026 Jul 29. pii: 2026.07.27.740961. [Epub ahead of print]
    A human cytokine response atlas to reconstruct underlying gene regulatory networks.
    Patrick O'Connell.
      Circulating cytokines encode immune state, yet their pleiotropy and cell-type specificity make constructing a unified atlas of immune cell responses to them challenging. Here, I transformed a single-cell atlas of approximately 10 million human peripheral blood mononuclear cells from 12 donors exposed to 90 cytokines into a multiscale model of cytokine response. A GPU-accelerated implementation of dimension-scalable single-cell perturbation integration network (D-SPIN) allowed for the creation of a signed, directed model of 9.6 million cells, 1,634 immune regulatory genes, and 40 cellular programs. The gene networks and cellular programs span canonical cytokine pathways and lineage relationships and delineated cytokine-specific activation and repression across immune states. Beyond established circuitry, the model nominated candidate regulatory interactions and identified the mitochondrial antioxidant SOD2 as a prominent hub of innate immune cell signaling. Next, I developed CytoCarto, a web application that projects cytokine profiles onto these networks to prioritize dysregulated programs, candidate effector genes, cellular contexts, and disease-associated signatures. In a proof-of-concept analysis I input the cytokine profile of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) undergoing an episode of sterile inflammation and found CytoCarto prioritized metabolically reprogrammed monocytes and SOD2 , consistent with a role for mitochondrial redox signaling in innate immunity.
    DOI:  https://doi.org/10.64898/2026.07.27.740961
  41. Pharmacol Res. 2026 Aug 21. pii: S1043-6618(26)00325-7. [Epub ahead of print] 108410
    Mitochondrial-centric regulatory networks in MASLD: integrating quality control, organelle interactions, and gut-liver communication.
    Jingwen Liu, Kewei Li, Ying Deng, Xi Li, Ruhan Yang, Ping Huang, Chunyan Li, Yueshui Zhao, Fukuan Du, Yu Chen, Jing Shen, Zhangang Xiao, Kangxing Zhu, Tao Shui, Jianqiao Zhong, Mingxing Li, Xu Wu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to liver mitochondrial dysfunction, which is driven not as an isolated event but by a self-amplifying injury loop involving impaired intrinsic quality control, aberrant organelle crosstalk, and dysregulated gut-liver signaling. This review summarizes findings in three interconnected regulatory layers: (1) intrinsic mitochondrial quality control (MQC) (PINK1/Parkin- and BNIP3/NIX-mediated mitophagy, Drp1/Mfn-driven dynamics, and chaperone/protease-maintained proteostasis); (2) organelle interactions (ER-mitochondria contacts, lipid droplet tethering, and lysosome crosstalk); and (3) extrinsic modulation via the gut-derived metabolites. We highlight that dysregulated mitophagy and mitochondrial fragmentation promote lipid accumulation and inflammation, whereas the abnormal formation of mitochondria-associated membranes (MAMs) exacerbates calcium overload and oxidative stress. Furthermore, short-chain fatty acids and bile acids derived from the gut differentially modulate mitochondrial bioenergetics. Preclinical evidence indicates that restoring MQC or targeting organelle interactions can improve MASLD symptoms. Given the multifactorial nature of MASLD, single-target interventions are insufficient; multi-target strategies and tissue-specific delivery are essential for clinical translation.
    Keywords:  MASLD; gut-liver axis; mitochondrial dynamics; mitochondrial quality control; mitophagy; organelle interactions
    DOI:  https://doi.org/10.1016/j.phrs.2026.108410
  42. J Paediatr Child Health. 2026 Aug 18.
    Enhancing Parents' Experiences of Paediatric Genomic Testing in Usual Outpatient Care: Insights From a Multi-Perspective Qualitative Study.
    Erin Crellin, Melissa Martyn, Selima Ymer, Maya Pinn, Emma Weisz, Clara Gaff, Belinda Dawson-McClaren.
       AIM: The aim of this research was to explore what makes (or would make) for good genomic care delivered wholly or in part by paediatricians.
    METHODS: An interpretive description, qualitative study with parents of children offered genomic testing as an outpatient for a condition other than cancer; general and subspecialist paediatricians; nurses; and genetic counsellors. Data were primarily collected retrospectively and analysed using inductive content analysis. Interpretation was enriched by the involvement of parent and paediatrician project advisors.
    RESULTS: Twenty-five parents and 20 health professionals participated. Most parents had received a genetic diagnosis for a child presenting with neurodevelopmental delay and/or epilepsy. Key aspects of good genomic care identified included: adopting a slow, multi-appointment approach to discussing genomic testing in certain instances; letting families know what to expect; signposting to information and psychosocial support services when disclosing results; communicating next steps; and adopting a team approach to aid sense-making. Paediatricians were not expected to do everything, with ongoing roles for genetic experts described. At different stages of the testing process, paediatricians existing and ongoing relationships with families were identified as an asset in helping promote good experiences.
    CONCLUSION: Genomic testing in usual paediatric outpatient care can be delivered well, with this research yielding practical guidance for paediatricians. Ongoing evaluation as models of care evolve will support the delivery of high-quality genomic care that best meets families' needs.
    Keywords:  exome sequencing; health services research; paediatrics; parents; qualitative research; rare diseases
    DOI:  https://doi.org/10.1111/jpc.70538
  43. J Community Genet. 2026 Aug 20. pii: 102. [Epub ahead of print]17(5):
    Diagnostic delay, care needs, and trust in healthcare among persons with rare disease and their next of kin living in Sweden.
    Maria Johansson Soller, Jamie Linnea Luckhaus, Stephanie Juran, Charlotta Ingvoldstad Malmgren.
      In Sweden, it is estimated that around half a million people live with a rare disease, and many more are affected through a family member. Despite this, little is known about patients' diagnostic journey, healthcare needs, and trust in the healthcare system. The study provides valuable insight into the diagnostic journey and healthcare experiences of individuals with rare diseases and their next of kin. An online cross-sectional survey was completed in 2021 by members of Rare Diseases Sweden. In total, 942 respondents representing 120 different diagnoses participated. Over half were people living with a rare disease (PLWRD), while the remaining respondents were caregivers to PWLRD (P-PWLRD). Slightly more than one third of the conditions involve intellectual disability, and one in five include motor impairment. Almost half involve complex healthcare needs. Most respondents were diagnosed as adults (44.4%), followed by childhood (27.9%) and at birth (16.7%). More than one third were diagnosed within six months of first healthcare contact, and nearly half within one year, while one in ten waited over ten years. Seven out of ten have consulted an expert in their condition. Those with diagnostic delays exceeding ten years were less likely to see a specialist, more likely to perceive unmet healthcare needs, and reported lower trust in healthcare and healthcare professionals.
    Keywords:  Diagnostic journey; Health care needs; Healthcare access; Healthcare satisfaction; Rare disease; Trust in healthcare
    DOI:  https://doi.org/10.1007/s12687-026-00931-6
  44. Neuromuscul Disord. 2026 Aug 13. pii: S0960-8966(26)01063-1. [Epub ahead of print]67 107395
    Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
    Madalena Couto, Mafalda Delgado Soares, Pedro Coelho, Rafael Roque, Marisa Brum.
      Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity. A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic. This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.
    Keywords:  MT-TS2 gene; Mitochondrial myopathy; Novel potentially pathogenic variant
    DOI:  https://doi.org/10.1016/j.nmd.2026.107395
  45. Stem Cell Res Ther. 2026 Aug 15. pii: 287. [Epub ahead of print]17(1):
    Stem cell-based therapies in pediatric disorders: translational advances, unresolved challenges, and future horizons.
    Hany E Marei.
      Pediatric disorders consist of genetic, hematologic, neurologic, autoimmune, and inflammatory diseases. These conditions impose long-term health challenges on children, despite many advancements with conventional medicine. Although conventional treatments increase life expectancy and provide better disease control, many present challenges such as toxicity, insufficient control of the disease, and adverse effects on normal growth, development, and quality of life. Many researchers have shown increased interest in using stem cell therapies as an alternative to current medications to allow for complete, sustainable repair of damaged tissues and modification of disease processes (i.e., using stem cells to regenerate tissue or change the way in which a disease occurs). This paper will provide the current information on stem cells used in the treatment of children and the many different types of stem cells, including: hematopoietic stem cells (and their derivatives), mesenchymal stem cells (and their derivatives), induced pluripotent stem cells, embryonic stem cells, tissue-specific progenitor cells, extracellular vesicles, and bioengineered products. This paper will also discuss what is known about the stem cells listed as well as their methods of action, where they might currently be better utilized, and future uses of these cells in children for a variety of types of pediatric diseases. Because each stem cell type listed has very different scientific background and clinical evidence, there is much variability in the amount of scientific evidence available to support stem cell therapies. For example, hematopoietic stem cell transplantation (HSCT) has over 50 years of clinical experience; thus, there are many studies defining the clinical efficacy and long-term outcomes associated with HSCT. Conversely, while there are many published studies supporting the use of mesenchymal stem cells (MSCs), extracellular vesicles (EVs), gene-edited cells, organoids, and many induced pluripotent stem cell-derived therapies, more evidence (clinical and basic science) is still needed to fully establish efficacy for the use of these various stem cells in children with pediatric diseases. In addition to needing more clinical evidence, stem cell-based therapies face many important challenges to the advancement of these therapies, including (but not limited to) long-term safety assessments, manufacturing standardization, regulatory oversight, ethical concerns, and equitable access to advanced therapies. Addressing these challenges will be important for future advances in the use of regenerative medicine in pediatric patients which will also require the rigorous evaluation of new stem cell therapies, the continued improvement of translational mechanisms, and the ongoing incorporation of new techniques (e.g., genome editing, organoid modeling, EV therapeutics, bioengineering, and artificial intelligence) to advance regenerative medicine and demonstrate its value through safe and reproducible clinical trial results.
    Keywords:  Cell-based therapy; Clinical translation; Extracellular vesicles (EVs); Gene editing; Induced pluripotent stem cells (iPSCs); Mesenchymal stem cells (MSCs); Neural stem cells (NSCs); Pediatric stem cell therapy; Regenerative medicine; Regulatory challenges
    DOI:  https://doi.org/10.1186/s13287-026-05204-0
  46. Ageing Res Rev. 2026 Aug 20. pii: S1568-1637(26)00304-1. [Epub ahead of print]122 103312
    Mitochondrial dysfunction in neurodegenerative diseases: Mechanisms and therapeutic advances.
    Zhaomin Yao, Yangwa Wei, Weiming Xie, Rui Gao, Ying Zhan, Xiaodan Wu, Wei Zhang, Yusong Pei, Guoxu Zhang, Zhiguo Wang.
      Neurodegenerative diseases associated with ageing are characterized by progressive neuronal dysfunction and loss, yet effective disease-modifying therapies remain elusive. Increasing evidence indicates that mitochondrial dysfunction is not merely a downstream consequence of neurodegeneration but represents an early and active driver of disease initiation and progression. This review addresses this critical gap by establishing an integrated framework that systematically connects mechanistic insights with translational applications. We demonstrate that mitochondrial impairment precedes classical neuropathological hallmarks, thereby positioning mitochondrial dysfunction as a primary driver rather than a secondary consequence of neurodegeneration. Through comprehensive analysis of disease-specific molecular signatures, we reveal how distinct mitochondrial regulatory failures converge on common downstream pathways: bioenergetic collapse through respiratory chain complex deficiencies, oxidative stress amplification via mitochondrial DNA damage and reactive oxygen species overproduction, calcium dysregulation, and compromised quality control through impaired mitophagy. Critically, we integrate emerging evidence demonstrating bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation, establishing a self-perpetuating pathogenic loop that accelerates disease progression. By synthesizing advances in multi-omics profiling, single-cell resolution analyses, and in vivo imaging biomarkers, we provide a systems-level perspective that transcends reductionist single-pathway models. Furthermore, we critically evaluate the translational landscape of mitochondria-targeted interventions, encompassing pharmacological agents with defined molecular targets, gene therapy approaches addressing mitochondrial DNA mutations, and lifestyle modifications promoting systemic metabolic resilience. Our comparative analysis reveals complementary mechanistic profiles and practical limitations across these modalities, supporting an integrated therapeutic paradigm that combines broad metabolic optimization with precision targeting of specific mitochondrial defects.
    Keywords:  Mitochondrial Dysfunction; Neurodegenerative Diseases; Neuronal Health; Oxidative Stress; Therapeutic Strategies
    DOI:  https://doi.org/10.1016/j.arr.2026.103312
  47. Mol Genet Metab Rep. 2026 Sep;48 101348
    Severe mitochondrial cardiomyopathy with m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene: A study of large family analysis.
    Shuichi Yatsuga.
      The m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene is a rare cause of mitochondrial cardiomyopathy (MCM). We report a Japanese family with this variant across three generations, demonstrating a wide clinical spectrum ranging from asymptomatic carriers to lethal infantile cardiomyopathy. The proband was a newborn male infant who developed severe hypertrophic obstructive cardiomyopathy, generalized hypotonia, and profound lactic acidosis (43.9 mmol/L) shortly after birth. Despite intensive care, the patient died at 11 days of age due to multiorgan failure. Autopsy revealed diffuse cardiac hypertrophy and abnormal mitochondria. Genetic analysis showed 98% heteroplasmy of the m.3303C > T variant in multiple tissues. Family screening revealed variant loads ranging from 6% to 100% in seven relatives, with clinical manifestations only appearing when the variant load exceeded 90%. One maternal uncle with 100% muscle heteroplasmy died at the age of 7 years from mitochondrial myopathy. Other family members with variant loads below 90% were asymptomatic. This study demonstrates that the m.3303C > T variant exhibited, within this family, an exceptionally high threshold effect, with severe phenotypes manifesting only at very high heteroplasmy levels (>90%), and highlights the importance of family screening for genetic counseling.
    Keywords:  Heteroplasmy; Hypertrophic cardiomyopathy; Infantile cardiomyopathy; Lactic acidosis; M.3303C > T variant; Mitochondrial DNA; Threshold effect; tRNALeu(UUR)
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101348
  48. Arch Med Res. 2026 Aug 17. pii: S0188-4409(26)00128-1. [Epub ahead of print]57(8): 103506
    Multi-Omics Integration in Clinical Practice for the Identification of Genetic Variants in Rare Diseases.
    Jonathan Olival, Jordi Pijuan, Natàlia Caelles-Gramunt, Nidia Barco-Armengol, Leila Maestro, Guerau Fernández, Janet Hoenicka, Francesc Palau.
      One of the main challenges in the field of rare diseases (RDs) remains the persistent lack of timely and accurate diagnoses. Currently, it is estimated that over half of patients remain undiagnosed. The recent development of high-throughput omics technologies, such as genomics, transcriptomics, epigenomics, proteomics, and metabolomics, is transforming the diagnosis and research of rare genetic diseases. These technologies allow for a deeper understanding of the underlying molecular mechanisms and greatly improve diagnostic accuracy. This review outlines a comprehensive clinical workflow that integrates deep phenotyping, genomic variant identification, and functional validation with multi-omics approaches to enhance diagnostic accuracy in RDs. We detail the key methodologies, bioinformatics tools, and developmental processes used in omics, focusing on their roles in identifying and prioritizing candidate variants, interpreting variants of uncertain significance, and generating clinically relevant information. Furthermore, we highlight the importance of both targeted and non-targeted functional validation strategies, which provide essential evidence of pathogenicity. The integration of multi-omics approaches will improve our understanding of RDs, enhance diagnostic accuracy in clinical settings, and lay the foundation for future therapeutic development within the framework of precision medicine.
    Keywords:  Diagnostics; Genetic variants; Genomics; Multi-omics; Rare diseases
    DOI:  https://doi.org/10.1016/j.arcmed.2026.103506
  49. Aging Cell. 2026 Aug;25(8): e70676
    The GLP-1-Mitochondria Axis in Metabolic Aging.
    Renin Chang, Andy P Tsai, Boyang Wang, Chia-Jung Li.
      Metabolic aging underlies a cluster of chronic conditions-type 2 diabetes, cardiovascular disease, sarcopenia, and neurodegeneration-that account for a substantial share of global morbidity and mortality. A common feature is progressive mitochondrial dysfunction: impaired bioenergetics, disrupted quality control, and loss of metabolic resilience. Reduced mitochondrial DNA copy number in peripheral blood leukocytes is associated with cardiometabolic disease and mortality, but pre-analytical variability, dependence on blood-cell composition, and uncertain relationship to tissue-level function mean it should be regarded as a candidate risk-associated biomarker rather than a validated measure of mitochondrial integrity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control, engage pathways implicated in mitochondrial biogenesis, dynamics, and mitophagy; whether these effects reflect direct receptor signaling, indirect consequences of weight loss, or secondary mediators such as interleukin-6 remains debated and appears tissue-dependent. In SELECT, semaglutide reduced major adverse cardiovascular events by 20% in obesity without diabetes, and a 2025 multi-omic study in aged male mice found GLP-1 RA treatment attenuated age-associated molecular signatures despite only modest changes in food intake and body weight. No trial, however, has incorporated a prespecified mitochondrial endpoint, human mechanistic evidence remains limited, and access to these therapies remains uneven worldwide. Here we synthesize mechanistic, preclinical, and clinical evidence for a proposed GLP-1-mitochondria axis, classify this evidence by receptor dependence and translational stage, distinguish disease-specific treatment effects from evidence for aging modification, examine four major controversies, and outline a research and policy agenda for responsible, evidence-graded development of GLP-1-based geroscience interventions.
    Keywords:  GLP‐1 receptor agonists; geroscience; healthy aging; metabolic aging; mitochondrial dysfunction; mitochondrial resilience; population health
    DOI:  https://doi.org/10.1111/acel.70676
  50. J Clin Epidemiol. 2026 Aug 18. pii: S0895-4356(26)00347-1. [Epub ahead of print] 112471
    Evaluating Test Accuracy Study Designs for Rare and Ultra-rare Conditions: Application to Newborn Blood Spot Screening.
    Sarah Batson, Silvia Lombardo, Mariska Leeflang, Sian Taylor-Phillips, John Marshall.
       OBJECTIVES: To update and expand an existing framework for diagnostic accuracy study designs in low-prevalence settings, evaluate its applicability to newborn screening (NBS) for rare and ultra-rare conditions, and provide practical considerations tailored to test accuracy assessment.
    METHODS: Two literature searches were conducted: (1) an update of a prior review to identify methodological papers on test accuracy in low-prevalence settings (MEDLINE and Embase, 2017-2025), and (2) a de novo search for systematic reviews of test accuracy studies on five conditions relevant to NBS across multiple databases. A 'best fit framework' synthesis was applied using an existing framework on diagnostic accuracy study designs as a base. Findings were reviewed and refined through expert consultation in a one-day workshop. We summarise the characteristics, strengths, limitations, and unique challenges of each study design, and provide practical considerations for their application in the NBS setting.
    RESULTS: The literature searches and expert input yielded 11 studies: seven methodological papers from search 1, three systematic reviews from search 2 and one methodological paper identified through expert input. None of the studies introduced new study designs. The base framework for diagnostic accuracy study designs remains unchanged but applying it to rare conditions in NBS requires methodological adaptions. Challenges include extremely low-prevalence, sample size limitations, broad disease spectra, variants of uncertain clinical significance, incidental findings, limited feasibility of timely, definitive reference standards, and temporal follow-up issues. While all study designs have potential utility in NBS, their suitability depends on the condition, available data, and context-specific challenges.
    CONCLUSION: No new study designs have emerged to address persistent challenges in low-prevalence settings. The foundational framework remains relevant, but its application in NBS-especially regarding large cohort studies-requires a flexible, context-specific approach. Given the need for sample enrichment and the rarity of conditions in NBS, two-gate studies are likely to be the most common, though other designs, such as adapted cohort studies and two-phase studies, are also viable, especially when enrichment strategies are applied. Future research should focus on developing tailored tools for assessing test accuracy in NBS.
    Keywords:  low prevalence; newborn bloodspot screening; newborn screening; rare diseases; test accuracy; ultra-rare diseases; very low prevalence
    DOI:  https://doi.org/10.1016/j.jclinepi.2026.112471
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