bims-polgdi Biomed News
on POLG disease
Issue of 2026–08–30
forty-four papers selected by
Luca Bolliger, lxBio
  1. From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
  2. 2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.
  3. Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
  4. Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.
  5. Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?
  6. Mitochondria as central regulators of cancer progression and antitumor immunity.
  7. Mitochondrial DNA A3243G variant-associated MELAS: Recent advances in clinical trials, therapeutic interventions, and disease-modifying strategies.
  8. Mitochondrial guardian and therapeutic target: The promise of TFAM in acute kidney injury.
  9. Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant.
  10. Emerging Roles of Extracellular Vesicle-Mediated Transfer of Mitochondrial and Mitochondrial Components in Cancer.
  11. Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
  12. Evolutionarily Conserved but Mechanistically Distinct Mitochondrial Responses to Loss of Timeless/Swi1.
  13. Traffic jam at the powerhouse: restoring protein homeostasis at the mitochondria via MFB1 and HSP31 collaboration with clinical implications. An Educational Primer for use with "Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae".
  14. Mitochondria as the Hub of Apoptosis: A Comprehensive Insight From Mitochondria to Interactions With Other Organelles.
  15. Constructing an Evidence-Based Validity Rationale for a Multi-component Endpoint in Heterogeneous Populations.
  16. The organellar biology of aging: A mitochondrial vantage.
  17. Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review.
  18. Circulating cell-free mitochondrial DNA as a redox-associated marker of mitochondrial homeostasis disruption during gastric carcinogenesis.
  19. Emerging microbiome-mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation.
  20. Adipose Stem Cell Mitochondrial Transplantation in ART: From Biological Rationale to Clinical Milestone.
  21. A propensity score-integrated win ratio method for placebo borrowing.
  22. Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.
  23. Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine.
  24. Concordant mtDNA heteroplasmy between trophectoderm and inner cell mass supports blastocyst-stage PGT-mt for m.14487T>C.
  25. Understanding cardiovascular aging as a disorder of mitochondrial network.
  26. Rare Diseases as Epistemic Objects: Exploring the Moral Role of Health Systems.
  27. Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders.
  28. The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling.
  29. A Function-Centric Framework for Mitochondrial Quality Control.
  30. Building a National Interoperable Rare Eye Disease Data Warehouse: Methodological Framework and Implementation Report From the French Rare Eye Disease Database (FREDD) Initiative.
  31. Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.
  32. Mitochondrial regulation of cellular senescence heterogeneity.
  33. Late-onset mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes with chronic intestinal pseudo-obstruction: a case-based review.
  34. Vitelliform retinal lesions: Uncommon adult-onset presentation of the common mitochondrial MELAS variant.
  35. Adaptive and degenerative mitochondrial remodeling define distinct redox states in age-related macular degeneration.
  36. A text mining and ontology-based approach using phenotypes to obtain relevant literature for rare diseases.
  37. Can nucleotide stress prevent molecular resolution of sterile inflammation?: A redox-metabolic hypothesis linking NAD+ depletion, oxidized mitochondrial DNA and PARP1 turnover.
  38. A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation.
  39. Traditional Chinese medicine research on rare diseases: Publication trends and future perspectives.
  40. Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.
  41. Equity in genome sequencing for rare disease diagnosis: a cross-sectional analysis of data from the UK 100,000 Genomes Project.
  42. Trust As the Foundation for Informed Decision-Making in Prenatal Genetic Screening and Diagnostic Testing: A Qualitative Study.
  43. The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.
  44. Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?
  1. J Inherit Metab Dis. 2026 Sep;49(5): e70236
    From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
    Simon Wetzel, Sebastian Porsdam Mann, Florian A Rosenberger.
      Proteomics by mass spectrometry has rapidly matured from a niche method into a standard tool. The recent 10-year trajectory of single-cell proteomics has opened a new biological dimension for studying disease. Mitochondrial diseases, with their pronounced cell-to-cell heterogeneity, are particularly, well-suited to these methods. Here, we discuss how this approach can serve as an orthogonal functional layer for rare disease diagnostics. We trace the evolution of rare disease diagnostics from biochemical enzyme assays through genomics, transcriptomics, proteomics and metabolomics, highlighting incremental gains in diagnostic yield from individual omics layers and their integration. We discuss the limitations of bulk approaches in capturing the functional consequences of genetic perturbations, the new opportunities opened up by single-cell measurements and how spatial single-cell proteomics can further enrich the biological signal of affected cells in diagnostic tissues. We observe that the persisting diagnostic gap reflects not only technological limitations but, increasingly, challenges in data sharing and infrastructure as well as interpretive frameworks for functional molecular evidence. In this context, we consider opportunities for artificial intelligence and the ethical dimensions of single-cell proteomics in rare disease diagnostics. Finally, we propose a single-cell deep visual proteomics (scDVP) framework for clinical diagnostics of rare diseases with cell-to-cell variability, arguing that mitochondrial diseases are an ideal proof-of-concept.
    Keywords:  diagnostics; mitochondria; omics ethics; rare diseases; single‐cell proteomics; spatial proteomics
    DOI:  https://doi.org/10.1002/jimd.70236
  2. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261473291
    2000-2025: Emerging therapies in primary mitochondrial disease: A structured review, horizon scan, and roadmap for the future.
    Amel Karaa, Maria Isabel G Lopez Sanchez, Clare Stuart, Luca Bolliger, Kate Murray, Maria E O'Hanlon, Brian Tseng, Philip Yeske, Sean Murray.
      Primary mitochondrial diseases (PMD) are ultra-rare, genetically diverse disorders that impair cellular energy metabolism and typically present with multisystemic symptoms. Over the past decades, the therapeutic landscape of PMD has evolved substantially. Early trials of non-specific antioxidant and metabolic therapies produced largely negative or mixed results, providing important methodological lessons for the field. More recent studies have adopted improved outcome measures, natural history-informed designs, and precision therapeutic approaches, including gene therapy and nucleoside therapy, which have shown encouraging clinical and regulatory progress. Regulatory agencies have only recently begun approving disease-modifying therapies for selected mitochondrial disorders. The European Medicines Agency (EMA) approved idebenone for Leber Hereditary Optic Neuropathy (LHON) in 2015 but only recently, in 2025 did the Food and Drug Administration (FDA) in the US approve a treatment for Barth syndrome and thymidine kinase 2 deficiency (TK2d). Friedreich's ataxia received regulatory approval in 2023 from both the EMA and FDA, marking another milestone in mitochondria-related disorders. To comprehensively review clinical and regulatory developments in PMD over the past two decades, we conducted a structured scoping review and horizon scan of published clinical trials and regulatory approvals in PMD from January 2000 to November 2025. Data sources included PubMed, Embase, https://ClinicalTrials.gov, and regulatory agency websites. Recent accelerated and full FDA approvals validate the feasibility of tailored evidence packages, but sustaining this momentum will require more rigorous alignment of trial design with molecular biology, strengthening of natural history infrastructure, deployment of sensitive biomarkers, and adoption of innovative statistical approaches. Early regulatory engagement and robust patient-community partnerships will be key.
    Keywords:  clinical trial; drug development; mitochondrial disease; rare disease
    DOI:  https://doi.org/10.1177/26330040261473291
  3. Curr Opin Pharmacol. 2026 Aug 27. pii: S1471-4892(26)00058-5. [Epub ahead of print]90 102662
    Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
    Lamiaa M ElAbbasy.
      Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.
    DOI:  https://doi.org/10.1016/j.coph.2026.102662
  4. Genes (Basel). 2026 Jul 23. pii: 850. [Epub ahead of print]17(8):
    Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.
    Albert Z Lim, Aye-Myat Moe, Renae J Stefanetti, Yi Shiau Ng.
      Primary mitochondrial diseases (PMDs) are one of the most common genetic disorders with an estimated prevalence of 1 in 4300. This review article summarises the latest updates in the field of mitochondrial medicine over the last decade. The availability of exome and genome sequencing in clinical practice has empowered clinicians to unravel the phenotypic heterogeneity of PMD and to end the diagnostic odyssey experienced by many patients and families. In unresolved cases, the detection of variant(s) of unknown significance by next-generation sequencing creates diagnostic and clinical uncertainties, and integrating a multi-omics approach can improve diagnostic yield. Alongside breakthroughs in genomic technologies, there is growing interest in using fluid biomarkers to guide diagnosis, monitor disease progression, and potentially serve as clinical trial endpoints. However, the clinical application of these fluid biomarkers in unselected patient cohorts with different disease onset and phenotypes would require more robust evidence. Natural history studies derived from national and international collaborations have provided insights into genotype-phenotype relationships and prognostic factors across several genotypes, including m.3243A>G, MT-ATP6, POLG, and TK2. Advances in therapeutic discoveries and clinical trials are challenging the obsolete dogma that PMDs are untreatable and bringing hope to patients; four compounds have been licensed, and many trials are in progress. Many barriers and challenges to translating laboratory discoveries into clinical therapy in PMD remain, including preclinical models for efficacy and safety testing, sample size, trial design, and the selection of outcome measures and trial endpoints.
    Keywords:  fluid biomarkers; outcome measures; phenotypes; trial endpoints; whole-genome sequencing
    DOI:  https://doi.org/10.3390/genes17080850
  5. Brain Sci. 2026 Aug 20. pii: 890. [Epub ahead of print]16(8):
    Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?
    Kate Erin Harris, Gerassimos Lascaratos, Kai-Yin Chau.
       BACKGROUND/OBJECTIVES: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders.
    METHODS: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue.
    RESULTS: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction.
    CONCLUSIONS: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target.
    Keywords:  ATP hydrolysis; ATP synthase; ATP synthesis; Complex V; bioenergetics; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/brainsci16080890
  6. Trends Endocrinol Metab. 2026 Aug 26. pii: S1043-2760(26)00176-1. [Epub ahead of print]
    Mitochondria as central regulators of cancer progression and antitumor immunity.
    Aurora Gomez-Duran, Inmaculada Martínez-Reyes.
      Mitochondria coordinate metabolic and signaling pathways that influence cancer progression across multiple stages of the disease. Beyond supporting tumor growth, mitochondria contribute to metastatic dissemination and shape interactions between tumor and immune cells through diverse outputs, including metabolite production, redox regulation, and mitochondrial genome dynamics. In this review, we discuss how mitochondrial functions sustain cancer cell proliferation, regulate pathways that facilitate metastatic progression, and influence antitumor immunity. We further highlight emerging roles for mitochondrial DNA variation, intercellular mitochondrial transfer, and mitochondrial dysfunction in immune cell exhaustion and senescence. Finally, we discuss how these advances are revealing therapeutic opportunities to target mitochondrial pathways and enhance the efficacy of current cancer immunotherapies.
    Keywords:  antitumor immunity; cancer metabolism; metastasis; mitochondria; mitochondrial genetics
    DOI:  https://doi.org/10.1016/j.tem.2026.07.005
  7. Intractable Rare Dis Res. 2026 Aug 31. 15(3): 219-231
    Mitochondrial DNA A3243G variant-associated MELAS: Recent advances in clinical trials, therapeutic interventions, and disease-modifying strategies.
    Kuan-Yu Chu.
      Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, most often caused by the m.3243A>G mitochondrial DNA variant, represents one of the most clinically significant inherited mitochondrial disorders. This variant disrupts mitochondrial tRNALeu(UUR) function, leading to impaired mitochondrial protein synthesis and progressive multisystem dysfunction. This narrative review synthesizes recent clinical trials, therapeutic advances, and emerging disease-modifying strategies for m.3243A>G-associated MELAS, with emphasis on evidence published between 2024 and 2026, drawing on PubMed/MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov, and the EU Clinical Trials Register. Key advances include: i) regulatory approval of high-dose taurine supplementation (9-12 g/day), which achieved complete prevention of stroke-like episodes in 60% of participants in a phase III trial; ii) phase IIb data (company-reported) indicating that sonlicromanol (KH176) showed signals of improvement in cognition, mood, and fatigue, supporting progression to a phase III registrational trial (KHENERFIN, NCT06451757); iii) ongoing trials of zagociguat and TTI-0102 targeting vascular dysfunction and oxidative stress; iv) KL1333, a novel NAD+ modulator, in phase II evaluation (FALCON trial); and v) promising preclinical gene-based approaches-including mitochondria-targeted TALENs, DdCBE base editors, and mitoARCUS nucleases-demonstrating heteroplasmy shifting in patient-derived cells and animal models, though direct clinical applicability to m.3243A>G MELAS requires further investigation. The therapeutic landscape for MELAS is evolving from symptomatic care toward mechanism-based disease modification, led by taurine as the first regulatory-approved disease-modifying therapy and complemented by late-stage small molecules and mitochondrial genome-editing technologies.
    Keywords:  NAD; cysteamine; genetic therapy; oxidative stress; taurine
    DOI:  https://doi.org/10.5582/irdr.2026.01026
  8. Cell Signal. 2026 Aug 28. pii: S0898-6568(26)00512-7. [Epub ahead of print] 112854
    Mitochondrial guardian and therapeutic target: The promise of TFAM in acute kidney injury.
    Luyao Zhang, Ziyi Yang, Rushuang Yue, Yi Ji, Rong Shi, Qianmei Zhou.
      Acute kidney injury (AKI) is a clinically significant syndrome characterized by rapid deterioration of renal function. Despite its complex and multifactorial pathogenesis, effective targeted therapies remain scarce. Mitochondrial dysfunction is increasingly recognized as a central driver of AKI progression. Mitochondrial transcription factor A (TFAM), a nucleus-encoded protein that governs mitochondrial DNA (mtDNA) maintenance, transcription and replication, plays an essential role in preserving mitochondrial integrity and biogenesis. This review systematically synthesizes current knowledge on TFAM biology, with a focus on its structural features, regulatory networks, and dynamic changes in the context of AKI. We integrate evidence showing that TFAM upregulation, whether through pharmacological interventions or genetic manipulation, consistently protects against tubular cell injury, preserves mitochondrial function, and attenuates inflammation across diverse AKI models. By providing a conceptual framework that links TFAM's molecular functions to its pathophysiological roles in the kidney, this review highlights TFAM as a promising therapeutic node. We also identify key knowledge gaps and propose future research directions to facilitate the translation of TFAM-targeted strategies into clinical practice.
    Keywords:  Acute kidney injury; Mitochondrial DNA; Mitochondrial dysfunction; Mitochondrial transcription factor A; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112854
  9. Neurol Genet. 2026 Aug;12(4): e200411
    Identification of Nuclear Genetic Loci Linked to Clinical Features of the m.3243A>G Mitochondrial DNA Variant.
    Róisín M Boggan, Theodora-Dafni Michalettou, Yi Shiau Ng, Imogen G Franklin, Lucas T Cortés, Charlotte L Alston, Emma L Blakely, Boriana Büchner, Enrico Bugiardini, Kevin Colclough, Catherine Feeney, Michael G Hanna, Andrew T Hattersley, Thomas Klopstock, Cornelia Kornblum, Michelangelo Mancuso, Kashyap A Patel, Robert D S Pitceathly, Chiara Pizzamiglio, Holger Prokisch, Jochen Schäfer, Andrew M Schaefer, Maggie H Shepherd, Annemarie Thaele, Rhys H Thomas, Doug M Turnbull, Cathy E Woodward, Robert McFarland, Robert W Taylor, Heather J Cordell, Sarah J Pickett.
       Background and Objectives: Mitochondrial DNA (mtDNA) disorders exhibit striking clinical variability that is poorly explained by known factors such as variant heteroplasmy, age, or sex. Nuclear genetic modifiers likely play a significant role in this heterogeneity. We aimed to characterize the nature of nuclear genetic involvement for 2 common syndromic presentations of the common pathogenic mtDNA variant, m.3243A>G: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD).
    Methods: We assembled a multicenter cohort of clinically ascertained carriers of m.3243A>G (total n = 488), identifying 198 individuals across 76 pedigrees suitable for genetic linkage analysis. We investigated 4 clinical features characteristic of MELAS and MIDD: diabetes, hearing impairment, stroke-like episodes, and encephalopathy. Haseman-Elston regression-based genetic linkage analysis was performed to identify regions of the nuclear genome cosegregating with these features. The effects of m.3243A>G heteroplasmy, age, and sex were accounted for using logistic regression; empirical significance thresholds were determined through feature-specific gene-dropping simulations. Association analyses were performed in 247 individuals using single-variant (SAIGE) and gene-based approaches (SAIGE-GENE+ and MAGMA) to refine candidate loci within a significant linkage region.
    Results: We identified significant genetic linkage to encephalopathy (chromosome 7q22; LOD = 3.72), and regions suggestive of genetic linkage on chromosomes 1, 5, 6, 11, and 13, for encephalopathy and stroke-like episodes. No linkage was identified for diabetes or hearing impairment. Association analysis within the chromosome 7 region identified variant rs62500792 (intergenic between SDHAF3 and TAC1) with the lowest p value (3.7 × 10-5), yet no variants reached the proportional significance threshold (5.3 × 10-6). Gene-based analyses highlighted PLOD3 (p = 3.9 × 10-3) and IMMP2L (p = 6.4 × 10-3) as candidates, as each showed the strongest gene-level signals within the linkage region across complementary burden-testing methods, although neither reached corrected significance thresholds.
    Discussion: The nuclear genetic architecture modifying m.3243A>G differs across clinical features. Severe neurologic features (encephalopathy and stroke-like episodes) may be influenced by a small number of nuclear genes with relatively large effect sizes, whereas the nuclear contribution to diabetes and hearing impairment appears more polygenic. This study highlights the value of large, well-characterized patient cohorts in identifying modifier loci and advancing knowledge of the mechanisms underlying phenotypic variability in mtDNA disease.
    DOI:  https://doi.org/10.1212/NXG.0000000000200411
  10. Cells. 2026 Aug 20. pii: 1502. [Epub ahead of print]15(16):
    Emerging Roles of Extracellular Vesicle-Mediated Transfer of Mitochondrial and Mitochondrial Components in Cancer.
    Yue Gu, Chen Gu, Runfang Pan, Baonian Liu.
      Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate the mechanisms governing the packaging of mitochondria and their constituents into EVs and subsequently highlight their multifaceted functions across various malignancies, including breast cancer, prostate cancer, blood malignancies, head and neck squamous cell carcinoma, digestive system cancers, etc. Mitochondrial cargo, such as intact mitochondria, mitochondrial DNA (mtDNA), and RNA (mtRNA), are shown to reconfigure metabolism, enhance bioenergetics, promote proliferation and invasion, induce drug resistance, and remodel TME by suppressing antitumor immunity. While previous reviews have predominantly focused on the role of mitochondrial transfer in individual cancers or specific systemic diseases, we made a comprehensive overview encompassing diverse cancer types. These findings suggest that EV-mediated mitochondrial cargo transfer represents a biological intercellular communication mechanism with implications for tumor progression and therapeutic resistance. It is worth noting that we also apply standardized evidence-grading frameworks (C1-C4) across cancer types to provide a critical assessment of the current evidence and identify key methodological gaps that must be addressed in future studies. Collectively, this review underscores the significance of EV-mediated mitochondrial transfer as an important biological process in cancer, presenting it as a promising frontier for novel diagnostic and therapeutic interventions.
    Keywords:  cancer; extracellular vesicles; mitochondrial transfer; mtDNA
    DOI:  https://doi.org/10.3390/cells15161502
  11. Biochem Biophys Res Commun. 2026 Aug 21. pii: S0006-291X(26)01232-5. [Epub ahead of print]834 154468
    Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
    Ryo Takahashi, Mizuho Okamoto, Tsukika Tanaka, Tsubasa Asukabe, Yui Tomiyama, Rena Okuizumi, Michio Sato, Akio Fujisawa, Yorihiro Yamamoto, Misato Kashiba.
      Aging and age related pathological conditions are long-term processes in which cellular states gradually change over extended periods. However, many experimental studies of oxidative stress in cultured cells rely on short-term exposure to exogenous oxidative agents, which may not adequately reflect chronic oxidative conditions. To address this limitation, we established a cellular model of long-term oxidative stress by reducing endogenous antioxidant capacity through inhibition of coenzyme Q10 (CoQ10) biosynthesis rather than applying acute oxidative insults. Using HepG2 cells treated with 4-nitrobenzoic acid, we compared mitochondrial responses to acute and chronic CoQ10 depletion. CoQ10 levels were reduced under both acute and chronic conditions and were restored by co- treatment with 4-hydroxybenzoic acid. Acute CoQ10 depletion resulted in a reduced number of mitochondria and mitochondrial enlargement, accompanied by an increase in mitochondrial DNA copy number (mtDNAcn). In contrast, long-term culture under continuous CoQ10 depletion restored mitochondrial number, size, and mtDNAcn to levels comparable to those of control cells, despite persistently reduced CoQ10 content. However, cell proliferation remained impaired, and mitochondrial ultrastructural properties differed from those of control cells, indicating incomplete recovery under chronic conditions. Furthermore, 4-hydroxybenzoic acid reversed the mitochondrial alterations observed under acute conditions. Together, these findings demonstrate that mitochondrial responses to CoQ10 deficiency are strongly time dependent and involve reversible yet incomplete adaptive remodeling, highlighting the importance of modeling chronic oxidative stress when interpreting mitochondrial phenotypes.
    Keywords:  Cell growth; CoQ10; Coenzyme Q10; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154468
  12. Biomolecules. 2026 Aug 12. pii: 1177. [Epub ahead of print]16(8):
    Evolutionarily Conserved but Mechanistically Distinct Mitochondrial Responses to Loss of Timeless/Swi1.
    Kalisse I Horne, Joshua Chang Mell, Chiaki Noguchi, Sri Havya Jana, Shriya Pinisetty, Rhea Masand, Christian Sell, Eishi Noguchi.
      Timeless and its fission yeast ortholog Swi1 are evolutionarily conserved components of the replication fork protection complex that ensures faithful DNA replication and genome stability. While their nuclear roles are well-characterized, their roles in mitochondrial genome maintenance remain unknown. Here, we demonstrate a previously unrecognized connection between Timeless/Swi1 and mitochondrial homeostasis. In fission yeast, swi1 deletion increased association of the DNA repair protein Rad52 with mitochondrial DNA sequences across the mitochondrial genome, suggesting altered mitochondrial genome maintenance. Unexpectedly, swi1∆ cells showed an increased mtDNA copy number and improved growth under respiratory conditions, suggesting activation of compensatory mechanisms that promote mitochondrial genome maintenance. The loss of Swi1 also partially rescued the growth defect under respiratory conditions and mtDNA loss associated with depletion of mitochondrial DNA polymerase γ, linking Swi1 to pathways regulating mitochondrial replication under stress. Consistent with these phenotypes, transcriptomic and pathway enrichment analyses revealed transcriptional changes indicative of reduced glycolysis and enhanced oxidative phosphorylation, suggesting a shift toward respiratory metabolism. In human cells, Timeless depletion elicited distinct mitochondrial responses depending on the cell type. While Timeless-depleted TE-11 and Saos-2 cells elicited mitochondrial phenotypes comparable to those observed in fission yeast, Timeless depletion in U-2 OS cells led to reduced mtDNA copy number, elevated mitochondrial reactive oxygen species, and decreased mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Despite these phenotypic differences, both fission yeast and human cells exhibited elevated levels of orthologs of the mitochondrial transcription factor A (TFAM) and the oxidative stress regulator NRF2, suggesting the conserved activation of compensatory mitochondrial and antioxidant pathways. Together, these findings identify an evolutionarily conserved connection between Timeless/Swi1 and mitochondrial homeostasis and reveal distinct adaptive responses to mitochondrial stress.
    Keywords:  DNA polymerase γ; Schizosaccharomyces pombe; Swi1; Timeless; fission yeast; mitochondria; mitochondrial genome; mtDNA; oxidative stress; stress response
    DOI:  https://doi.org/10.3390/biom16081177
  13. Genetics. 2026 Aug 26. pii: iyag203. [Epub ahead of print]
    Traffic jam at the powerhouse: restoring protein homeostasis at the mitochondria via MFB1 and HSP31 collaboration with clinical implications. An Educational Primer for use with "Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae".
    Mahima Ghosh, Patricia Melloy.
      
    Keywords:   AAC2 ; HSP31 ; MFB1 ; budding yeast; cytotoxicity; mitochondrial protein import; proteostasis
    DOI:  https://doi.org/10.1093/genetics/iyag203
  14. MedComm (2020). 2026 Sep;7(9): e70911
    Mitochondria as the Hub of Apoptosis: A Comprehensive Insight From Mitochondria to Interactions With Other Organelles.
    Rubin Tan, Jinming Zhao, Rong Wang, Yue Shi, Zaozao Chen, Yixuan Ma, Na Li, Wenqing Duan, Duo Lin, Chunxiang Zhang.
      Apoptosis is a core program regulating organismal homeostasis and plays a pivotal role in the onset and progression of most diseases. Increasing evidence in recent years indicates that mitochondria are not only central to cellular metabolism but also play a pivotal role in regulating apoptosis. However, no systematic review elucidating how mitochondria finely regulate apoptotic processes through multidimensional mechanisms, including apoptosis-resistant diseases such as cancer. This paper systematically summarizes the molecular mechanisms by which mitochondria mediate apoptosis. We focus on the regulation of cytochrome c (Cyt c) release by the Bcl-2 protein family and the activation of downstream caspase cascades. Furthermore, we provide an in-depth analysis of intrinsic factors, including mitochondrial structural remodeling (membrane rupture, cristae remodeling, and membrane lipid redistribution), dynamics imbalance (fusion, fission, and mitophagy), and mitochondrial DNA abnormalities, as well as extrinsic factors involving interorganelle interactions with the endoplasmic reticulum, lysosomes, and other organelles. Additionally, we review clinical and preclinical advances in drugs targeting these pathways. This review aims to provide a comprehensive perspective on the complex network of mitochondrial regulation of apoptosis and offer valuable insights for developing novel clinical therapeutic strategies for cancer and other diseases.
    Keywords:  MAM; MOMP; apoptosis; mitochondria; mitochondrial autophagy; mitochondrial transplantation; mtDNA
    DOI:  https://doi.org/10.1002/mco2.70911
  15. Ther Innov Regul Sci. 2026 Aug 22.
    Constructing an Evidence-Based Validity Rationale for a Multi-component Endpoint in Heterogeneous Populations.
    Bryce B Reeve, Laine E Thomas, Kevin P Weinfurt.
      Multi-component endpoints can be necessary in regulatory trials when diseases manifest heterogeneously across and within patients, as in many rare neurodevelopmental disorders, but they require explicit justification to support an evidence-based validity rationale consistent with the Food and Drug Administration's Patient-Focused Drug Development guidance for clinical outcome assessments (COAs). This paper presents a practical framework for constructing and evaluating that rationale. The framework emphasizes: selecting meaningful aspects of health (MAHs) that are important to patients and plausibly affected within the trial timeframe; defining component concepts of interest (COIs) and selecting fit-for-purpose COAs for each component; documenting component-level justification for interpreting COA scores as reflecting their COIs in the context of use; and providing endpoint-level justification for interpreting treatment effects on the aggregate value as reflecting effects on the MAH(s). It highlights key design choices, including component selection and prioritization with patient/caregiver input, transparent scoring and weighting strategies, handling missing data, and ensuring adequate precision for the proposed design and analysis plan, and describes risks unique to multi-component endpoints, including benefit dilution, harm masking, and interpretive ambiguity. When the trade-offs among different endpoint strategies are considered thoughtfully and explicitly communicated along with an endpoint rationale grounded in patient-focused evidence, multi-component endpoints can provide a credible, fit-for-purpose approach to evaluating treatment benefit in heterogeneous populations.
    Keywords:  Clinical outcome assessments; Clinical trials; Multi-component endpoints; Patient-focused drug development; Rare disease
    DOI:  https://doi.org/10.1007/s43441-026-01037-4
  16. Mol Biol Rep. 2026 Aug 28. pii: 1477. [Epub ahead of print]53(1):
    The organellar biology of aging: A mitochondrial vantage.
    Madhusmita Pala, Abinash Nayak, Bandita Rath.
      Aging is a progressive, multi-scale decline in physiological function driven by the accumulation of cellular and molecular damage. Mitochondrial dysfunction has emerged as an established hallmark of aging owing to its critical involvement in bringing about aging-associated changes. Oxidative damage to the organellar genome impairs its function, causing redox imbalance and energy depletion. Concurrently, defective poly (ADP-ribose) polymerase 1 (PARP1) signaling and reduced cellular NAD+ levels affect molecular regulators such as SIRT1 (sirtuin 1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, which are central to mitochondrial dynamics and function. This axis does not operate in isolation but instead communicates with other organelles such as the endoplasmic reticulum, lysosome, and peroxisome to facilitate age-related changes. Most intriguingly, mitochondria also generate several retrograde signals to regulate nuclear gene expression, including the transcriptional regulators vital for mitochondrial function and other master regulators of aging. In essence, aging-associated organellar alterations, mitochondrial dysfunction, and inter-organellar crosstalk work in a loop to promote aging progression. More research in the field may unravel the mechanistic details of the organellar crosstalk that works in concert with classical aging pathways to sustain aging progression, which may help promote healthier aging.
    Keywords:  Aging; Cellular senescence; Gene regulation; Mitochondria; Retrograde signals
    DOI:  https://doi.org/10.1007/s11033-026-12674-1
  17. Nutrients. 2026 Aug 19. pii: 2702. [Epub ahead of print]18(16):
    Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review.
    Sergio Abanades, Irene Fernández, Nuria Capdevila, Francisco Cardona.
      Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune-metabolic regulation. This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework. Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.
    Keywords:  ME/CFS; NAD+; fatigue; fibromyalgia; glutathione; micronutrition; mitochondrial dysfunction; myalgic encephalomyelitis/chronic fatigue syndrome; precision nutrition
    DOI:  https://doi.org/10.3390/nu18162702
  18. Free Radic Biol Med. 2026 Aug 24. pii: S0891-5849(26)01048-8. [Epub ahead of print]256 257-270
    Circulating cell-free mitochondrial DNA as a redox-associated marker of mitochondrial homeostasis disruption during gastric carcinogenesis.
    Tie Zhao, Justice Afrifa, Yingwei Xue, Jing Chen, Yunlong Li, Dong Wang, Ting Yang, Xiao Liang, He Zhang, Shuaihang Pang, Mengdi Cai, Wayne A Schroder, Songbin Fu, Jingcui Yu.
      Circulating cell-free mitochondrial DNA (ccf-mtDNA) is an emerging non-invasive marker across cancers. Yet, in gastric cancer (GC), its relationship to tissue mtDNA content, oxidative remodeling and somatic mtDNA variants, and thus its basis in mitochondrial homeostasis, remains poorly defined. We analyzed 169 individuals: 70 GC patients, 29 with precancerous gastric lesions and 70 healthy controls. MtDNA copy number was measured by quantitative PCR, and plasma biomarkers of oxidative damage (8-hydroxy-2'-deoxyguanosine, 8OH-dG; 4-hydroxynonenal, 4HNE) and of antioxidant capacity (glutathione peroxidase-1, GPX-1) were measured by ELISA. MtDNA variants were identified by next-generation sequencing. In MKN-28 GC cells, mitochondrial transcription factor A (TFAM) was manipulated with lentiviral vectors to alter mtDNA content. The results showed that GC progression was accompanied by higher ccf-mtDNA, shifts in plasma oxidative damage and antioxidant markers, and accumulation of mtDNA variants, alongside lower mtDNA content in cancers than in adjacent tissues. In GC cells, lowering mtDNA content by TFAM silencing promoted the malignant phenotype and increased intracellular superoxide-related fluorescence. By multiplex immunohistochemistry, tissue markers of mitochondrial maintenance and mtDNA release declined without a rise in caspase-3. D-loop variants already present at the precancerous stage suggest early mitochondrial changes, whereas predicted deleterious coding variants affecting respiratory chain components were observed in GC tissues. These findings support a redox-associated model of mitochondrial homeostasis that links impaired mitochondrial maintenance, mtDNA instability, and ccf-mtDNA accumulation, and provide a tissue-anchored mechanistic basis for the circulating mtDNA changes detected by plasma-based approaches in GC.
    Keywords:  Cell-free mitochondrial DNA; D-loop variant; Gastric cancer; Mitochondrial DNA copy number; Oxidative stress; TFAM
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.046
  19. Front Cell Infect Microbiol. 2026 ;16 1866924
    Emerging microbiome-mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation.
    Xinxing Lu, Wenbin Sun, Daowei Zhang, Bin Hou, Huiyu Tai, Wenqing Yu, Xuehua Pu.
      Recent studies highlight a complex interaction between the gut microbiome and host mitochondrial dynamics in the modulation of immune responses as well as susceptibility to infectious and inflammatory pathologies. Recent empirical studies elucidate that metabolites derived from microbiota, encompassing short-chain fatty acids, trimethylamine, and indole derivatives, orchestrate mitochondrial functionality and the production of reactive oxygen species, which subsequently affect NLRP3 inflammasome activation. Dysbiosis within the gut microbiota has been documented to aggravate mitochondrial stress in host intestinal epithelial cells and other tissue-resident cells, facilitate the release of mitochondrial DNA (mtDNA), and initiate inflammatory pathways across a spectrum of conditions, including colitis, neurodegeneration, cardiovascular disorders, and sepsis. In contrast, the application of probiotics, postbiotics, and phytochemicals may restore microbial equilibrium, bolster mitochondrial integrity through mitophagy and PINK1/Parkin pathways, and mitigate NLRP3 inflammasome-mediated pyroptosis. Furthermore, experimental findings suggest that mtDNA functions as a damage-associated molecular pattern, activating cGAS-STING and NLRP3 signaling pathways, thereby establishing a connection between alterations in microbiota and systemic inflammation. The microbiome-mitochondria axis has been further associated with organ-specific immune responses, encompassing interactions among the gut-lung, gut-brain, gut-kidney, and gut-liver systems. Notably, the liver serves as a primary intermediary hub, receiving gut-derived metabolites and inflammatory mediators through the portal circulation and thereby linking intestinal microbial signals to peripheral immune and metabolic responses. Collectively, these investigations emphasize the emerging mechanistic significance of microbiota-induced modulation of mitochondrial function in host defense mechanisms, thereby illuminating potential therapeutic approaches that focus on microbial composition, mitochondrial dynamics, and inflammasome signaling to alleviate infectious and inflammatory pathologies. This review integrates contemporary understandings of the interactions between microbiota, mitochondria, and NLRP3 inflammasome activation, thereby establishing a framework for prospective translational research.
    Keywords:  NLRP3 inflammasome; host defense; infectious diseases; microbiome–mitochondria; mtDNA-mediated immunomodulation
    DOI:  https://doi.org/10.3389/fcimb.2026.1866924
  20. Cells. 2026 Aug 10. pii: 1438. [Epub ahead of print]15(16):
    Adipose Stem Cell Mitochondrial Transplantation in ART: From Biological Rationale to Clinical Milestone.
    Helaruwan Pasan Kumara Wijethunga Arachchilage, Sanath Udayanga Kankanam Gamage, Atsushi Morimoto, Yoshiharu Morimoto.
      Oocyte quality is the primary determinant of success in assisted reproductive technologies (ART), and mitochondrial dysfunction is increasingly recognized as a central mediator of poor oocyte competence across advanced maternal age, recurrent implantation failure, polycystic ovary syndrome, endometriosis, and obesity. Chemical interventions improve the mitochondrial microenvironment but cannot restore depleted mitochondrial mass, while heterologous mitochondrial replacement remains constrained by ethical, legal, and biological limitations. This review examines the biological basis for mitochondrial intervention in oocytes, evaluates chemical and cellular therapeutic approaches, and assesses the evidence for autologous Adipose Stem Cell-derived Mitochondria ENergy Transfer (ASCENT). Mitochondria govern oocyte ATP production, calcium-mediated meiotic integrity, and redox homeostasis, and their disruption contributes to aneuploidy, fertilization failure, and embryonic arrest. Among cellular interventions, autologous adipose-derived stem cell mitochondrial transplantation offers minimally invasive tissue accessibility, morphological compatibility with oocyte mitochondria, robust membrane potential, and a preclinically validated Mito-ICSI delivery platform. Notably, ASCENT is currently the only autologous approach for which safety across three consecutive offspring generations has been reported in a mammalian model, with primary maternal origin of offspring mtDNA confirmed. Together, preclinical efficacy, transgenerational safety, and human proof-of-concept support progression toward a rigorously designed clinical trial, while ASC-derived mitochondria hold broader relevance in regenerative medicine.
    Keywords:  Adipose Stem Cell Energy Transfer (ASCENT); Mito-ICSI; adipose-derived stem cells; autologous therapy; mitochondrial dysfunction; mitochondrial transplantation
    DOI:  https://doi.org/10.3390/cells15161438
  21. Stat Methods Med Res. 2026 Aug 26. 9622802261478737
    A propensity score-integrated win ratio method for placebo borrowing.
    Yurong Chen, Michael Sonksen, Tuo Wang, Yingdong Feng, Joon Jin Song.
      Leveraging external control data has been used to enhance the efficiency of clinical trials, especially in rare diseases where recruitment is often challenging. However, directly pooling data from different studies without appropriate adjustments can lead to biased results when populations differ across these studies. In addition to limited sample sizes, trials for rare diseases commonly assess treatment efficacy through multiple clinical endpoints using composite endpoints. The win ratio has gained attention for composite endpoint analysis, as it enables prioritized comparisons that account for the relative clinical importance of each endpoint. Motivated by these two challenges, we proposed novel propensity score (PS)-integrated win ratio methods to incorporate external control data. Specifically, two PS-based weighting approaches, PS-ratio and PS-difference, are proposed to adjust for between-study baseline covariate differences, thereby mitigating the risk of potential bias. Simulation studies and real-world case analysis demonstrate that the proposed methods consistently improve statistical power while maintaining proper Type I error control. This framework offers a robust and practical solution for composite endpoint analysis using external controls, with particular relevance to rare disease trials and regulatory decision-making.
    Keywords:  Win ratio; composite endpoint; inverse probability of treatment weighting; placebo borrowing; propensity score
    DOI:  https://doi.org/10.1177/09622802261478737
  22. Sci Adv. 2026 Aug 28. 12(35): eadu0632
    Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.
    Fangbing Chen, Yanhui Liang, Wei Zheng, Aobo Yao, Ning Wang, Huangyao Chen, Zhenpeng Zhuang, Meng Lian, Yu Zhao, Zhen Ouyang, Zhaohai Zhou, Weikai Ge, Qishuai Liu, Yinghua Ye, Liangxue Lai, Kepin Wang.
      The accumulation of mitochondrial DNA (mtDNA) mutations is a primary driver of mitochondrial dysfunction, which is intrinsically linked to aging and various pathologies. POLG, the catalytic subunit of DNA polymerase gamma, is essential for mtDNA replication; notably, a deficiency in its proofreading function precipitates the accumulation of mtDNA mutations. In this study, by combining prime editing with somatic cell nuclear transfer technology, we successfully generated a mitochondrial mutator pig model expressing proofreading-deficient POLG. These pigs exhibited elevated somatic mtDNA mutation loads and recapitulated key premature aging phenotypes, including weight loss, rough hair coat, anemia, structural alterations in the skin and testicular interstitium, increased apoptosis, and the up-regulation of senescence-associated markers, culminating in shortened life span. Given the physiological and metabolic similarities between pigs and humans, this mitochondrial mutator pig model represents an ideal preclinical tool for dissecting the mechanistic role of mtDNA mutations in aging and age-related pathologies and for accelerating the translation of therapeutic strategies.
    DOI:  https://doi.org/10.1126/sciadv.adu0632
  23. Int J Mol Sci. 2026 Aug 17. pii: 7334. [Epub ahead of print]27(16):
    Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine.
    Victoriano Pérez-Vázquez, Juan Manuel Guzmán-Flores, Katya Vargas-Ortiz, Carmen Palacios-Reyes, Joel Ramírez-Emiliano.
      Obesity and type 2 diabetes (T2D) are multifactorial metabolic disorders characterized by progressive dysfunction of multiple organs and biological systems. Although mitochondrial dysfunction is a hallmark of disease progression, the mechanisms linking metabolic stress to coordinated tissue dysfunction remain incompletely understood. Comparative proteomic studies have consistently identified coordinated remodeling of oxidative phosphorylation, fatty acid oxidation, tricarboxylic acid cycle activity, redox regulation, mitochondrial proteostasis, and adaptive signaling across metabolically affected organs, revealing conserved organizational principles underlying mitochondrial adaptation. However, these findings have largely been interpreted within reductionist, pathway-centered frameworks. Here, we integrate evidence from comparative proteomics, mitochondrial biology, bioenergetics, redox biology, signaling, and systems biology to propose the concept of mitochondrial-centered biological networks (MCBNs), in which mitochondria function as dynamic regulatory hubs coordinating interconnected processes that collectively determine metabolic adaptation and tissue resilience. Building on this framework, we introduce the Mitochondrial Homeostasis Hypothesis, which proposes that preservation or restoration of mitochondrial homeostasis depends on coordinated regulation of MCBNs and constitutes a fundamental systems-level mechanism underlying resistance to obesity, T2D, and hypercaloric diet-induced metabolic dysfunction. Curcumin represents a well-studied network-modulating intervention that coordinately influences mitochondrial bioenergetics, metabolic flexibility, redox homeostasis, proteostasis, inflammatory signaling, and adaptive stress responses, supporting the concept that mitochondrial homeostasis is preserved through coordinated network regulation rather than isolated modulation of individual molecular pathways. Finally, we discuss how emerging technologies, including functional proteomics, redox proteomics, spatial and single-cell proteomics, acetylomics, integrated multi-omics, and artificial intelligence-assisted network analysis, provide unprecedented opportunities to quantitatively characterize MCBNs, validate the proposed hypothesis, identify network-based biomarkers, and accelerate the development of network-guided precision mitochondrial medicine.
    Keywords:  comparative proteomics; curcumin; mitochondrial homeostasis; mitochondrial-centered biological networks; network medicine; obesity; precision mitochondrial medicine; systems biology; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms27167334
  24. J Assist Reprod Genet. 2026 Aug 27.
    Concordant mtDNA heteroplasmy between trophectoderm and inner cell mass supports blastocyst-stage PGT-mt for m.14487T>C.
    Maria Tofilo, Ilya Volodyaev, Evgenii Tretiakov, Olga Kokorina, Svetlana Avdeichik, Anna Smirnova, Elena Grechenko, Anna Filimonova, Natalia Sudarikova, Anastasia Kirillova, Ilya Mazunin.
       PURPOSE: Is blastocyst-stage trophectoderm (TE) biopsy informative for preimplantation genetic testing of the mitochondrial DNA (mtDNA) variant m.14487 T > C (MT-ND6), by providing heteroplasmy estimates representative of the inner cell mass (ICM), within a combined PGT-A/PGT-mt workflow?
    METHODS: Single IVF/ICSI cycle study in one carrier woman; six blastocysts were obtained and underwent day 5-6 TE biopsy followed by combined PGT-A and targeted mtDNA heteroplasmy assessment.
    RESULTS: Six blastocysts underwent combined PGT-A/PGT-mt (day 5, n = 2; day 6, n = 4). PGT-A classified three embryos as euploid, two as aneuploid, and one as mosaic. PGT-mt showed a bimodal distribution of m.14487 T > C heteroplasmy: three embryos were < 18% (11.4-13.5%) and three were > 70% (73.2-99.6%); only one embryo met the predefined transfer criteria (euploid; 11.4% heteroplasmy). After warming and embryo fractionation, heteroplasmy estimates from the original TE biopsy and the corresponding post-warming embryo fraction (the remaining TE, ICM, or combined TE + ICM) were closely concordant, with only small paired differences.
    CONCLUSION: These findings provide variant-specific evidence that blastocyst TE biopsy can be representative of the ICM for m.14487 T > C, supporting combined PGT-A/PGT-mt at the blastocyst stage. Nevertheless, given the possibility of heteroplasmy shifts later in development, prenatal diagnosis and postnatal follow-up remain advisable when a heteroplasmic embryo is transferred.
    Keywords:  Heteroplasmy; ICM; Leigh syndrome; MT-ND6; Mitochondrial DNA; PGT-mt; TE; m.14487T>C
    DOI:  https://doi.org/10.1007/s10815-026-04012-y
  25. J Cardiovasc Aging. 2026 ;pii: 12. [Epub ahead of print]6(2):
    Understanding cardiovascular aging as a disorder of mitochondrial network.
    Taslima Akter Shila, Dhrubo Ahmad, Jianli Zhao, Huilan Tan, Bo Wang, John Zhang, Yajing Wang.
      Cardiovascular aging is increasingly recognized as a mitochondrial-initiated systemic network dysfunction, a progressive, integrative failure driven by deteriorating mitochondrial quality and signaling. This review synthesizes emerging evidence linking comprehensive mitochondrial pathology to the erosion of cardiovascular resilience as a network-level dysfunction. Age-dependent remodeling of mitochondrial ultrastructure and component composition disrupts respiratory efficiency, positioning bioenergetic insufficiency as a central determinant of reduced stress tolerance across the cardiovascular system. Concurrently, defects in mitochondrial fission-fusion dynamics and impaired mitophagy propagate dysfunction within the mitochondrial network, amplifying the decline in energetic capacity. Beyond energy failure, the release of mitochondrial DNA, vesicles, and peptides activates innate immune sensors such as the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway, initiating chronic sterile inflammation that propagates maladaptive remodeling cascades throughout cardiovascular tissues and distal organs. We challenge the traditional view of mitochondria solely as energy producers, revealing that uncoupled perfusion and energy metabolism, together with nitric oxide imbalance, can serve as early indicators of diastolic dysfunction and ischemic susceptibility. Additionally, we introduce the concept of "mitochondrial age", a composite measure that integrates respiratory function, imaging-based structural indices, and circulating mitochondrial biomarkers to quantify mitochondrial health. This metric may serve as a translational tool for assessing cardiovascular aging through mitochondrial network communication. Finally, we highlight rejuvenation strategies aimed at restoring mitochondrial youthfulness, ranging from behavioral interventions (exercise, time-restricted feeding) to metabolic and molecular therapies targeting nicotinamide adenine dinucleotide (NAD+) metabolism, mitophagy, and endothelial mitochondrial protection. Collectively, this review defines cardiovascular aging as a network-level mitochondrial disorder, offering new conceptual and therapeutic directions for preserving cardiac and vascular function.
    Keywords:  Cardiovascular aging; endothelial dysfunction; epidemiology; heart failure with preserved ejection fraction; hypertension; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.20517/jca.2026.07
  26. Sociol Health Illn. 2026 Sep;48(7): e70255
    Rare Diseases as Epistemic Objects: Exploring the Moral Role of Health Systems.
    Nicolás Schöngut-Grollmus, Dolores Steverlynck, Fernanda Manríquez-Castillo, Sebastián Rojas-Navarro.
      This article explores how rare diseases reveal the moral and epistemic foundations of healthcare systems. Based on narrative interviews with 11 Chilean patients and 10 professionals, this study shows how the absence of standardised protocols-such as clinical guidelines, treatment pathways and referral standards-exposes informal, discretionary and morally complex decision-making processes. Contrary to the ideal of evidence-based care, rare disease treatment often relies on personal networks, institutional gaps and improvisation. We frame rare diseases as epistemic objects, conditions that challenge classification systems and highlight the normative assumptions behind health decisions. Introducing the concept of decisional justice, we examine how health systems support (or fail to support) fair and accountable decision-making. Patients become epistemic activists, whereas professionals navigate fragmented institutions with little guidance. Rare diseases act as diagnostic tools that expose structural inequities and the invisibility of certain conditions. They reveal how ignorance can translate into neglect, shifting responsibility to individuals and deepening disparities. We argue that healthcare systems are not only logistical but also moral infrastructures, shaping what can be known and acted upon. Thus, health justice must also involve moral recognition and epistemic inclusion, not just resource distribution.
    Keywords:  epistemic injustice; health decision‐making; healthcare inequalities; moral infrastructure; rare diseases
    DOI:  https://doi.org/10.1111/1467-9566.70255
  27. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261476231
    Interim analysis of an international multi-site prospective natural history study evaluating the clinical presentation and progression of Leigh syndrome spectrum disorders.
    Leigh Syndrome Roadmap Project Natural History Study Consortium
       Background: Leigh Syndrome Spectrum (LSS) is the most common pediatric mitochondrial disease syndromic presentation. However, its natural history has not been well-characterized, particularly across diverse populations.
    Objectives: Information obtained through robust, prospective natural history studies (NHSs) in LSS will be foundational to accurately counsel newly diagnosed families, develop effective therapeutics, and identify outcome measures for future clinical trials.
    Design: We describe an ongoing multi-site, international, patient advocacy group funded, observational NHS in LSS. We employed a multi-site international federated design with local regulatory review coupled with central regulatory and coordinator support. To date, NHS outcome measures have been collected on LSS participants across 5 sites every 3 to 6 months for up to 3.8 years.
    Methods: Objective and subjective outcome measures were carefully selected by the international LSS outcome measure working group. Study data across sites were anonymized and combined for cleaning and analysis at the Data Coordinating Center (Children's Hospital of Philadelphia). Descriptive statistics of the study cohort and inter-measure correlations were analyzed across NHS assessments.
    Results: Preliminary analysis of the first 74 participants was completed to characterize demographics, symptomatology, and clinical history. The average age at enrollment was 10.7 years, ranging from 0 to 50 years. The most common gene disorders were MT-ATP6 (22%, n=16), MT-ND5 (8%, n=6) and SURF1 (8%, n=6). No statistically significant between-group differences were detected by sex or genetic etiology. High inter-measure correlation between all the outcome measures and "gold standard" outcomes provides justification for future use of these assessments in both NHSs and clinical trials.
    Conclusion: We have demonstrated the feasibility of prospectively collecting robust international-site LSS NHS data through multi-site collaboration. These LSS community data will be critical for informing therapeutic development, outcome measure selection and clinical trial design, and providing baseline comparator evidence for development of future therapeutic interventions.
    Keywords:  Leigh syndrome spectrum; mitochondrial disease; natural history; neurodegenerative disease
    DOI:  https://doi.org/10.1177/26330040261476231
  28. Biomolecules. 2026 Aug 20. pii: 1218. [Epub ahead of print]16(8):
    The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling.
    Jada Sangha, David A Hood.
      Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle.
    Keywords:  NLRP3 inflammasome; exercise; inflammation; mitochondria; mtROS; muscle atrophy; skeletal muscle
    DOI:  https://doi.org/10.3390/biom16081218
  29. Biomolecules. 2026 Jul 30. pii: 1116. [Epub ahead of print]16(8):
    A Function-Centric Framework for Mitochondrial Quality Control.
    Fulya Ozcan, Filip Vujovic, Ramin M Farahani.
      Mitochondrial quality control (QC) comprises interconnected pathways that preserve organelle function by detecting damage and mediating repair, remodelling, or elimination of defective components. Although many sub-organellar QC mechanisms are well characterised, stress is often sensed first at the level of mitochondrial function rather than at individual molecular targets. Functional domains such as oxidative folding, bioenergetics, redox balance, pH, and thermogenesis act as sensory portals that detect perturbations and trigger adaptive reprogramming of mitochondrial activity. In this perspective, we provide a conceptual perspective for mitochondrial QC as a mechanistically integrated network, emphasising how changes in these functional states couple diverse QC modules-including proteases, antioxidant systems, mitochondrial dynamics, mitophagy, and mitochondrial-derived vesicles-into a unified surveillance system. We propose that primary stressors, such as redox imbalance, are progressively converted into secondary stress signals, including reactive oxygen species accumulation, membrane depolarisation, metabolite redistribution, and altered lipid or nucleic-acid structure. These secondary signals propagate across mitochondrial and cytosolic compartments, amplifying QC by coordinating the engagement of repair, remodelling, and organelle-elimination pathways. This cascading transformation of stress signals not only limits the impact of the initial insult but also enhances adaptive capacity by driving synergistic deployment of QC processes across multiple mechanistic layers.
    Keywords:  cell cycle; electron transport chain; mitochondria; quality control; signalling pathways
    DOI:  https://doi.org/10.3390/biom16081116
  30. JMIR Med Inform. 2026 Aug 25. 14 e99206
    Building a National Interoperable Rare Eye Disease Data Warehouse: Methodological Framework and Implementation Report From the French Rare Eye Disease Database (FREDD) Initiative.
    Camille Beluffi Marin, Marilyne Oswald, Laura Ratenet, Matthieu Stoll, Kirsley Chennen, Nathalie Chabin, Julie Hubert, Grégoire Rey, Guylène Le Meur, Vasily Smirnov, Isabelle Meunier, Isabelle Audo, Hélène Dollfus.
       Background: Rare eye diseases are characterized by low prevalence, clinical heterogeneity, and fragmented data collection, which limit the reliability of analysis results and multicenter research. In France, the development of health data warehouses is strictly regulated by national data protection authorities. While international initiatives aim to harmonize rare disease registries, capturing hyperspecialized, multimodal clinical records and ophthalmology-specific imaging within a fully compliant and sustainable infrastructure remains a major operational challenge.
    Objective: This study aims to describe the methodological framework, regulatory implementation, and early operational outcomes of FREDD (French Rare Eye Disease Database), a national interoperable health data warehouse dedicated to rare eye diseases, and to analyze its key success factors, technical bottlenecks, and long-term financial sustainability models.
    Methods: Developed under the oversight of the French National Institute of Health and Medical Research (Institut national de la santé et de la recherche médicale; INSERM), the warehouse implements a centralized 3-layer architecture encompassing data collection, processing, and research reuse environments. The dataset extends the national minimum rare disease dataset with detailed ophthalmology variables structured through a dynamic electronic case report form, as well as a dedicated collection of ophthalmic images. Interoperability is achieved using international domain ontologies and a custom parsing tool (FREDDEX) designed to automatically prefill clinical data from the existing French national rare disease registry. Centralized monitoring, data curation, and cross-center quality tracking are driven by a dedicated in-house dashboard (FREDDIn [FREDD Insights]), while unstructured retinal images are processed through a standardized pseudonymization and human-verified validation pipeline.
    Unlabelled: Official regulatory authorization was obtained in April 2024, and active data collection began in March 2025 across 5 pilot expert centers, focusing its initial phase on inherited retinal dystrophies, primarily retinitis pigmentosa. Over a 1-year period, the warehouse successfully integrated clinical data from 1649 patients-representing 20.3% of all retinitis pigmentosa cases registered nationally-and accumulated more than 10,000 ophthalmic images. The centralized dashboard maintained an overall data inconsistency rate of approximately 7%, chiefly reflecting logical dependencies. Among the included patients, 36.7% (605/1649) patients had associated imaging data, with fundus photography being the most widely available modality (768/1649, 46.6%).
    Conclusions: The implementation of this database demonstrates that a highly specialized, multimodal health data warehouse can be successfully deployed in a highly regulated environment when regulatory anticipation, governance formalization, and technical flexibility are addressed in parallel. While initial development was supported by institutional grants, long-term sustainability will require a structured cost-recovery model. Future milestones will focus on expanding center coverage nationwide, refining image annotation frameworks for AI readiness, and deploying automated export pathways toward European registries.
    Keywords:  clinical research; data governance; data interoperability; health data warehouse; inherited retinal dystrophies; rare eye diseases; regulatory bodies; retinitis pigmentosa; secondary use of health data
    DOI:  https://doi.org/10.2196/99206
  31. J Genet Genomics. 2026 Aug 22. pii: S1673-8527(26)00272-9. [Epub ahead of print]
    Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.
    Yanchun Ji, Feilong Meng, Yinglong Gao, Zhipeng Nie, Yunfan He, Juanjuan Zhang, Ya Li, Minglian Zhang, Jianyong Wang, Yongming Zhang, Shihui Wei, Jun Qin Mo, Min-Xin Guan.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease mainly driven by the m.11778G>A mutation, and its incomplete penetrance and diverse inheritance patterns remain unclear. This study integrates clinical and genetic analyses of 419 Han Chinese pedigrees carrying this mutation, covering 5262 matrilineal relatives. Distinct phenotypic heterogeneity emerges, including sporadic, maternal and complex transmission patterns; 209 pedigrees contain only single affected individuals, which suggests that the m.11778G>A mutation alone fails to cause disease. Full mitochondrial DNA sequencing and haplogroup screening identify multiple mitochondrial genetic modifiers. Haplogroups D4j, M7, M9, and M10 are significantly enriched in maternally inherited families with elevated disease penetrance. Haplotype-specific variants ND4 11696G>A, ND1 3394T>C, and ND6 14502T>C synergistically aggravate mitochondrial dysfunction together with m.11778G>A, and secondary mtDNA mutations disrupting complex I or mitochondrial tRNA metabolism also raise disease susceptibility. Nuclear modifiers PRICKLE3 and YARS2, as well as X-linked sex-specific regulatory factors, are also identified. Overall, LHON results from the interaction of mitochondrial and nuclear genetic factors. This research constructs a comprehensive genetic landscape of LHON, highlights the vital role of modifier genes, and provides theoretical support for precision therapies targeting mitochondrial and nuclear pathways.
    Keywords:  Chinese; Inheritance pattern; Leber hereditary optic neuropathy (LHON); Mitochondrial DNA mutation; Mitochondrial haplogroup; Nuclear modifier gene
    DOI:  https://doi.org/10.1016/j.jgg.2026.08.007
  32. Front Cell Dev Biol. 2026 ;14 1866640
    Mitochondrial regulation of cellular senescence heterogeneity.
    Minseo Ahn, Sung-Jin Yoon, Jae Ho Seo.
      Cellular senescence is a stable cell-cycle arrest program accompanied by extensive metabolic remodeling and acquisition of a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that senescence is not a uniform endpoint but a heterogeneous spectrum of cell states shaped by the nature of the initiating stimulus. Mitochondria have recently emerged as central regulators of this heterogeneity by integrating metabolic, redox, and inflammatory signaling. Senescent cells share common mitochondrial features-including increased mitochondrial mass, elevated reactive oxygen species (ROS), impaired mitophagy, and altered metabolic programs-yet distinct senescence subtypes exhibit unique mitochondrial adaptations. Replicative senescence is governed by a telomere-mitochondria feedback loop, whereas stress- and oncogene-induced senescence involve rapid mitochondrial stress responses and stimulus-specific metabolic rewiring. Therapy-induced senescence further introduces context-dependent mitochondrial dependencies that influence therapeutic resistance and senolytic vulnerability. In this review, we synthesize current understanding of mitochondrial regulation across senescence subtypes and highlight how mitochondrial dysfunction actively drives senescence heterogeneity. We further discuss emerging therapeutic strategies that exploit mitochondrial vulnerabilities to selectively modulate or eliminate senescent cells. Understanding mitochondrial control of senescence heterogeneity provides a conceptual framework for developing precision interventions in aging and cancer.
    Keywords:  cellular senescence; metabolic reprogramming; mitochondrial dysfunction; mitophagy; reactive oxygen species (ROS); senescence heterogeneity; senescence-associated secretory phenotype (SASP); senolytics
    DOI:  https://doi.org/10.3389/fcell.2026.1866640
  33. Front Mol Biosci. 2026 ;13 1857438
    Late-onset mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes with chronic intestinal pseudo-obstruction: a case-based review.
    Lin Zhang, Junjian Lin, Fengying Li, Yujie Jia, Junhua Li, Xiaopeng Wang.
       Background: Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes (MELAS) is rare in people over 40 years of age, and gastrointestinal complications of MELAS are also rare, especially Chronic Intestinal Pseudo-Obstruction (CIPO).
    Case Presentation: This report describes a 60 years old MELAS patient with a mutation rate of only 6.29% in the m.3243A>G gene, accompanied by CIPO. After treatment, MELAS symptoms can be controlled, but intestinal obstruction recurs and worsens. At present, patients fast and rely on intravenous nutrition to sustain their lives.
    Discussion: The low proportion of m.3243A>G mutations in patients may be related to their advanced age, but the high or low proportion of gene mutations detected in blood samples is not related to the severity of symptoms. MELAS combined with CIPO is rare and different from other intestinal obstructions. CIPO has no cause of mechanical intestinal obstruction and may be related to dysfunction of smooth muscle mitochondria or involvement of the enteric nervous system.
    Conclusion: For complications of MELAS beyond the nervous system, early consideration should be given to the possibility of MELAS. Early genetic testing has important clinical significance for the treatment and prognosis of patients. This article will provide a literature review on the multi system performance of MELAS.
    Keywords:  chronic intestinal pseudo-obstruction; late-onset; m.3243A>G gene mutation; mitochondrial encephalomyopathy; mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
    DOI:  https://doi.org/10.3389/fmolb.2026.1857438
  34. Mol Genet Metab. 2026 Aug 19. pii: S1096-7192(26)00528-7. [Epub ahead of print]149(1-2): 110245
    Vitelliform retinal lesions: Uncommon adult-onset presentation of the common mitochondrial MELAS variant.
    Jai Kumar Rajavoor Muniswamy, Michael Stewart, Eric Eggenberger, Karthik Muthusamy.
      
    Keywords:  MT-TL1 (m.3243A>G); Mitochondrial disease; Retinal dystrophy; Vitelliform macular dystrophy
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110245
  35. Redox Biol. 2026 Aug 22. pii: S2213-2317(26)00364-2. [Epub ahead of print]96 104365
    Adaptive and degenerative mitochondrial remodeling define distinct redox states in age-related macular degeneration.
    Cecilia Giulivi, Carol Villafuerte-Trisolini, Zoe Lee Greenblatt, Jennifer Dang, Atena Tork, Rida Mullah, Sophie Le, Angela Min, Maya Nair, Aldo Vorkapich, Huy-An Tran, Elizabeth Doyle, Alestor Law, Owen O'Keefe, Annabelle Wu, Bradley Shibata, Ana Ripolles-Garcia, Sara M Thomasy, R Alan Harris, Rui Chen, Yin Allison Liu, Glenn Yiu.
      Age-related macular degeneration (AMD) is associated with mitochondrial dysfunction and oxidative stress, yet the relationship between mitochondrial remodeling, redox homeostasis, and disease progression remains poorly understood. Nonhuman primates (NHPs) develop spontaneous AMD-related phenotypes, including punctate deposits and soft drusen, providing a unique animal model to investigate mitochondrial pathology in the aging retinal pigment epithelium (RPE). We integrated quantitative mitochondrial ultrastructural profiling with flavoprotein fluorescence imaging, plasma metabolomics, and whole-exome sequencing to characterize mitochondrial and redox alterations in aged rhesus macaques with AMD-related lesions. Flavoprotein fluorescence imaging demonstrated increased metabolic heterogeneity in eyes with soft drusen, consistent with altered mitochondrial redox states and oxidative stress. Morphometric analysis identified distinct mitochondrial remodeling patterns across phenotypes. Normal aging was characterized by concentric cristae and type I paracrystalline inclusions. Eyes with punctate deposits exhibited increased mitochondrial fusion-associated morphology, hyperbranching, and type I paracrystalline inclusions, consistent with a stress-responsive mitochondrial remodeling pattern. In contrast, eyes with soft drusen exhibited reduced fusion-associated morphology, reduced structural complexity, and ultrastructural features consistent with mitochondrial deterioration. These ultrastructural patterns were accompanied by distinct plasma metabolomic signatures. Punctate deposits were associated with altered glycolytic, tricarboxylic acid cycle, and redox-buffering metabolites, consistent with differences in stress-responsive metabolism, whereas soft drusen exhibited metabolomic signatures consistent with altered redox homeostasis. Whole-exome sequencing identified a mitochondrial DNA variant, MT:9582G > A, in cytochrome c oxidase subunit III (COX3) associated with the drusen phenotype. Collectively, these findings identify distinct mitochondrial remodeling patterns associated with AMD-related phenotypes in aged rhesus macaques. The convergence of ultrastructural, imaging, metabolomic, and genetic analyses suggests that punctate deposits and soft drusen are associated with different mitochondrial and redox-related responses to chronic retinal stress. These findings provide a framework for future studies investigating mitochondrial biology and redox-driven mechanisms in AMD.
    Keywords:  Age-related macular degeneration; Mitochondria; Nonhuman primates; Redox homeostasis; Retinal pigment epithelium; Rhesus macaques
    DOI:  https://doi.org/10.1016/j.redox.2026.104365
  36. iScience. 2026 Sep 18. 29(9): 117183
    A text mining and ontology-based approach using phenotypes to obtain relevant literature for rare diseases.
    Jesús Pérez-García, Federico García-Criado, Florencio Pazos, Mónica Chagoyen, Elena Rojano, Pedro Seoane, Juan A G Ranea.
      Diagnosing rare diseases remains a major challenge due to limited clinical knowledge and the frequent absence of diagnostic criteria. We present a digital framework that leverages large language models and biomedical text embeddings to bridge this gap. By mapping Human Phenotype Ontology terms to a shared vector space with millions of PubMed abstracts and full-text articles, our method enables phenotype-driven semantic search and ranks literature relevant to patient symptoms, even without explicit disease mentions. Validated on OMIM-derived benchmarks and applied to RASopathies, including NF1, Noonan, and Costello syndromes, our approach retrieved expected findings, supporting differential diagnosis and research. The framework is implemented in an open-source Python package, py-semtools, and it can be integrated into clinical decision support systems or adapted to other ontologies and corpora. This work demonstrates how AI-driven informatics can enhance rare disease diagnosis and exemplifies the role of digital tools in transforming precision medicine and healthcare delivery.
    Keywords:  human phenotype ontology; language models; phenotypic profiling; rare diseases; semantic similarity; text mining
    DOI:  https://doi.org/10.1016/j.isci.2026.117183
  37. Free Radic Biol Med. 2026 Aug 26. pii: S0891-5849(26)01031-2. [Epub ahead of print]
    Can nucleotide stress prevent molecular resolution of sterile inflammation?: A redox-metabolic hypothesis linking NAD+ depletion, oxidized mitochondrial DNA and PARP1 turnover.
    Xie Han, Ling Wu, WeiTing Zu, Mei Zhao.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.029
  38. Autophagy. 2026 Aug 28.
    A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation.
    Ian Collinson, Robin A Corey, Adam G Grieve.
      The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) - followed by PARL-mediated cleavage and degradation. This happens in healthy mitochondria with a high membrane potential (ΔΨ) across the inner-membrane - required for passage of proteins into or across the inner-membrane. The second being surface stabilization, Parkin activation and initiation of mitophagy upon membrane depolarization. But what if PINK1 acts in active mitochondria as well? Our recent work identifies a third fate - matrix entry! The findings expand the biology of PINK1 beyond mitochondrial surveillance for quality control alone. They suggest an additional mitophagy-independent regulatory role within the matrix, which turns out to be governed by the unusual properties of its TMD for the conferral of a decisive conformational switch.
    Keywords:  Mitochondria; PARL; PINK1; Parkinson’s disease; transmembrane
    DOI:  https://doi.org/10.1080/15548627.2026.2726091
  39. Intractable Rare Dis Res. 2026 Aug 31. 15(3): 268-272
    Traditional Chinese medicine research on rare diseases: Publication trends and future perspectives.
    Li-Ming Chen, Xin-Yi Chen, Bo-Wen Liu, Ying Mu, Qi Kang, Huan-Gan Wu.
      Traditional Chinese medicine (TCM) has increasingly attracted the attention of researchers as a potential complementary or supportive approach for selected rare diseases, but the characteristics and evidentiary strength of this literature remain unclear. This Correspondence summarizes publication patterns identified for the 121 conditions in the First Chinese Rare Disease List using Chinese and English sources searched from database inception through June 30, 2021. Fifty-five rare diseases were identified in 3,030 TCM-related publications, though the ten most frequently studied conditions accounted for more than 80% of the literature. Generalized myasthenia gravis, idiopathic pulmonary fibrosis, and multiple sclerosis together accounted for nearly half of all publications. Clinical studies and case reports or experience summaries predominated, whereas experimental studies represented only 9.03%. Oral herbal formulas were the most frequently reported intervention, and more than 95% of publications originated from mainland China. These patterns indicate growing interest but a fragmented, geographically concentrated, and methodologically limited evidence base; publication volume should not be interpreted as evidence of efficacy or safety. Future research should prioritize mechanistic studies, standardized and innovative clinical designs, rigorous safety and quality-control procedures, real-world evidence, patient-centered outcomes, and international collaboration to clarify the potential roles and limitations of TCM in rare disease management.
    Keywords:  clinical evidence; publication trends; rare diseases; research methodology; traditional Chinese medicine
    DOI:  https://doi.org/10.5582/irdr.2026.01041
  40. Curr Protoc. 2026 Sep;6(9): e70451
    Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.
    Xavier R Chapa-Dubocq, Sukanya G Gakare, Walia Zahra, Meagan Donovan, Keishla M Rodriguez-Graciani, Tanner Hoole, Scott Edwards, Patricia E Molina, Michael C Salling, Janos Paloczi, Liz Simon.
      Mitochondria are essential for maintaining the high energetic demands of the heart and brain, generating ATP required for contractile function, neuronal signaling, and ionic homeostasis. In both tissues, metabolic flexibility is critical for maintaining bioenergetic efficiency, redox balance, and cellular viability. Despite their importance, existing experimental approaches to assess mitochondrial bioenergetic function present notable limitations. Isolated mitochondria and permeabilized cell assays provide precise control over substrates and respiratory states but disrupt organelle integrity and remove native cellular and extracellular context. Conversely, measurements in isolated or cultured cells preserve intact mitochondria but introduce phenotypic and metabolic artifacts. These constraints highlight the need for an intermediate platform that preserves native tissue architecture and cellular diversity while enabling quantitative assessment of mitochondrial bioenergetics. Building on prior demonstrations of respiration measurements in intact cardiac and neural tissue, we describe a tissue punch-based approach that enables region-specific analysis of mitochondrial function in small ex vivo tissue slices of intact heart and brain. This method preserves cytoarchitecture, and intercellular interactions while remaining compatible with high-resolution Seahorse respirometry analysis. Tissue punches allow multiple technical replicates from individual organs, reduce variability associated with isolation procedures, and enable assessment of regional metabolic heterogeneity, such as atrial versus ventricular myocardium or discrete brain regions. Here we present detailed and reproducible workflow protocols for brain and cardiac tissue punch preparation and extracellular flux analysis, including guidance on sample acquisition, punch sizing, normalization strategies, and data interpretation, with considerations for adapting the protocols across multiple pre-clinical models. © 2026 Wiley Periodicals LLC. Support Protocol: Preparation, Reagent Setup, and Instrumentation Basic Protocol 1: Cardiac tissue preparation Basic Protocol 2: Brain tissue preparation: rodents Basic Protocol 3: Brain tissue preparation: nonhuman primates Basic Protocol 4: Placement of tissue punches on Seahorse organoid plate Basic Protocol 5: Mitochondrial respiration measurements Basic Protocol 6: Tissue disruption for total protein quantification.
    Keywords:  Seahorse XF analysis; animal models; bioenergetics; brain slices; heart slices; mitochondrial metabolism; tissue‐based respirometry
    DOI:  https://doi.org/10.1002/cpz1.70451
  41. EBioMedicine. 2026 Aug 26. pii: S2352-3964(26)00336-1. [Epub ahead of print]131 106452
    Equity in genome sequencing for rare disease diagnosis: a cross-sectional analysis of data from the UK 100,000 Genomes Project.
    Sam Tallman, Loukas Moutsianas, Thuy Nguyen, Yoonsu Cho, Maxine Mackintosh, Dalia Kasperaviciute, Matthew A Brown, Jamie M Ellingford, Karoline Kuchenbaecker, Matt J Silver.
       BACKGROUND: Genome sequencing has improved rare disease diagnosis and is now part of routine clinical care in the National Health Service in England. Automated prioritisation pipelines narrow millions of variants per patient to a small subset for clinical review, a process that relies on allele frequency resources that do not fully represent human genetic diversity. We assessed ancestry-related differences in variant prioritisation and diagnostic outcomes in patients from the UK 100,000 Genomes Project.
    METHODS: We analysed 29,405 rare disease probands with genome sequencing and linked clinical outcomes data. We used multivariable regression to assess ancestry-related differences in the number of variants prioritised for clinical review, the proportion of prioritised variants that were recorded as diagnostic, and diagnostic yield. We also evaluated the use of ancestry-stratified allele frequency filters derived from an independent, diverse UK cohort (n = 33,724).
    FINDINGS: Compared with the European ancestry group, the East African group had nearly three times more variants prioritised for clinical review (IRR 2.77, 95% CI 2.33-3.29). Other non-European groups also had significantly higher counts. Diagnostic yield was similar across ancestry groups after adjustment (LRT p = 0.1650). Prioritised variants were less likely to be recorded as diagnostic in East African (OR 0.32, 95% CI 0.22-0.46), West African (0.47, 0.39-0.57), South Asian (0.65, 0.58-0.73), and Middle Eastern (0.68, 0.54-0.86) groups. Applying ancestry-stratified allele-frequency filters removed 3.1% of prioritised variants overall-24.3% in the East African group-without loss of diagnostic sensitivity, including 29.5% of recorded VUS in this group.
    INTERPRETATION: Differences in the likelihood of prioritised variants being recorded as diagnostic partly reflect limitations of current allele frequency resources, which use broad population groupings that mask within-group diversity. Increased representation of diverse ancestries in reference databases and better estimation of ancestry-appropriate allele frequencies will help reduce inefficiencies and improve equity in variant prioritisation for rare disease diagnosis.
    FUNDING: The UK Department of Health and Social Care and the EU's Horizon 2020 Research and Innovation Programme.
    Keywords:  Equity; Genetic ancestry; Genetic diagnosis; Genomics; Rare disease; Variant prioritisation
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106452
  42. Health Expect. 2026 Aug;29(4): e70832
    Trust As the Foundation for Informed Decision-Making in Prenatal Genetic Screening and Diagnostic Testing: A Qualitative Study.
    Miller Finkelstein, Christina Collart, Lenicia Jenkins, Richard Frankel, Norah Crossnohare, John Bridges, Monique Katsuki, Susannah Rose, Marsha Michie, Megan Allyse, Michael Rothberg, Marissa Coleridge, Brownsyne Tucker-Edmonds, Ruth M Farrell.
       BACKGROUND: Prenatal genetic screening and diagnostic testing (PS&D) requires pregnant patients to make time-sensitive, high-stakes decisions that often involve multifaceted risk assessments and deeply personal values. These decisions are becoming increasingly complex as the clinical integration of new genomic science and technologies advances alongside parallel changes in maternal-foetal medicine, neonatology, and reproductive health services. Despite these changes, there is limited guidance on how best to prepare patients to formulate PS&D decisions with significant implications for obstetric outcomes. The goal of this study was to characterise pregnant patients' perceptions of the decision-making process and identify facilitators and barriers for them to make informed decisions about their PS&D options.
    METHODS: We conducted a qualitative study of pregnant and postpartum individuals receiving obstetric care within a large healthcare system. Participants, enroled across early pregnancy, late pregnancy, and postpartum periods, completed in-depth semi-structured interviews exploring their experiences, preferences, and needs related to PS&D decision-making. Interviews were recorded, transcribed verbatim, and analysed by a multidisciplinary team using inductive thematic analysis, supported by iterative coding, memoing, and theme identification.
    RESULTS: Most participants were < 35 years of age (48 of 61) and had a prior pregnancy (42 of 61). Four major subthemes emerged around a central concept of trust affecting medical decision-making: (1) Trust as a means of navigating the complexity of PS&D: Patients relied heavily on their obstetric (OB) providers to interpret complex information and guide decisions, particularly as testing decisions became more consequential and time sensitive. (2) Trust as a prerequisite for informed decision-making: Patients emphasised that psychological safety and relational continuity were necessary before they could ask questions, disclose concerns, or integrate medical information with personal values. (3) Erosion of trust due to perceived bias, judgement, or assumptions: Provider bias, whether expressed through communication style, assumptions about patient preferences, or perceived judgement, undermined trust and impeded informed, values-aligned decisions. (4) Structural barriers in prenatal care models: Limited continuity, time constraints, and triaged group-based care created obstacles to building trust and compounded difficulties in discussing sensitive topics across multiple providers.
    CONCLUSIONS: Our findings suggest that trust is a core component of informed PGT decision-making and central to supporting patient-centred communication amid uncertainty, cascading decisions, and evolving genomic technologies. Strategies to build and maintain trust, particularly within multi-provider prenatal care models, are essential to enabling informed, values-concordant prenatal decision-making. System-level interventions that promote continuity, unbiased communication, and structured agenda-setting help strengthen prenatal care delivery and improve patient experience and outcomes.
    PATIENT OR PUBLIC CONTRIBUTION: Patients were involved in three main aspects of the study: (1) identifying the need for research that supports PS&D decision-making through our prior work with patients as part study participation in focus groups, interviews, and survey studies, (2) contributing to the development of the interview guide through direct feedback to the instrument's questions and methods of data collection, and (3) participating in the study interview and providing their perspectives on how to support them and other pregnant patients as they face a myriad of pre and posttest decisions.
    DOI:  https://doi.org/10.1111/hex.70832
  43. Biochem Soc Trans. 2026 Sep 23. 54(9): 1155-1167
    The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.
    Lilia Colina-Tenorio, Martina Bohuslavová, Alexander W Bruce, Hassan Hashimi.
      Cristae are mitochondrial subcompartments that give the organelle its distinctive appearance. More significantly, mitochondria are the proverbial powerhouses as cristae house the molecular machinery underlying cellular respiration, a process that converts carbon sources into ATP by chemiosmosis. The form of cristae is invariably connected to their bioenergetic function. Here, we review our current understanding of the molecules underpinning crista formation. Not surprisingly, respiratory chain multiprotein complexes are involved in crista formation, with F1FO-ATP synthase dimers being eminent membrane sculptors. But crista formation also requires factors that are not directly part of the respiratory chain. The most ancient is the MICOS complex, which delineates the subcompartment and acts as a hub for crista biogenesis. The mitochondrial inner membrane (IM), from which cristae emerge, is remodelled by different dynamin-related proteins in animals and fungi. Cardiolipin is an integral component of the membranous fabric of the IM. To begin to grasp general design principles underlying crista formation, we synthesize findings from canonical animal and yeast experimental models with those from diverse protists and other eukaryotes. However, how these molecules are orchestrated during crista formation remains a hidden piece in our understanding of how cells differentiate in specialized forms. We highlight the few knowns about crista formation in a handful of organisms to guide research into the many unknowns about how complex subcompartments represented by mitochondrial cristae are formed.
    Keywords:  ATP synthase; MICOS; cristae; dynamin-related protein; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1042/BST20260167
  44. Biomedicines. 2026 Aug 07. pii: 1781. [Epub ahead of print]14(8):
    Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?
    Maciej Karbownik, Marcin Fidura, Renata Perlikowska.
      Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; drug development; prion diseases; protein targeting; secretory pathway dysfunction; therapeutic targets
    DOI:  https://doi.org/10.3390/biomedicines14081781
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