bims-polgdi Biomed News
on POLG disease
Issue of 2026–02–08
fifty-five papers selected by
Luca Bolliger, lxBio
  1. Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.
  2. Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
  3. Suppression of interferon signaling via small-molecule modulation of TFAM.
  4. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  5. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  6. Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito-Nuclear Epistasis in Drosophila.
  7. Leveraging mitochondrial stress to improve healthy aging.
  8. Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
  9. KLINSE: a comprehensive service model for rare disease information and care management support.
  10. Expanding the cognitive spectrum of mitochondrial diseases.
  11. Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
  12. Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
  13. Spatial Mapping of CoQ10 Repletion by BPM31510 in a Genetic Mouse Model (Coq4F147C) of Coenzyme Q Deficiency.
  14. Intergenerational and organ-specific alterations in mitochondrial DNA copy number following preconception irradiation.
  15. Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
  16. Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
  17. Tell you what I'm gonna do for you: Navigating personal literacies and motivation in rare disease research.
  18. The potential of whole genome sequencing in pharmacogenetics: a retrospective health record study in rare disease patients.
  19. Environmental enrichment as a mitochondria-targeting systems strategy across neurodegenerative diseases and retinal dystrophies.
  20. The Ketogenic Diet in the Neonatal Intensive Care Setting: The Case of a Preterm Newborn With Mitochondrial DNA Depletion Syndrome Type 13 (MTDPS13).
  21. Fahr Syndrome, Hypoparathyroidism and Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome.
  22. Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
  23. Diagnostic challenges in mitochondrial encephalomyopathy with m.10158T>C mutation: a case report and literature review.
  24. Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis: potential mechanisms and therapeutic implications.
  25. FPGDKG 1.0: An Integrated Facial Phenotype-Gene-Disease Knowledge Graph for Rare Disease Diagnosis and Explanation.
  26. Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.
  27. Embedding ethics into Genomics England's Generation Study.
  28. Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.
  29. Advancing Neuropediatric Rare Disease Diagnosis Through Clinical Genome Sequencing.
  30. Proteostasis of organelles in aging and disease.
  31. Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.
  32. Stimulatory Effects of (+)-Epicatechin on Mitochondrial Biogenesis and Function in Skeletal Muscle of Aged Rats: Underlying Mechanisms.
  33. Maximizing Access to Cell and Gene Therapy for Patients with Rare Diseases.
  34. Mitochondria and Moon: Footprints Shaping Life's Evolution and Cosmic Exploration.
  35. Mitochondrial Transplantation Therapy for Ischemic Stroke: Progress and Challenges.
  36. Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
  37. Deciphering the modulatory role of short-chain fatty acids in Parkinson's disease via phosphorylation-dependent signaling mechanisms.
  38. Mitochondrial specialization and signaling shape neuronal function.
  39. Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
  40. Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer.
  41. A Framework for Bioinformatic Reporting in Prenatal Sequencing: Insights From a Systematic Review.
  42. Editorial: Molecular mechanisms and precision medicine in rare diseases.
  43. Novel pharmacological therapies in development.
  44. The Metal-Organic Framework NH2-MIL-101(Fe) Modulates Arsenate Bioaccumulation, Biotransformation, Trophic Transfer, and Mitochondrial Genotoxicity in Daphnia magna-Zebrafish Food Chain.
  45. Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury.
  46. Elucidating the genetic landscape of inherited retinal disorders in India.
  47. Non-invasive administration of exosomes.
  48. Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets.
  49. Mendelian Randomization Analysis Uncovers the Causal Link Between Gut Microbiota and Cerebrovascular Diseases.
  50. Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
  51. A dynamic displacement mechanism drives protein import into mitochondria.
  52. Stem Cell Therapy for Inflammatory Diseases: Progress, Challenges, and Future Directions.
  53. Letter to the editor: Mitochondrial DNA patterns among individuals living with HIV-1 on dolutegravir with hyperglycemia.
  54. Kikuchi-Fujimoto Disease and Hemophagocytic Lymphohistiocytosis: A Rare Combination of Two Rare Diseases.
  55. Artificial intelligence and machine learning in neurodegenerative disease management: A 21st century paradigm.
  1. Mol Genet Metab. 2026 Jan 27. pii: S1096-7192(26)00036-3. [Epub ahead of print]147(3): 109753
    Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.
    Alessandra Maresca, Monica Moresco, Giulia Amore, Chiara La Morgia, Maria Lucia Valentino, Giada Capirossi, Giulia Sacchetti, Valerio Carelli, Christian Vedeler, Laurence A Bindoff, Kristin N Varhaug.
      Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT-TL1 gene leads to clinical manifestations ranging from the classical MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome to milder phenotypes such as MIDD (maternally inherited diabetes and deafness) or a spectrum of clinical features of intermediate severity defined as MELAS-Spectrum. The heterogeneous disease course makes the identification of biomarkers for monitoring disease progression challenging, particularly if we consider the occurrence of stroke-like episodes (SLEs), which remain unpredictable events. Here, we assessed two biomarkers, neurofilament light chain (NF-L) and circulating cell free-mtDNA (ccf-mtDNA), in a cross-sectional study in MELAS patients, including both patients in the interictal period and during SLEs, and MELAS-Spectrum patients. Both biomarkers were significantly elevated in MELAS patients during SLEs, compared to the other patients. In addition, we found significant correlation between NF-L and m.3243 A > G blood heteroplasmy in MELAS patients, as well as between NF-L and clinical severity in the whole patients cohort. Despite the limitations derived from the small sample size and the cross-sectional sample collection, our study confirms the value of NF-L and ccf-mtDNA as biomarkers efficiently hallmarking SLEs, highlighting their potential use to monitor the progression of MELAS.
    Keywords:  Blood biomarkers; Cell free mitochondrial DNA; Inflammation; Mitochondrial diseases; Neurodegeneration; Neurofilaments light chain
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109753
  2. Brain. 2026 Feb 02. pii: awag037. [Epub ahead of print]
    Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
    Marton Szabo, Daniel Lagos, Emily Cross, Jack Collier, Rita Horvath.
      Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.
    Keywords:  mitochondria derived vesicles (MDVs); mtDNA; mtDNA release, primary mitochondrial diseases (PMD); pathogen-associated molecular patterns (PAMPs); sterile-inflammation
    DOI:  https://doi.org/10.1093/brain/awag037
  3. Elife. 2026 Feb 06. pii: RP108742. [Epub ahead of print]14
    Suppression of interferon signaling via small-molecule modulation of TFAM.
    Dionisia Sideris, Husan Lee, Lyndsay Olson, Kalyan Nallaparaju, Keiichiro Okuyama, Jeffrey Ciavarri, Robert Lafyatis, Mads Larsen, Bo Lin, Irene Alfaras, Jason Kennerdell, Toren Finkel, Yuan Liu, Bill Chen, Lin Lyu.
      The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.
    Keywords:  TFAM; cGAS-STING pathway; cell biology; human; interferon sinaling; mitochondria; mitochondrial DNA; small molecule
    DOI:  https://doi.org/10.7554/eLife.108742
  4. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  5. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699287. [Epub ahead of print]
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfam fl/fl Ub Cre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2026.01.13.699287
  6. Aging Cell. 2026 Feb;25(2): e70405
    Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito-Nuclear Epistasis in Drosophila.
    Rita Ibrahim, Christin Froschauer, Susanne Broschk, David R Sannino, Adam J Dobson.
      The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is a leading example, which can extend healthy lifespan in a range of animals, but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for any putative translation. Here, in Drosophila, we test for genetic variation in lifespan response to a dominant-negative form of the insulin receptor, along with a metric of fecundity to evaluate corollary fitness costs/benefits. We also partition genetic variation between DNA variants in the nucleus (nDNA) and mitochondrial DNA (mtDNA), in a fully-factorial design that allows us to assess 'mito-nuclear' epistasis. We show that reduced IIS can have either beneficial or detrimental effects on lifespan, depending on the combination of mtDNA and nDNA. This suggests that, while insulin signalling has a conserved effect on ageing among species, intraspecific effects can vary genetically, and the combination of mtDNA and nDNA can act as a gatekeeper.
    DOI:  https://doi.org/10.1111/acel.70405
  7. Sports Med Health Sci. 2026 Jan;8(1): 23-33
    Leveraging mitochondrial stress to improve healthy aging.
    Abril Gorgori-Gonzalez, Silvana Soto-Rodriguez, Eva Tamayo-Torres, Esther Garcia-Dominguez, Vicente Sebastia, Juan Gambini, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera.
      Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis. Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage. Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.
    Keywords:  Frailty; Mitochondrial dysfunction; Mitohormesis; Muscle homeostasis; Phytochemicals; Resistance training
    DOI:  https://doi.org/10.1016/j.smhs.2025.10.003
  8. Mol Genet Metab. 2025 Dec 11. pii: S1096-7192(25)00696-1. [Epub ahead of print]147(3): 109704
    Clinical and biochemical footprints of primary mitochondrial disorders: proposed nosology.
    Martina Messina, Rebecca Ganetzky, Carlos R Ferreira, Nenad Blau, Shamima Rahman.
      Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).
    Keywords:  Biomarkers; ICIMD; IEMbase; Inherited metabolic disorders; Signs and symptoms
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109704
  9. Orphanet J Rare Dis. 2026 Jan 31.
    KLINSE: a comprehensive service model for rare disease information and care management support.
    Katrin Jäger, Elke Dannenmann-Stern, Sevda Inbasi, Ute Grasshoff, Christina Vossler-Wolf, Holm Graessner.
      
    Keywords:  Care management support; Clinical Information Center for Rare Diseases; Diagnosis-informed therapy; Rare diseases
    DOI:  https://doi.org/10.1186/s13023-026-04217-5
  10. Neurol Sci. 2026 Feb 04. 47(3): 228
    Expanding the cognitive spectrum of mitochondrial diseases.
    Anna Rita Giovagnoli, Costanza Lamperti, Ioana Raluca Mihai, Alessia Catania.
      
    Keywords:  Attention; Memory; Mitochondrial disease; Social cognition; Theory of mind
    DOI:  https://doi.org/10.1007/s10072-026-08827-6
  11. bioRxiv. 2026 Jan 25. pii: 2026.01.25.701366. [Epub ahead of print]
    Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.
    Noe Baruch-Torres, Joon Park, Josue Mora-Garduño, Arkanil Roy, Anupam Singh, G Andrés Cisneros, Luis G Brieba, Smita S Patel, Y Whitney Yin.
      Accurate replication of mitochondrial genome (mtDNA) integrity, which is essential for cellular metabolism and energy supply, relies primarily on DNA polymerase gamma (Pol γ), Twinkle helicase, and mitochondrial single-stranded DNA binding protein (mtSSB). Twinkle alone exhibits little helicase activity while reports indicate that Pol γ displays from modest to limited unwinding activity. This led us to dissect Pol γ strand displacement activity using structural, biochemical and in silico approaches. Here, we show that human Pol γ carries out robust strand displacement synthesis at physiological concentrations of divalent metal ions which reveals that distinct metal-binding sites can independently regulate DNA synthesis and unwinding activities. We further showed that Pol γ can displace RNA/DNA hybrid with comparable efficiency as DNA/DNA duplex, representing a key implication on RNA primer removal to preserve mtDNA integrity. Our cryo-electron microscopy structures of Pol γ complexed with a template containing downstream dsDNA and an incoming nucleotide revealed the structural mechanism for the strand displacement activity. We identified four conformational states that represent successive stages of DNA unwinding, accompanied by coordinated rearrangement of the downstream DNA and Pol γ elements that mediate strand displacement. This work establishes biochemical and structural mechanisms of Pol γ strand displacement activity, providing fundamental insight into human mitochondrial DNA replication and integrity.
    Graphical abstract:
    DOI:  https://doi.org/10.64898/2026.01.25.701366
  12. Ageing Res Rev. 2026 Feb 03. pii: S1568-1637(26)00043-7. [Epub ahead of print] 103051
    Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
    Jingge Xu, Xingyi Li, Zhiyu Zhang, Jiahui Wu, Haiyang Yu, Yuzheng Wu, Dan Wang, Ruixia Bao, Tao Wang, Yi Zhang, Qian Chen.
      As a metabolically active organ, kidney has to challenge progressive functional decline with ageing. Meantime, in the pathogenesis of kidney diseases, renal dysfunction also accelerates an individual's ageing trajectory, leading to premature senescence and a disconnect between biological age and chronological age. Mitochondrial dysfunction is a well-recognized characteristic of kidney ageing, whereas preserving mitochondrial homeostasis can effectively delay the ageing process. This review summarizes classical alterations in mitochondrial function across renal health and disease, including impaired biogenesis with peroxisome proliferator's-activated receptor γ coactivator α (PGC-1α) suppression, fission-fusion imbalance with overactivation of dynamin-related protein 1 (DRP1), mitophagy defects linked to abnormalities in the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, oxidative stress cascades featuring mitochondrial reactive oxygen species (mtROS)-mediated damage, and dysregulation of mitochondrial protein quality control. Moreover, we critically evaluate mitochondrial transfer as novel, non-canonical pathways beyond classical bioenergetics, generally through tunneling nanotubes (TNTs)/ extracellular vesicle-containing mitochondria (EVMs)/ free mitochondrial, and inter-organelle communication. We also discuss alternative mitochondria-targeted therapeutics and dissect their clinical translation hurdles. Appropriate interventions on mitochondrial transfer represents a promising strategy for preventing kidney ageing to maintain long-term renal health and extend lifespan. However, the majority of the studies we reviewed are based on animal and cellular models of other diseases, the relationship between renal ageing and mitochondrial transfer has not been adequately explored in clinical trials, and there is still a long way to go.
    Keywords:  Ageing kidney; Mitochondrial donor cells; Mitochondrial homeostasis; Mitochondrial transfer; Pharmacological therapeutics
    DOI:  https://doi.org/10.1016/j.arr.2026.103051
  13. J Lipid Res. 2026 Jan 28. pii: S0022-2275(26)00013-1. [Epub ahead of print] 100987
    Spatial Mapping of CoQ10 Repletion by BPM31510 in a Genetic Mouse Model (Coq4F147C) of Coenzyme Q Deficiency.
    Eliana Barriocanal-Casado, Sylwia A Stopka, Alba Pesini, Juan J Aristizabal-Henao, Srada Karmacharya, Devon Van Cura, Ryan Zhang, Kelsey R Nickerson, Kashni Grover, Oksana Zavidij, Sarah R Wessel, Niven R Narain, Vijay Modur, Stephane Gesta, Michael A Kiebish, Catarina M Quinzii.
      Primary Coenzyme Q10 (CoQ10) deficiency is a rare mitochondrial disorder caused by mutations in genes involved in CoQ biosynthesis (e.g., COQ4) that result in impaired mitochondrial respiration, oxidative stress, and dysfunction across multiple organ systems due to decreased mitochondrial levels of CoQ10. Although oral CoQ10 supplementation has been examined for standard of care, poor absorption and inadequate tissue and intracellular distribution have resulted in a lack of clinically significant efficacy. BPM31510 is a lipid nanoparticle formulation of oxidized CoQ10 designed to improve bioavailability and targeted uptake into the mitochondria. In the current study, we assessed the efficacy of BPM31510 to increase CoQ levels in Coq4F147C mice, a novel genetic knock-in model of primary CoQ deficiency. CoQ9, the main form of CoQ in mice, and CoQ10 were significantly decreased in brain, kidney, heart, and muscle of Coq4F147C mice compared to Coq4+/+ mice. BPM31510 treatment significantly increased oxidized CoQ10 levels across all tissues, mediated by the nanoliposome biodistribution of oxidized CoQ10 in BPM31510. MALDI-MSI demonstrated regional and spatial restoration of CoQ10 within the brain, including the cerebellum, myocardium, and renal cortex of Coq4F147C mice. These results demonstrate that BPM31510 successfully concentrates pharmacologically active CoQ10 in target tissues that are not reachable with oral therapy, in a genetic model of primary CoQ deficiency. We enabled the visualization of sub-organ CoQ10 localization to specifically demonstrate CoQ10 restoration. This study establishes proof-of-concept for spatial quinomics, a new methodology that combines spatial metabolomics with quinomics to evaluate next-generation CoQ10-based therapeutics for mitochondrial disorders.
    Keywords:  CoQ10 deficiency; MALDI; MSI; mass spectrometry; mitochondrial disease; quinomics
    DOI:  https://doi.org/10.1016/j.jlr.2026.100987
  14. Redox Biol. 2026 Jan 30. pii: S2213-2317(26)00052-2. [Epub ahead of print]90 104054
    Intergenerational and organ-specific alterations in mitochondrial DNA copy number following preconception irradiation.
    Ryosuke Seino, Hisanori Fukunaga.
      Ionizing radiation, a potent inducer of redox stress, perturbs both nuclear and mitochondrial genomes, yet how such stress shapes mitochondrial inheritance across generations remains unclear. In this study, we examined intergenerational and organ-specific mitochondrial responses to parental X-ray irradiation in mice. Eight-week-old male and female C57BL/6N mice were exposed to 2 Gy of single whole-body X-ray irradiation before mating, generating paternal-, maternal-, and dual-irradiated lineages. In the parents, peripheral blood-derived mitochondrial DNA copy number (mtDNAcn) transiently increased one day after exposure, consistent with a rapid mitochondrial response to redox stress. In newborn offspring, mtDNAcn displayed clear organ- and parent-of-origin specificity: brain mtDNAcn decreased in paternal- and dual-irradiation lineages, heart mtDNAcn remained unchanged, and liver mtDNAcn showed the most pronounced depletion across all irradiated lineages. No significant inter-organ correlations in mtDNAcn were observed. All irradiated lineages exhibited increased body weight and increased liver weight at birth, with a significant positive association between these traits. Liver weight was negatively associated with hepatic mtDNAcn. Multiple regression analysis further showed that maternal pre-exposure mtDNAcn and offspring hepatic mtDNAcn independently predicted neonatal liver weight. Taken together, these findings demonstrate that preconception irradiation induces acute mitochondrial responses in parents and is associated with intergenerational, organ-specific mtDNAcn dysregulation that manifests as offspring birth outcomes. Parental irradiation perturbs organ-specific mitochondrial genome regulation and predisposes the next generation to altered growth-related traits.
    Keywords:  Growth-related traits; Intergenerational effect; Mitochondrial DNA copy number; Preconception exposure; Radiation
    DOI:  https://doi.org/10.1016/j.redox.2026.104054
  15. FASEB Bioadv. 2026 Feb;8(2): e70088
    Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
    Takanaga Shirai, Hideto Hanakita, Kohei Takeda, Yu Kitaoka, Kaori Ishikawa, Kazuto Nakada, Tohru Takemasa.
      Mitochondrial function is essential for skeletal muscle health, and its disruption leads to atrophy and functional decline. This study examines the impact of denervation on skeletal muscle mitochondria in polymerase gamma (PolG)(+/mut) mice, which accumulate mitochondrial DNA (mtDNA) mutations due to a partial deficiency in polymerase gamma proofreading. Using a 14-day denervation protocol, we assessed muscle mass, mtDNA copy number, oxidative stress and mitochondrial dynamics in wild-type (WT) and PolG(+/mut) mice. Our findings reveal that while denervation significantly reduced muscle wet weight and mitochondrial enzyme activity, no genotype-specific differences in muscle atrophy were observed. However, PolG(+/mut) mice displayed more disorganized mitochondrial cristae and elevated oxidative stress markers, indicating greater mitochondrial vulnerability. Despite these changes, the lack of significant differences in mitochondrial proteins and gene expression between genotypes may reflect an adaptive antioxidant response, including increased catalase expression, although the compensatory nature of this response cannot be conclusively determined. These results suggest that oxidative stress-related responses are involved in mitochondrial adaptations during denervation-induced muscle atrophy. The increased expression of antioxidant enzymes, such as catalase, in PolG(+/mut) mice suggests that antioxidant mechanisms are activated in response to increased oxidative stress. These findings underscore the importance of controlling oxidative stress for maintaining muscle health.
    Keywords:  atrophy; mitochondria; mtDNA; oxidative stress; polymerase gamma; skeletal muscle
    DOI:  https://doi.org/10.1096/fba.2025-00072
  16. bioRxiv. 2026 Jan 23. pii: 2026.01.22.701145. [Epub ahead of print]
    Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
    Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.
      As highly dynamic organelles, mitochondria play an essential role in neuronal survival and synaptic function. Excitotoxicity is as a critical factor that promotes mitochondrial dysfunction after traumatic brain injury (TBI). Intercellular mitochondrial transfer and exogenous mitochondrial transplantation are emerging concepts to understand mitochondrial trafficking in response to mitochondrial dysfunction; however, robust in vivo evidence remains limited on the extent of these processes in the central nervous system (CNS). There is a significant knowledge gap in our understanding of mitochondrial transfer mechanisms under both normal physiological conditions and after experimental TBI. Mouse lines expressing mitochondrial green-fluorescent dendra-2 (mtD2) and GFP (mtGFP) targeted to inner and outer mitochondrial membranes, respectively, were used to study astrocyte-specific (Aldh1l1-CreER; mtD2 f/f - AmtD2 and Aldh1l1-CreER; mtGFP f/f - AmtGFP) and neuron-specific (CamK2aCre; mtD2 f/f - NmtD2 and CamK2aCre; mtGFP f/f - NmtGFP) mitochondrial dynamics and bioenergetics in acute TBI and excitotoxicity. At 24 hrs following TBI, neurons in the NmtD2 mouse brain exhibited rapid and significant alterations in mitochondrial morphology, including changes in total mitochondrial volume, volume distribution, and sphericity. Synaptic neuronal (SN) mitochondria display robust deficits in mitochondrial bioenergetics and complex protein levels while non-synaptic neuronal (NSN) mitochondria show State III bioenergetics and complex proteins at control levels. These findings are accompanied by a marked increase in astrocyte-derived mitochondria (AmtGFP) transfer to neurons at 24 hrs post-injury, compared to control animals, but no increase in transfer to neuronal synapses. While TBI also altered astrocytic mitochondrial morphology in the cortex, astrocytic mitochondrial bioenergetics remained preserved. Single-cell RNA-seq analysis of astrocytes revealed significant transcriptional reprogramming following TBI, characterized by the upregulation of genes associated with mitochondrial homeostasis and the machinery for organelle trafficking. In vitro co-cultures of primary cortical astrocytes and neurons demonstrated that astrocytes can transfer mitochondria to neurons via direct contact and that NMDA-mediated excitotoxicity further enhanced this astrocyte-to-neuron mitochondrial transfer. Furthermore, astrocytic-derived extracellular vesicles containing mitochondria (EV-mito) deliver mitochondria to neurons and EV-mediated mitochondrial transfer significantly ameliorated NMDA-induced mitochondrial dysfunction in primary cortical neurons. Together, these findings show that astrocytes take on a TBI-related phenotype that facilitates dynamic changes in mitochondrial networks and mitochondrial trafficking to neurons. Astrocytic transfer of respiratory-competent mitochondria support is an intrinsic neuroprotective response to injury that supports mitochondrial function in neuronal soma, dendrites, and axons but not at the neuronal synapse. Finally, we show therapeutic potential of exogenous mitochondrial transfer, particularly via EV-mito, for treating neurological disorders associated with excitotoxicity, such as TBI.
    DOI:  https://doi.org/10.64898/2026.01.22.701145
  17. Patient Educ Couns. 2026 Feb 02. pii: S0738-3991(26)00033-9. [Epub ahead of print]146 109500
    Tell you what I'm gonna do for you: Navigating personal literacies and motivation in rare disease research.
    Kara A Ayik.
      
    DOI:  https://doi.org/10.1016/j.pec.2026.109500
  18. Eur J Hum Genet. 2026 Feb 04.
    The potential of whole genome sequencing in pharmacogenetics: a retrospective health record study in rare disease patients.
    Madeline Gorny, Katja S Just, Tim Krüger, Matthias Begemann, Florian Kraft, Thomas Eggermann, Jeremias Krause, Miriam Elbracht.
      The clinical relevance of pharmacogenetics (PGx) is becoming increasingly evident as knowledge in this field expands. As of May 2025, 209 clinical guideline annotations are already listed on the internationally recognized ClinPGx website. Nevertheless, except for a few indications, the implementation of PGx in clinical practice currently remains limited in most countries. At the same time, whole genome sequencing (WGS) is increasingly applied in clinical diagnostics, particularly for rare and oncological diseases. These data could also be used for simultaneous PGx analysis. In a retrospective study, we analysed short-read WGS data from 1,000 individuals, including index patients with suspected rare disorders and their relatives. For a subset of 359 individuals, medical reports were reviewed to document drug prescriptions. Guidelines published by PGx consortia on ClinPGx were used for phenotype assignment and interpretation. Clinically relevant PGx variants were detected in 97% (n = 970) of the cohort. Among patients with drug prescriptions (n = 359), 30% (n = 111) had been prescribed at least one medication for which their PGx profile would recommend therapy adjustment. Additionally, CNVs and rare variants were detected, which in 28% (n = 8) resulted in modified therapeutic recommendations. While the most (cost)-efficient strategy for broad PGx implementation remains subject of future research, our findings demonstrate that existing WGS data, such as those generated in the context of rare disease patients, could provide substantial benefits for PGx diagnostics with minimal additional effort.
    DOI:  https://doi.org/10.1038/s41431-026-02025-w
  19. Front Neurosci. 2026 ;20 1744873
    Environmental enrichment as a mitochondria-targeting systems strategy across neurodegenerative diseases and retinal dystrophies.
    Dario Rusciano, Caterina Gagliano, Alessandro Avitabile, José Fernando Maya-Vetencourt.
      Mitochondrial dysfunction is a central contributor to neurodegenerative disorders affecting both the central nervous system and the retina, where impaired energy metabolism, oxidative stress, and defective cellular resilience converge to drive progressive neuronal loss. Environmental enrichment (EE), a multimodal non-pharmacological paradigm, has emerged as a powerful modulator of brain and retinal plasticity in preclinical models, promoting adaptive responses that support mitochondrial function and neurotrophic signaling. This review synthesizes evidence indicating that EE influences mitochondrial quality control, redox homeostasis, synaptic resilience, and neuroimmune balance across a range of experimental models of neurodegeneration and retinal dystrophy. While these effects converge on shared downstream pathways, important disease-, cell-type-, and context-specific differences exist, and mechanistic generalization across systems requires caution. Human studies remain limited, heterogeneous, and often focused on functional outcomes rather than direct biological endpoints, resulting in modest and variable effect sizes. Rather than proposing EE as a stand-alone therapy, we frame it as a system-level, disease-modifying context that may enhance endogenous protective capacity and potentially complement pharmacological, genetic, or rehabilitative interventions, pending disease-specific validation. Forward-looking perspectives, including digitally mediated and AI-supported EE-inspired approaches, are discussed as conceptual strategies whose biological relevance will depend on future studies integrating functional outcomes with validated molecular and metabolic biomarkers. Together, the available evidence positions EE as a biologically grounded, non-invasive framework for promoting neuro- and retino-protective resilience, while underscoring the need for rigorously designed translational and clinical studies to define its therapeutic boundaries and mechanisms of action.
    Keywords:  environmental enrichment; mitochondria; neurodegeneration; neuronal plasticity; oxidative stress; retinal dystrophy; visual system
    DOI:  https://doi.org/10.3389/fnins.2026.1744873
  20. Case Rep Genet. 2026 ;2026 6492770
    The Ketogenic Diet in the Neonatal Intensive Care Setting: The Case of a Preterm Newborn With Mitochondrial DNA Depletion Syndrome Type 13 (MTDPS13).
    Gabriele D'Amato, Mattia Gentile, Rossella Carella, Antonio Giannini, Maria Felicia Faienza, Albina Tummolo.
       Background: Mitochondrial DNA depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder presenting in early infancy with encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Patient-derived cells typically exhibit impaired mitochondrial oxidative phosphorylation and a marked reduction in mitochondrial DNA (mtDNA) copy number.
    Case Report: We report the case of a male preterm neonate born at 31 + 3 weeks of gestation following a pregnancy marked by severe polyhydramnios. At birth, his weight was 1400 g. Physical examination revealed dysmorphic features, redundant and lax skin, and generalized muscular hypotonia. Laboratory investigations showed marked lactic acidosis associated with lactic aciduria, ketonuria, and urinary biomarkers indicating activation of preoxidative phosphorylation biochemical pathways to sustain ATP production. Echocardiography demonstrated mild, early-onset hypertrophic cardiomyopathy. The Exome Analysis Clinical and Biochemical Markers: The exome analysis, performed within the first week of life, highlighted a pathogenic variant in homozygous state of FBXL4 gene (c.1648_1649delGA), which led to the diagnosis of MTDPS13. In this clinical contest, a ketogenic diet (KD) was started with a daily caloric intake of 120 kcal/kg and an initial ketogenic ratio of 1:1. These intakes were administered both with a parenteral nutrition and continuous nasogastric tube feeding and were gradually increased and adapted on a day-by-day basis according to lactic acidosis, growth increase, and common metabolic parameters such as glucose, electrolytes, creatinine, and blood urea nitrogen. After 3 days of this treatment approach, a significant reduction in lactate levels and improvement in acid-base balance and growth trend were observed along with clinical and cardiovascular parameters. At discharge from neonatal intensive care unit, the KD was continued at home and during follow-up. The infant showed stability in the clinical and biochemical markers.
    Conclusions: This is the first documented report of the use of a KD in a preterm neonate with this mitochondrial disorder during the early days of life. Prompt genetic confirmation and early initiation of KD may enable a more targeted and effective management of MTDPS within the neonatal intensive care setting.
    DOI:  https://doi.org/10.1155/crig/6492770
  21. AACE Endocrinol Diabetes. 2026 Jan-Feb;13(1):13(1): 102-106
    Fahr Syndrome, Hypoparathyroidism and Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome.
    Jing Li, Xiaodi Wang, Yanmei Guo, Wenwen Wang, Shujuan Wu, Jingmin Sun.
       Background/Objective: We describe a 5-year-old boy with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome presenting with epilepsy, refractory hyperlactatemia, and profound hypoparathyroidism accompanied by Fahr syndrome-like brain calcifications. This case expands the known phenotypic spectrum of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome by demonstrating concurrent parathyroid dysfunction and basal ganglia calcifications. The objective of this report is to characterize this unique neuroendocrine presentation and highlight diagnostic considerations for similar cases.
    Case Presentation: A previously healthy 5-year-old boy presented with 2 days of vomiting, diarrhea, and 1 generalized tonic-clonic seizure. Examination revealed lethargy, positive Chvostek sign, and positive Trousseau sign. Laboratory results showed plasma-free calcium 0.98 mmol/L (reference range, 1.15-1.33), lactate 6.0 mmol/L (reference, 0.7-2.1), and parathyroid hormone 6.62 pg/mL (reference, 12-65). Brain imaging demonstrated symmetrical basal ganglia calcifications. Treatment included levetiracetam, calcium and vitamin D supplementation. Genetic testing confirmed mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with m.3243A>G mutation. Follow-up showed persistent hyperlactatemia (peak 8.4 mmol/L) and worsening hypoparathyroidism (parathyroid hormone <3 pg/mL).
    Discussion: The severity and persistence of parathyroid hormone suppression in this case contrasts with typical mitochondrial disorder presentations. The concurrence of Fahr-type calcifications and profound hypoparathyroidism suggests potential mitochondrial dysfunction in calcium-regulating tissues.
    Conclusion: This case illustrates a severe neuroendocrine phenotype of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome. Unexplained hypoparathyroidism with basal ganglia calcifications should prompt consideration of mitochondrial disorders, even without classic stroke-like episodes.
    Keywords:  Fahr syndrome; MELAS syndrome; hypoparathyroidism; mitochondrial disorders; neuroendocrine disorders; pediatric endocrinology
    DOI:  https://doi.org/10.1016/j.aed.2025.09.007
  22. Cell Metab. 2026 Feb 03. pii: S1550-4131(26)00003-3. [Epub ahead of print]38(2): 257-259
    Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
    Filip J Larsen.
      Huang et al.1 show a J-shaped relationship between vigorous activity and cognitive decline, with maximal benefit ∼1,000-1,300 MET-min/week and harm with excessive exercise. Using UK Biobank data, mechanistic models, and an RCT, they implicate lactate-driven mitochondria-derived vesicles that reach the hippocampus, disrupt synapses, and impair cognition.
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.003
  23. Front Integr Neurosci. 2025 ;19 1709380
    Diagnostic challenges in mitochondrial encephalomyopathy with m.10158T>C mutation: a case report and literature review.
    Zhuqing Luan, Zhigang Liang.
      Mitochondrial encephalomyopathy is a complex disorder with heterogeneous clinical manifestations that often complicate its clinical diagnosis. We report the first documented case of a 52-year-old woman harboring a novel and rare genotypic combination: the m.10158T>C point mutation together with a 12.8-kb large-scale mtDNA deletion. After a protracted diagnostic course involving multiple prior misdiagnoses, the definitive diagnosis was ultimately established through integrated genetic, histopathological, and neuroimaging evaluation. This case underscores both the diagnostic challenges in mitochondrial disorders and the critical need for systematic differentiation from common neurological mimics such as encephalitis and stroke.
    Keywords:  case report; mitochondrial DNA; mitochondrial encephalomyopathy; point mutation; stroke; stroke-like episodes
    DOI:  https://doi.org/10.3389/fnint.2025.1709380
  24. Neurobiol Dis. 2025 Dec;pii: S0969-9961(25)00376-6. [Epub ahead of print]217 107159
    Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis: potential mechanisms and therapeutic implications.
    Tian Xie, Ho Tin Fok, Zehao Quan, Chun-Yuan Ku, Isaac Oluwatobi Akefe, Daniel Schweitzer.
       BACKGROUND: Multiple Sclerosis (MS) is a heterogeneous neuroinflammatory disease with complex aetiology and diverse clinical presentations, often accompanied by neurodegenerative pathology. While current therapies primarily focus on immunomodulation, emerging evidence underscores a critical bidirectional interplay between mitochondrial dysfunction and lipid dysregulation in driving MS progression. Understanding this metabolic-mitochondrial axis may reveal novel therapeutic opportunities beyond immune modulation.
    OBJECTIVE: This scoping review systematically maps recent literature (2015-2025) to delineate the mechanistic connections between mitochondrial dysfunction and lipid dysregulation in MS, identify current knowledge gaps, and highlight translational opportunities for targeted intervention.
    METHODS: A systematic search of PubMed, Embase, and Scopus was conducted in 2025 following PRISMA-ScR guidelines. Thirty-six eligible studies examining mitochondrial-lipid interactions in human MS and preclinical models were included and synthesised thematically.
    RESULTS: Evidence converges on a self-reinforcing pathological cycle in MS, where dysregulated lipid metabolism impairs mitochondrial integrity, amplifying reactive oxygen species generation, energy failure, and further lipid disruption. This cascade contributes to oligodendrocyte injury, demyelination, ferroptosis, and axonal degeneration. Importantly, therapeutic strategies that restore lipid-mitochondrial homeostasis, such as mitochondrial antioxidants, lipid modulators, and metabolically active immunotherapies, demonstrate promising neuroprotective effects in preclinical studies.
    CONCLUSION: The evidence supports a model in which the bidirectional feedback loop between mitochondrial dysfunction and lipid dysregulation represents a significant mechanism contributing to neurodegeneration in MS. Clinically, these insights highlight opportunities for earlier diagnosis and more personalised disease management through the integration of lipid-based biomarkers into patient monitoring and treatment selection. Targeting this metabolic axis holds significant promise for developing next-generation disease-modifying therapies to slow disease progression, enhance neuroprotection, and improve functional recovery across different MS subtypes.
    Keywords:  Demyelination; Lipid metabolism; Mitochondria; Multiple sclerosis; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.nbd.2025.107159
  25. IEEE J Biomed Health Inform. 2026 Feb 03. PP
    FPGDKG 1.0: An Integrated Facial Phenotype-Gene-Disease Knowledge Graph for Rare Disease Diagnosis and Explanation.
    Mengqiao He, Jie Song, Shumin Ren, Yuxin Zhang, Jiale Du, Jinhua Feng, Rongrong Wu, Bairong Shen.
      Rare diseases pose significant diagnostic challenges due to their low prevalence, limited clinical awareness, and pronounced phenotypic heterogeneity. Early and accurate diagnosis is essential but remains difficult, especially in resource-limited settings where comprehensive genetic testing is unavailable. Distinctive facial phenotypes can offer accessible diagnostic clues, yet overlapping features and broad phenotypic spectra often hinder precise identification. To address these challenges, we present the Facial Phenotype-Gene-Disease Knowledge Graph (FPGDKG), a unified resource integrating multi-source data on facial phenotypes, genes, and diseases. The knowledge graph comprises 23,096 nodes and 239,236 relationships. We demonstrate the utility of FPGDKG through three representative use cases: (1) phenotype-based automated diagnosis of rare diseases using machine learning models; (2) explainable diagnosis by jointly presenting phenotype, genotype, and literature evidence for each prediction. The accuracies of the presented evidence, as validated quantitatively, are 73.67$\%$ for phenotype, 59.57$\%$ for gene, and 90.59$\%$ for literature evidence; (3) embedding-based matching to support differential diagnosis for ultra-rare diseases. To facilitate clinical use and research, we also developed an interactive online platform that offers intuitive visualization, information retrieval, and explainable decision support (http://bioinf.org.cn:8060/). Through three representative use cases, we show that FPGDKG supports promising diagnostic performance and enhances explainability by providing multi-dimensional evidence, making it a valuable tool for transparent, data-driven rare disease diagnosis.
    DOI:  https://doi.org/10.1109/JBHI.2026.3659898
  26. Amino Acids. 2026 Feb 01. 58(1): 8
    Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.
    Abdilatif Aynaashe, Petri Kursula.
      Amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT) are two distinct neurodegenerative disorders. While ALS is characterised by rapidly progressive motor neuron degeneration, leading to severe complications and death, CMT as a peripheral neuropathy is less severe, and patients have a longer life span, although with a compromised quality of life. Despite their clinical differences, current knowledge suggests that familial ALS (fALS) and CMT may share common genetic and molecular mechanisms. We aimed to identify shared genes mutations and molecular pathways between fALS and CMT through a literature and database search. Thirteen genes were identified, involved in distinct cellular processes: axonal transport (DYNC1H1, KIF5A, SPG11, DCTN1), protein homeostasis (NEFH, VCP, SOD1), RNA metabolism (GARS, SETX), cellular stress response (HSPB1, FIG4), and mitochondrial function (MFN2, CHCHD10). While these linkages to the two diseases are rare for each gene, understanding possible mechanistic commonalities at the molecular level can initiate new research directions, help in identifying additional common genes between neurodegenerative disorders, and improve diagnostics.
    Keywords:  ALS; Axonal transport dysfunction; CMT; Mitochondrial dysfunction; Molecular mechanism; Neurodegeneration; Protein aggregation; RNA transport and metabolism; Stress response dysfunction
    DOI:  https://doi.org/10.1007/s00726-026-03500-w
  27. BMJ Open. 2026 Feb 02. 16(2): e112134
    Embedding ethics into Genomics England's Generation Study.
    Harriet Etheredge, Natalie Banner, Meekai To, Amanda Pichini, Joanna Ziff, Mathilde Leblond, Alice Tuff-Lacey, Richard Scott, Ellen Thomas.
      The Generation Study is a large-scale research initiative led by Genomics England in partnership with the National Health Service, aiming to evaluate the use of whole genome sequencing in newborn screening, as well as ongoing research use of these genomic data. The Generation Study will sequence 100 000 newborn genomes in England to potentially identify approximately 200 rare and treatable conditions. This paper outlines the study's approach to embedding ethics from inception through implementation. A model of 'ethical embeddedness' that emphasises transparency, trustworthiness and responsiveness to uncertainty is utilised. Drawing on the deliberations of a multidisciplinary Ethics Working Group, public dialogue findings and design research, the paper presents key decisions and our approach to complex ethical challenges including consent, potential impact of the study on clinical services and navigating uncertainty. The paper also reflects on the ethical tensions inherent in balancing research ambitions with operational realities, particularly in a context of evolving genomic science and sometimes limited regulatory clarity. By embedding ethics into the study's design and delivery, we hope to foster public trust and inform future policy and practice.
    Keywords:  Genomic Medicine; MEDICAL ETHICS; Mass Screening
    DOI:  https://doi.org/10.1136/bmjopen-2025-112134
  28. Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00007-3. [Epub ahead of print]88 102117
    Probability of Mitochondrial DNA heteroplasmy in different tissues from European populations.
    Daniel R Cuesta-Aguirre, Ana Onieva, M Pilar Aluja, Cristina Santos.
      Mitochondrial DNA (mtDNA) heteroplasmy complicates genetic analyses due to its variability across individuals and tissues. We analyzed over 400 Spanish blood samples and integrated published Massively Parallel Sequencing (MPS) data from ten additional European tissues. Heteroplasmy was tissue-specific, with skeletal muscle, kidney, and liver showing the highest levels, while the intestines, skin, and cerebellum had the lowest. Blood uniquely displayed more heteroplasmies in coding than non-coding regions. Several conserved positions not previously described as hotspots showed high frequencies. These results establish the first comprehensive tissue-specific heteroplasmic profile of the complete mitochondrial genome in a European population, improving the interpretation of mtDNA variation in forensic and biomedical contexts.
    Keywords:  Heteroplasmic profile; Heteroplasmy; Massively Parallel Sequencing (MPS); Mitochondrial DNA (mtDNA); Point heteroplasmy
    DOI:  https://doi.org/10.1016/j.mito.2026.102117
  29. Pediatr Neurol. 2026 Jan 14. pii: S0887-8994(26)00017-2. [Epub ahead of print]177 28-45
    Advancing Neuropediatric Rare Disease Diagnosis Through Clinical Genome Sequencing.
    Fabio Sirchia, Silvia Kalantari, Diana Carli, Mariia Zadorozhna, Francesco Bassanese, Erin Thorpe Venti, Ryan J Taft, Akanchha Kesari, Lorena Sorasio, Vincenzo Antona, Andrea Guala, Agnese Feresin, Anna Basile, Francesco Licciardi, Jessica Garau, Paolo Gasparini, Enrico Grosso, Alessandro Mussa, Giovanni Battista Ferrero, Alfredo Brusco, Elisa Giorgio.
       BACKGROUND: Many patients with rare genetic diseases remain undiagnosed or receive a molecular diagnosis only after years. In this study, we want to evaluate the usefulness of clinical genome sequencing (cGS) in a cohort of complex neuropediatric patients with undiagnosed rare genetic diseases.
    METHODS: Between 2018 and 2022, our Medical Genetics Units in Torino, Trieste and Pavia partnered with the iHope program, a philanthropic initiative by Illumina Inc., with the aim of offering family-based cGS within the Italian National Health Service (Servizio Sanitario Nazionale) diagnostic process. A multidisciplinary team of pediatricians, clinical geneticists, and molecular biologists selected 64 cases. Inclusion criteria consisted of suspicion of an ultra-rare monogenic disease and at least one negative result from a first-tier genetic test.
    RESULTS: A definitive molecular diagnosis was achieved in 57.8% of the patients. All patients and families underwent clinical re-evaluation to assess the diagnostic relevance of the laboratory findings, which led us to reclassify 10 variants of unknown significance as responsible for the probands' phenotypes. Diagnoses impacted patients' management, enabling palliative care referrals, avoiding unnecessary invasive tests, and guiding follow-up treatments.
    CONCLUSIONS: Our study confirms that the use of cGS in a rare disease setting increased the diagnostic yield even in complex cases where other methods had previously failed. We speculate that introducing cGS as first-tier test within the Italian Servizio Sanitario Nazionale might offer both diagnostic and economic advantages.
    Keywords:  Diagnostic utility; Genome sequencing; Mendelian conditions; Molecular diagnoses; Rare diseases; Undiagnosed diseases
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.01.004
  30. FEBS J. 2026 Feb 04.
    Proteostasis of organelles in aging and disease.
    Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.
      To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.
    Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules
    DOI:  https://doi.org/10.1111/febs.70439
  31. JCI Insight. 2026 Jan 29. pii: e195170. [Epub ahead of print]
    Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.
    Natalia W Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol-features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.
    Keywords:  Autoimmune diseases; Autoimmunity; Immunology; Lupus; NK cells
    DOI:  https://doi.org/10.1172/jci.insight.195170
  32. J Med Food. 2026 Feb 04. 1096620X261421080
    Stimulatory Effects of (+)-Epicatechin on Mitochondrial Biogenesis and Function in Skeletal Muscle of Aged Rats: Underlying Mechanisms.
    Israel Ramirez-Sanchez, Rosa Ordoñez-Razo, Veronica Najera, Guillermo Ceballos, Francisco Villarreal.
      Mitochondrial dysfunction affects skeletal muscle (SkM) function and is critical in the etiology of age-related sarcopenia. The sirtuin 1-PGC1α pathway is a key regulator of mitochondrial mass, structure, and function. However, pathway activity decreases with aging. Cacao flavanols show promise in their ability to activate mitochondrial pathways. We evaluated the capacity of the flavanol (+)-epicatechin (+Epi) to stimulate such a pathway and favorably impact mitochondrial and oxidative stress (OS)-associated endpoints in aged SkM. Using 23-month-old male Sprague-Dawley rats, an 8-week oral administration of +Epi (1 mg/kg/day) was implemented, and results were compared versus vehicle-treated controls. Assessments included the nicotinamide adenine dinucleotide (NAD)/sirtuin 1/PGC1α pathway, acetylated proteins levels, mitochondrial function and biogenesis, as well as OS-related endpoints in SkM. +Epi increased the NAD/NADH ratio, activation of sirtuin 1, the deacetylation of nuclear protein content, including that of PGC1α. Also, +Epi induced increases of TFAM and NRF1 mRNA levels, deacetylation of mitochondrial complex I and V, increases in complex I activity, sirtuin 3, complexes I and V, mitofilin, and TFAM protein levels. SkM citrate synthase activity and ATP content increased with +Epi. OS markers in proteins and lipids were reduced, while buffering systems (superoxide dismutase 2 and catalase protein and activities) increased. In white blood cells, we documented serial reductions in mitochondrial DNA content and citrate synthase activity with aging, which were either fully or partially reversed with +Epi. Results demonstrate that +Epi treatment yields positive effects on mitochondrial biogenesis and function, leading to decreased OS and improved SkM bioenergetics in aged rats.
    Keywords:  atrophy; epicatechin; mitochondria
    DOI:  https://doi.org/10.1177/1096620X261421080
  33. Hum Gene Ther. 2026 Feb 04. 10430342261422716
    Maximizing Access to Cell and Gene Therapy for Patients with Rare Diseases.
    Terence R Flotte, Guangping Gao.
      
    DOI:  https://doi.org/10.1177/10430342261422716
  34. Adv Physiol Educ. 2026 Feb 04.
    Mitochondria and Moon: Footprints Shaping Life's Evolution and Cosmic Exploration.
    Seshadri Reddy Varikasuvu.
      This Viewpoint explores a novel and striking analogy between mitochondrial cristae and lunar footprints, highlighting both visual and conceptual parallels. By integrating metaphor, and connecting cellular architecture with human exploration, it illustrates how enduring imprints mark milestones in evolution and discovery. The analogy offers a perspective for teaching physiology that links structure and function with imagination and interdisciplinary thinking. Students can better appreciate how microscopic cellular features reflect evolutionary milestones while recognizing that scientific inquiry, whether at the cellular or cosmic scale, is driven by the same human desire to know and to advance.
    Keywords:  Evolution; Lunar footprint; Metaphor; Mitochondria; Physiology education
    DOI:  https://doi.org/10.1152/advan.00268.2025
  35. Cell Mol Neurobiol. 2026 Feb 06.
    Mitochondrial Transplantation Therapy for Ischemic Stroke: Progress and Challenges.
    Zhi-Hong Zhao, Xue-Ling Yang, Zi-Wei Lu, Tao Li, Li-Li Zhao, Ye Li, Mei-Juan Dang, Gui-Lian Zhang, Kun Chen, Hong Fan.
      
    Keywords:  Ischemic stroke; Mitochondrial damage; Mitochondrial quality and quantity control system; Mitochondrial transplantation; Mitochondrial uptake and internalization
    DOI:  https://doi.org/10.1007/s10571-026-01682-1
  36. Curr Opin Neurol. 2026 Jan 30.
    Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
    Fanny Eysert, Gaëlle Deportes, Elodie Delaquaize, Mounia Chami.
       PURPOSE OF REVIEW: Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD.
    RECENT FINDINGS: Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients.
    SUMMARY: Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.
    Keywords:  Alzheimer's disease; biomarkers; mitochondria; mitophagy; peripheral cells and fluids
    DOI:  https://doi.org/10.1097/WCO.0000000000001457
  37. PeerJ. 2026 ;14 e20688
    Deciphering the modulatory role of short-chain fatty acids in Parkinson's disease via phosphorylation-dependent signaling mechanisms.
    Jiaji Liu, Ruijun Su.
      Parkinson's disease (PD), the world's second most prevalent neurodegenerative disorder, is characterized by progressive neuronal degeneration mediated through intricate pathological mechanisms. Phosphorylation signaling pathways have been increasingly recognized as critical modulators in the development and progression of PD. Meanwhile, short-chain fatty acids (SCFAs), primarily produced by gut microbiota, have shown considerable neuroprotective potential by promoting autophagy, alleviating mitochondrial dysfunction, and regulating neuroinflammatory responses. Recent research suggests that SCFAs may influence the phosphorylation dynamics of key signaling pathways, including MAPKs, NF-κB, JAK/STAT, PI3K/Akt, AMPK, and Nrf2/Keap1/ARE, thereby modulating disease pathophysiology. This review aims to systematically evaluate how SCFAs modulate phosphorylation pathways to influence neuroinflammation, α-synuclein aggregation, and mitochondrial dysfunction in PD. By investigating this issue, we identify potential molecular targets and propose future research directions, offering new insighreviewts and strategies for the development of novel therapeutic and preventive interventions for PD.
    Keywords:  Parkinson’s disease; Pathogenesis; Short-chain fatty acids; Signalling pathways
    DOI:  https://doi.org/10.7717/peerj.20688
  38. Trends Neurosci. 2026 Feb 03. pii: S0166-2236(25)00263-2. [Epub ahead of print]
    Mitochondrial specialization and signaling shape neuronal function.
    Benjamin Chun-Kit Tong, Francesco Gubinelli, Lena F Burbulla, Angelika B Harbauer.
      Neurons are specialized cells designed to process information and transmit it, often across long distances. In many neurons, the axonal volume far exceeds the somato-dendritic volume, creating a need for long-range transport and local polarization mechanisms. In addition, action potential firing and restoration of ionic gradients, as well as dynamic changes in synaptic plasticity, further increase the energetic demands of neurons. In this review, we highlight the roles mitochondria play in vertebrate neuronal biology and how mitochondrial functionality is tuned to support the unique demands of neurons. We cover the influence of mitochondrial positioning, ATP generation and Ca2+ buffering on neuronal function, and explore the role of mitochondria in neurotransmitter metabolism and local protein translation.
    Keywords:  Ca(2+) signaling; local translation; neuronal cell biology; neurotransmitter metabolism; respiration; transport
    DOI:  https://doi.org/10.1016/j.tins.2025.12.006
  39. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699119. [Epub ahead of print]
    Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
    Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.
      Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.
    DOI:  https://doi.org/10.64898/2026.01.13.699119
  40. Oncol Lett. 2026 Mar;31(3): 117
    Unveiling mitochondrial DNA copy number alterations: Insights into progression from cervical intraepithelial neoplasia to cervical cancer.
    İzzet Özgürlük, Haktan Bağış Erdem, Mustafa Tarık Alay, Okan Oktar, Firdevs Şahin-Duran, Ezgi Çevik-Demir, Aysu Yeşim Tezcan, Hüseyin Levent Keskin.
      Mitochondrial dysfunction has been increasingly implicated in carcinogenesis, with alterations in mitochondrial DNA (mtDNA) copy number reported across various cancer types. However, the role of mtDNA copy number changes in the progression from cervical intraepithelial neoplasia to invasive cervical cancer remains insufficiently characterized. The present study aimed to elucidate the association between mitochondrial DNA copy number (mtCN) variations and the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, and to evaluate the potential of mtCN as a biomarker for cervical cancer risk stratification. A cohort of 100 participants from the Gynecology and Obstetrics Clinic of Ankara Etlik City Hospital (Ankara, Türkiye) was enrolled. Cervical samples from the participants were categorized into four groups as follows: Normal (n=32), low-grade squamous intraepithelial lesion (CIN1; n=21), high-grade squamous intraepithelial lesion (CIN2/3; n=23) and cervical cancer (n=8). The remaining 16 samples were excluded from the analysis due to inadequate DNA yield or quality. Quantitative PCR was employed to quantify mtCN relative to nuclear DNA. Differences in mtCN according to disease category, smoking status and human papillomavirus (HPV) status were analyzed, and logistic regression modeling was performed to identify independent predictors of high-risk cervical disease (HSIL and invasive cancer). The study revealed a statistically significant stepwise increase in mtCN concomitant with increasing disease severity, reaching the highest level in cervical cancer. Notably, HPV-positive samples exhibited elevated mtCN levels compared with HPV-negative samples. In addition, smoking was associated with a significant increase in mtCN within cervical tissues. A triple model comprising mtCN fold change, smoking status and HPV status demonstrated superior predictive performance for distinguishing high-risk cervical disease, with a sensitivity of 79% and specificity of 92%. The findings indicate that mtCN alterations are associated with the progression of CIN to cervical cancer, particularly in cases who are HPV positive and smoke. To substantiate these findings and evaluate their clinical utility, larger longitudinal studies with standardized assessment protocols are imperative. However, the present study underscores the potential of mtCN as a biomarker for cervical cancer risk assessment and highlights the necessity for continued exploration into its role in tumorigenesis and diagnostic applications.
    Keywords:  HPV; cervical cancer; cervical intraepithelial neoplasia; logistic regression model; mtDNA copy number alteration; smoking
    DOI:  https://doi.org/10.3892/ol.2026.15470
  41. Prenat Diagn. 2026 Jan 30.
    A Framework for Bioinformatic Reporting in Prenatal Sequencing: Insights From a Systematic Review.
    Ashley J Pritchard, Karen Mei Xian Lim, Graeme Smith, Elizabeth Scotchman, Alexander Gibbs, Patrick Lombard, Natalie J Chandler.
      Genomic sequencing has become a key tool in the investigation of foetal anomalies, with a growing shift from targeted panels to exome and genome sequencing. These broader approaches generate significantly more data, underscoring the need for robust bioinformatics pipelines. However, practices vary widely between laboratories. This systematic review explores current differences in bioinformatics workflows, the transparency of reporting, and the clinical impact of these variations. Using a search strategy from a previous review of prenatal sequencing studies (2018-2022), we identified 89 new records. Combined with 65 from the earlier review, a total of 154 articles were included. Data extraction focused on bioinformatics pipeline details across all analytical stages, with attention to clinical relevance. We found that reporting of bioinformatics methods was frequently incomplete. Tool names and versions were often omitted, quality control steps were poorly described, and filtering strategies lacked reproducibility. These deficiencies in reporting hinder readers from fully interpreting the sequencing results and understanding the potential limitations. To address this, we propose a checklist of essential bioinformatics metrics to improve reporting standards and support reproducible, clinically meaningful analyses.
    DOI:  https://doi.org/10.1002/pd.70085
  42. Front Mol Biosci. 2026 ;13 1778169
    Editorial: Molecular mechanisms and precision medicine in rare diseases.
    Hector Rodriguez Cetina Biefer, Abdallah Elkhal, Mohamed Taha Moutaoufik.
      
    Keywords:  biochemical pathway; biochemistry; cellular models; diagnosis; omics; personalized medicine; rare diseases; therapeutic targets
    DOI:  https://doi.org/10.3389/fmolb.2026.1778169
  43. Curr Opin Neurol. 2026 Jan 30.
    Novel pharmacological therapies in development.
    Piero Perucca, Emilio Perucca.
       PURPOSE OF REVIEW: To review progress in developing new pharmacological treatments for epilepsy, focusing on agents in clinical development.
    RECENT FINDINGS: Over 30 different treatments are currently in clinical development, including novel small molecules, nucleic acid-based therapies, stem cells, microbiome-targeting bacteria, and repurposed drugs originally approved for other indications. Most of these treatments target rare epilepsies, particularly the developmental and epileptic encephalopathies, reflecting a development shift from common epilepsies to rare drug-resistant syndromes where unmet therapeutic needs are greatest. Most compounds are still in early development, and publicly accessible data consist mainly of conference reports and congress abstracts. For only two compounds (the Kv7 activator azetukalner and the inhaled emergency treatment Staccato alprazolam) has evidence of efficacy been obtained from relatively large, well designed randomized placebo-controlled trials.
    SUMMARY: New paradigms in drug discovery have brought to development innovative treatments with diverse targets and mechanisms of action. Many of these treatments are etiology-targeting and have the potential for disease-modifying effects. Although high-quality evidence is awaited, there is hope that over the next few years, much needed life-changing therapies will be widely available for millions of people with disabling, drug-resistant epilepsies.
    Keywords:  antiseizure medications; clinical trials; disease modification; drug development; drug treatment; epilepsy; seizures
    DOI:  https://doi.org/10.1097/WCO.0000000000001456
  44. Environ Sci Technol. 2026 Feb 01.
    The Metal-Organic Framework NH2-MIL-101(Fe) Modulates Arsenate Bioaccumulation, Biotransformation, Trophic Transfer, and Mitochondrial Genotoxicity in Daphnia magna-Zebrafish Food Chain.
    Xia Luo, Zhenzheng Fang, Kewei Ren, Hongyan Zou, Qingqing Liu.
      Metal-organic frameworks (MOFs) are promising adsorbents for arsenate (As(V)) remediation; however, their ecological risks during co-occurrence with As(V) in aquatic ecosystems remain poorly understood. This study investigated the effects of NH2-MIL-101(Fe) on As(V) bioaccumulation, trophic transfer, biotransformation, and mitochondrial genotoxicity across generations using a Daphnia magna-Danio rerio (zebrafish) food chain exposure model consisting of a 14 day exposure and a 26 day depuration phase. NH2-MIL-101(Fe) increased total arsenic bioaccumulation in D. magna (15.2-fold) and zebrafish tissues (2.0-18.6-fold at day 14 and 2.6-33.8-fold at day 40), while reducing the biomagnification factor from 0.045 to 0.026. It promoted arsenic uptake, likely via oxidative-stress-mediated upregulation of aqp7 and formation of As(V)-MOF complexes, and enhanced As(V) secondary methylation, associated with as3mt upregulation. Co-exposure increased zebrafish mitochondrial DNA (mtDNA) damage through inducing excessive reactive oxygen species and inhibiting antioxidant enzymes, accompanied by adenosine triphosphate depletion and locomotor decline. The mtDNA damage was transmitted to offspring, demonstrating multigenerational mitochondrial toxicity. These findings reveal that NH2-MIL-101(Fe)-As(V) coexposure increased arsenic burden across trophic levels, particularly in lower trophic levels, and amplifies heritable mitochondrial genotoxicity in aquatic food chains.
    Keywords:  arsenate; bioaccumulation; metal–organic frameworks; mitochondrial genotoxicity; trophic transfer
    DOI:  https://doi.org/10.1021/acs.est.5c14971
  45. J Control Release. 2026 Feb 03. pii: S0168-3659(26)00083-0. [Epub ahead of print]392 114682
    Mitochondria-targeted coenzyme Q10 nanocarriers evaluated by particle size and lipid composition alleviate early acetaminophen-induced liver injury.
    Mitsue Hibino, Yukari Muramatsu, Hideyoshi Harashima, Yuma Yamada.
      Acetaminophen (APAP) overdose-induced liver damage is a serious clinical issue primarily caused by mitochondrial dysfunction in hepatocytes. Coenzyme Q10 (CoQ10) exhibits mitochondrial protective effects and is considered a promising therapeutic candidate. However, it has difficulty targeting liver mitochondria because of its high hydrophobicity and low bioavailability. To address the therapeutic limitations of CoQ10 caused by poor mitochondrial bioavailability, this study aimed to establish a rational design to systematically evaluate how particle size and lipid composition influence the therapeutic efficacy of CoQ10-loaded nanocarriers on APAP-induced liver injury (AILI). Three types of CoQ10-loaded mitochondrial-targeted nanocarriers (CoQ10-MITO-Porter) of different particle sizes (50, 100, 200 nm) and CoQ10-LP, which mimics liposomes used in clinical applications, were prepared using a microfluidic device. These nanocarriers were administered to AILI model mice at early stages of disease, and their hepatic and mitochondrial accumulation, therapeutic impact on serum biomarkers, histological damage, and CoQ10 delivery efficiency were evaluated systematically. The 50-nm CoQ10-MITO-Porter showed the highest hepatoprotective efficacy, indicated by marked attenuation of serum alanine aminotransferase levels and reduced hepatic necrosis. The effect decreased with increasing particle size and was minimal for CoQ10-LP. These results highlight the importance of systematic evaluation of nanocarrier physicochemical properties to achieve effective mitochondrial delivery of CoQ10in early-phase AILI. These findings are expected to serve as a foundation for the development of mitochondria-targeted nanomedicines that alleviate early-phase hepatic damage and may extend to other mitochondrial-related diseases.
    Keywords:  Antioxidant drug; Lipid nanoparticle; Liver targeting; Microfluidics; Mitochondria targeting; Poorly water-soluble drug
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114682
  46. Hum Genomics. 2026 Jan 30.
    Elucidating the genetic landscape of inherited retinal disorders in India.
    Grace Priyaranjini Mathias, Kadarkarai Raj Rajendran, Ruchita Selot, Rohit Shetty, Govindasamy Kumaramanickavel, Arkasubhra Ghosh, Anuprita Ghosh.
       BACKGROUND: Inherited retinal diseases (IRDs) are highly diverse and rare genetic disorders causing mild to complete vision loss across different age groups, with a notably higher disease burden in India. Although genetic testing has improved diagnostic accuracy, India's distinct genetic landscape, shaped by diverse racial backgrounds, admixtures, endogamy, and consanguinity, presents unique challenges. Additionally, phenotype overlaps, non-canonical presentations, genetic heterogeneity, and insufficient literature evidence contribute to clinically and genetically unsolved cases. Since genetic variant reporting commonly relies on information from non-Indian population databases, it is important to build comprehensive knowledge from published Indian data for its unbiased representation in relevant clinical resources. This review aims to assess the current state of Indian IRD research and its lacunae, as this understanding is essential to gauge the readiness of research institutions and tertiary centres for maximizing accessibility to genetic testing and potential treatment options.
    METHODS: We screened 764 PubMed-sourced Indian IRD articles until October 2023 and analysed 21,158 IRD cases from 287 publications reporting clinical and/or genetic data, and further found that 80 publications (n = 628 cases) reported genetic variants (v = 686 variants). Relevant literature was analysed to assess demographic distribution, genetic trends and the research landscape in India.
    RESULTS AND CLINICAL SIGNIFICANCE: Our analyses draw a comprehensive sketch of publication-derived demographics and genetic insights into major IRDs reported in India. They emphasize the urgent need for comprehensive and timely clinical and genetic reporting, since Indian IRD research remains fragmented. This calls for integrated nationwide efforts in systematic reporting through an extensive national IRD case registry for improving diagnostic accuracy, enhancing patient recruitment for clinical trials, and expanding access to emerging therapeutics.
    Keywords:  Case registry; Case reports; Ethnicity-specific; Genetic heterogeneity; Genetics; India; Inherited retinal disorders; Phenotype-genotype correlation; Syndromic retinal disorders
    DOI:  https://doi.org/10.1186/s40246-025-00903-w
  47. J Control Release. 2026 Feb 03. pii: S0168-3659(26)00075-1. [Epub ahead of print]392 114674
    Non-invasive administration of exosomes.
    Teertha Ayanji, Na Yan, Litian Jia, Ke Cheng.
      Exosomes, as naturally derived extracellular vesicles, have emerged as promising therapeutic carriers due to their intrinsic biocompatibility, low immunogenicity, and ability to facilitate intercellular communication. In recent years, the non-invasive administration of exosomes has gained increasing attention as a strategy to enhance patient compliance and improve drug delivery efficiency while circumventing the limitations associated with traditional invasive routes. This review provides a comprehensive overview of the non-invasive delivery of exosome-based therapeutics, spanning oral, intranasal, inhalation, ocular, and transdermal administration. Moreover, we discuss underexplored pathways with unique anatomical and physiological advantages for systemic and local therapy, including sublingual, otic, rectal, and vaginal delivery. Each administration route will outline the key anatomic and biological barriers that exosomes must overcome, along with commonly employed strategies to address them. We further explore the therapeutic potential of non-invasive exosome delivery across various diseases, highlighting the advantages and limitations of each approach. Finally, we discuss the current challenges in translating non-invasive exosome delivery into clinical practice and propose future directions to advance this goal.
    Keywords:  Exosomes; Inhalation delivery; Intranasal delivery; Ocular delivery; Oral delivery; Transdermal delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114674
  48. Annu Rev Biophys. 2026 Feb 05.
    Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets.
    Shashank Ranjan Srivastava, Aadish Rawat, Radhakrishnan Mahalakshmi.
      Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane carry out bidirectional flux of metabolites and ions and serve as the first line of communication between the cytosol and mitochondria. They are now recognized as indispensable for mitochondrial function and cellular homeostasis, mitochondria-endoplasmic reticulum communication, lipid and cholesterol biogenesis, Ca2+ homeostasis, and mitochondria-mediated apoptosis. The unique structural features of VDACs are also important in redox regulation. VDAC dysregulation by interaction with amyloid-β, α-synuclein, Tau, or tubulin can lead to neurodegeneration. Here, we provide insights into the structures, isoform-specific molecular functions, cellular interactome, variations, and unique regulatory elements of VDACs and their direct implications in widespread burdens like cancer and neurodegeneration in humans. We discuss how deducing isoform-specific structure-function studies of VDACs has the potential for successful development of next-generation diagnostics-guided therapeutics.
    DOI:  https://doi.org/10.1146/annurev-biophys-061124-102155
  49. Neurol India. 2026 Jan 01. 74(Suppl 1): S9-S20
    Mendelian Randomization Analysis Uncovers the Causal Link Between Gut Microbiota and Cerebrovascular Diseases.
    Zhi-Bo You, Piao Cao, Sheng-Tao Yao, Zhi-Miao Luo.
       ABSTRACT: The intestinal microbiome represents the most extensive microbial community within the human body, significantly influencing neurodevelopment, aging, maintenance of normal physiological functions, and brain disorders, including ischemic stroke. Emerging research indicates that the gut microbiome might affect cerebrovascular health via multiple mechanisms. However, since many of these studies are observational, establishing a direct causal link remains challenging. Mendelian randomization, leveraging genetic variations, provides a novel approach to evaluate causality. We reviewed recent studies employing Mendelian randomization to investigate the potential causal associations between the gut microbiome and cerebrovascular diseases. Our analysis synthesizes findings from Mendelian randomization studies that connect specific gut microbial compositions with cerebrovascular conditions such as stroke and its subtypes, aneurysms, atherosclerosis, and cerebral small vessel disease. This aims to offer a more definitive framework for understanding the causal relationship between the gut microbiome and cerebrovascular health.
    Keywords:  Causal inference; mendelian randomization; stroke
    DOI:  https://doi.org/10.4103/neurol-india.Neurol-India-D-24-00850
  50. J Neurochem. 2026 Feb;170(2): e70365
    Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
    Yubo Wang, Stuart A Lipton.
      Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.
    Keywords:  GWAS; S‐nitrosylation; neurodegenerative disease
    DOI:  https://doi.org/10.1111/jnc.70365
  51. bioRxiv. 2026 Jan 14. pii: 2026.01.14.699430. [Epub ahead of print]
    A dynamic displacement mechanism drives protein import into mitochondria.
    Iva Sucec, Undina Guillerm, Jakob Schneider, Iniyan Ganesan, Niklas Webling, Anna Kapitonova, Conny Steiert, Frank Schmelter, Antoine Feignier, Rajkumar Singh, Laura F Fielden, Julia Dung, Doron Rapaport, Beate Bersch, Karin B Busch, Francois Dehez, Nils Wiedemann, Paul Schanda.
      Most mitochondrial proteins are produced in the cytosol and imported through the translocase of the outer mitochondrial membrane (TOM) to reach their final destination. Although this protein entry gate has been structurally characterized, it remains unclear how precursor proteins are handed off from the cytosolic receptor domains to the translocation pore. Here we show that the cytosolic domain of Tom22 - traditionally viewed as the central TOM receptor - acts not as a structured scaffold but as a largely disordered, flexible segment that plays an active role in precursor transfer. Atomic-level structural techniques and in vivo experiments identified a conserved short linear motif that forms a transient α-helical element within this disordered domain. By binding to the canonical precursor protein binding sites of the receptors Tom20 and Tom70, this critical α-helical segment acts as a precursor protein displacement element (PPDE). This competitive interaction facilitates the release of preproteins directly above the import pore, and thereby drives translocation across the outer mitochondrial membrane. These findings reveal that flexibility, rather than rigid structure, underlies the central transfer step of mitochondrial outer-membrane protein translocation. Our results point to a versatile mechanism for ligand displacement in chaperone, receptor, and transport systems that must balance selective binding with efficient release.
    DOI:  https://doi.org/10.64898/2026.01.14.699430
  52. MedComm (2020). 2026 Feb;7(2): e70616
    Stem Cell Therapy for Inflammatory Diseases: Progress, Challenges, and Future Directions.
    Chen Wu, Zhi-Ping Jin, Shu-Qiang Weng, Ji-Min Zhu, Ling Dong.
      Inflammatory diseases, encompassing conditions like inflammatory bowel disease and rheumatoid arthritis, present a significant clinical challenge with substantial treatment-refractory patient populations despite biologic therapy advances. Stem cell therapeutics have emerged as a transformative approach, leveraging multifaceted regenerative mechanisms to address the complex pathophysiology of these conditions, which involves genetic, microbial, immunological, and epithelial dysregulation. This review focuses on comparing the clinical efficacy of contemporary stem cell strategies. We analyze outcomes across diverse cell sources, with a detailed examination of delivery methodologies. Our systematic analysis demonstrates superior efficacy with targeted delivery systems, particularly in managing localized inflammatory lesions (e.g., fistulas) and tissue restoration. Notably, minimally processed cellular interventions, such as autologous fat grafting and stromal vascular fraction therapy, show unexpected therapeutic promise. Critical translational barriers include suboptimal cell homing, limited engraftment persistence, and uncharacterized long-term safety profiles. We propose strategic solutions through induced pluripotent stem cell platforms, precision genetic modifications, and advanced delivery technologies. By integrating mechanistic insights with robust clinical evidence, this review establishes an evidence-based framework for optimizing stem cell therapeutics in inflammatory disease management. The analysis addresses fundamental scalability and safety considerations while identifying promising avenues for personalized regenerative medicine approaches in treatment-refractory inflammatory conditions.
    Keywords:  hematopoietic stem cell; hematopoietic stem cell transplantation; induced pluripotent stem cell; inflammatory bowel disease; inflammatory disease; mesenchymal stem cell
    DOI:  https://doi.org/10.1002/mco2.70616
  53. J Acquir Immune Defic Syndr. 2026 Feb 02.
    Letter to the editor: Mitochondrial DNA patterns among individuals living with HIV-1 on dolutegravir with hyperglycemia.
    Allan Buzibye, Ahmet Hoke, Robert C Bollinger, Denis Omali, Sangwon F Kim, Ik-Rak Jung, Eva Laker, Bernard S Bagaya, Barbara Castelnuovo, Yukari C Manabe.
      
    DOI:  https://doi.org/10.1097/QAI.0000000000003838
  54. Mediterr J Hematol Infect Dis. 2026 ;18(1): e2026006
    Kikuchi-Fujimoto Disease and Hemophagocytic Lymphohistiocytosis: A Rare Combination of Two Rare Diseases.
    Mariam Markouli, Panagiotis Diamantopoulos, Asimina Chalioti, Stavroula Lontou, Marina Mantzourani.
      
    Keywords:  Epstein-Barr virus (EBV); Hemophagocytic lymphohistiocytosis; Hyperferritinemia; Kikuchi-Fujimoto disease; Lymphadenopathy
    DOI:  https://doi.org/10.4084/MJHID.2026.006
  55. Neurobiol Dis. 2026 Feb 03. pii: S0969-9961(26)00051-3. [Epub ahead of print] 107307
    Artificial intelligence and machine learning in neurodegenerative disease management: A 21st century paradigm.
    Shaik Basha, Pranavi Ks, Ahana Chattopadhyay, Aparna Ramakrishna Pai, Krishna Kishore Mahato.
      Neurodegenerative diseases represent a major and growing clinical challenge due to their progressive nature, biological heterogeneity, and limited therapeutic options. Recent advances in artificial intelligence (AI) have introduced new analytical strategies for extracting clinically relevant information from complex biomedical data, offering complementary tools to established diagnostic and research approaches. This review provides a critical and method-comparative synthesis of AI applications in neurodegenerative diseases, with emphasis on studies published between 2022 and 2025. Rather than cataloging algorithms, the review evaluates how specific AI methodologies are selected, implemented, and validated across diverse data modalities, including molecular profiles, neuroimaging, biosensors, speech, gait, and electronic health records. Across Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, the reviewed evidence indicates that AI-based models can support early risk stratification, disease characterization, and monitoring when applied within clearly defined analytic and clinical contexts. Importantly, performance gains are shown to depend strongly on data quality, feature representation, validation design, and alignment between model architecture and biological signal, rather than on algorithmic complexity alone. Emerging paradigms, including multimodal integration and next-generation AI frameworks, are discussed in relation to their methodological contributions rather than clinical readiness. By systematically comparing analytical strategies and highlighting sources of variability across studies, this review underscores the importance of methodological transparency, uncertainty-aware evaluation, and biological interpretability. Collectively, the work positions AI as an enabling and adjunctive analytical framework that can enhance neurodegenerative disease research and clinical decision support when deployed with rigor and caution, providing a balanced perspective on current capabilities and future directions.
    Keywords:  Alzheimer's disease; Artificial intelligence; Machine learning; Neurodegenerative diseases; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nbd.2026.107307
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