bims-polgdi Biomed News
on POLG disease
Issue of 2026–01–18
forty-five papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial diseases.
  2. The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?
  3. Mitochondrial Disorder in a Child With Brainstem Lesions Mimicking Thiamine Deficiency.
  4. Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
  5. Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.
  6. What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
  7. Evaluation of MASSARRAY technique in detecting mitochondrial disease mutations.
  8. A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
  9. Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
  10. Towards CRISPR-based editing of the mitochondrial genome in yeast.
  11. F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
  12. Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets.
  13. Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
  14. Potassium ion homeostasis modulates mitochondrial function.
  15. Research Progress on Idebenone in Neurodegenerative Diseases.
  16. Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
  17. Mitochondrial transfer: a Janus-faced force in health and disease.
  18. Pollutant-regulated mitophagy: new perspectives in environmental toxicology.
  19. PAtient-Centric epilepsy clinical trIal model For Improved health outcomes using Cannabidiol (PACIFIC study)-a methodology for developing patient-centred clinical trials in rare epilepsy syndromes.
  20. Mitochondrial DNA common deletion in cancer: Emerging evidence and methodological challenges.
  21. Mitochondria Derived From iPSCs Control by Reciprocal Regulation of Th17/Treg and Anti-Fibrosis.
  22. Cellular Senescence, Inflammaging and Cardiovascular Disease.
  23. Organelle dysfunction and TNT-mediated aggregate spreading in neurodegeneration.
  24. Targeting mitochondrial complexes for cancer therapy.
  25. Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.
  26. Fasting as Medicine: Mitochondrial and Endothelial Rejuvenation in Vascular Aging.
  27. A comprehensive approach to evaluating the clinical utility of genome sequencing in rare disease: A large prospective Canadian cohort.
  28. Targeted delivery of genome editors in vivo.
  29. When Real-World Data Miss Rare Diseases.
  30. Quality control and signaling pathways at stalled ribosomes.
  31. Assessment of circulating cell-free mitochondrial DNA as a damage associated molecular pattern in predicting severity and mortality of sepsis and septic shock patients.
  32. Pharmacotherapy Risks in Rare Genetic Diseases: Cross-Referencing ACMG Secondary Findings v3.2 List With Clinical Databases.
  33. Understanding and teaching rare diseases: from historical origins to modern classification.
  34. The history of paraneoplastic neurologic disorders of the CNS, PNS, and autonomic nervous systems: Perspective on the past toward a brighter future.
  35. Adenosine signaling as a hub for the action of novel antidepressant strategies.
  36. mtDNApipe: A Pioneering Pipeline for High-Sensitivity Detection of Low-Frequency Mitochondrial DNA Mutations.
  37. Alternative Polyadenylation in Aging and Aging-Related Diseases.
  38. The predicament of heritable confounders.
  39. Immunotherapies in autoimmune movement disorders and cerebellar ataxia.
  40. Vascularised Brain Organoids: Engineering Strategies and Neurobiological Applications.
  41. Oenological tannins mitigate rotenone-induced mitochondrial impairments and oxidative stress, with concomitant detection of urolithin A in the brain.
  42. Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.
  43. Sirtuin 4 Knockout Aggravates Sepsis-Induced Acute Liver Injury by Enhancing Mitochondrial Fission and Mitophagy in Hepatocytes.
  44. Metabolic GLUT1 Priming with Disulfide-Stabilized Micelles Enables Noninvasive mRNA Delivery across the Blood-Brain Barrier.
  45. Mitochondrial DNA 6mA Methylation by METTL4 Drives Neuroinflammation via cGAS-STING Activation in Vascular Cognitive Impairment.
  1. Nat Biotechnol. 2026 Jan;44(1): 38
    Mitochondrial diseases.
      
    DOI:  https://doi.org/10.1038/s41587-025-02973-6
  2. NAR Mol Med. 2026 Jan;3(1): ugaf042
    The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?
    Justin C St John.
      For quite some time, knowledge about mitochondria and the mitochondrial genome has been primarily limited to energy production. However, there is now increasing evidence that they have many important roles in cell function and that synergy between the nuclear and mitochondrial genomes is an essential prerequisite to developmental outcome. This review describes the mitochondrial genome and its contribution to overall cellular genomic content; and discusses mitochondrial DNA (mtDNA) inheritance. mtDNA homoplasmy and heteroplasmy are defined and distinctions between pathogenic and non-pathogenic rearrangements are drawn; how they are transmitted; and their effects on oocyte quality and developmental outcomes. This is followed by analysis of mtDNA replication and changes in mtDNA copy number during development; why they need to happen; and how they influence developmental outcomes. Changes to nuclear DNA methylation events are then discussed in the context of changes to mtDNA replication throughout development. This leads to the concept of 'genomic balance', which defines how cells at any stage of development require adjustments to both genomes to ensure successful cellular function and development; and how this process can be perturbed by some of the more invasive assisted reproductive technologies designed to treat infertility and mtDNA disease.
    DOI:  https://doi.org/10.1093/narmme/ugaf042
  3. Cureus. 2025 Dec;17(12): e98909
    Mitochondrial Disorder in a Child With Brainstem Lesions Mimicking Thiamine Deficiency.
    Mohamad A Asfour, Jennifer Nedimyer Horner, Kanika Gupta, Gleidson Silva, Tushar Chandra, Gian Rossi.
      Mitochondrial diseases are among the most common genetic disorders. Known as the "powerhouse" of the cell, mitochondria generate energy via oxidative phosphorylation, a process that involves five enzyme complexes. The MT-ND5 gene, which encodes part of Complex I, is especially prone to mutations and is linked to various mitochondrial disorders. Since mitochondria are concentrated in metabolically active organs such as the brain, heart, liver, muscles, and kidneys, these systems are particularly vulnerable to dysfunction. In the brain, mitochondrial disease symptoms often arise in regions with high metabolic demand, such as the brainstem. Disruptions in oxidative phosphorylation due to nicotinamide adenine dinucleotide (NADH)-ubiquinone oxidoreductase chain 5 (MT-ND5) mutations can prevent energy production from meeting cellular demands, leading to serious neurological consequences. This report describes the neuroimaging and clinical presentation of a child with an MT-ND5 pathogenic variant, highlighting characteristic MRI findings and the diagnostic challenges posed by overlapping features with other metabolic disorders, such as thiamine deficiency.
    Keywords:  brain; genetic diseases; magnetic resonance imaging; mitochondria; mitochondrial disease; mt-nd5; neuroradiology; oxidative phosphorylation; thiamine deficiency
    DOI:  https://doi.org/10.7759/cureus.98909
  4. Redox Biol. 2026 Jan 09. pii: S2213-2317(26)00017-0. [Epub ahead of print]90 104019
    Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
    Jiahui Wang, Rongqing Li, Li Qian.
      Intercellular mitochondrial transfer is recognized as a central mechanism that shapes redox homeostasis, metabolic plasticity, and cellular resilience across multiple tissues. Through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction channels (GJCs), and cell fusion, mitochondria move between donor and recipient cells to restore bioenergetic capacity, buffer oxidative stress, and tune redox-sensitive signaling networks. Recent work has begun to clarify the regulatory framework governing donor-recipient specificity, cargo selection, and the stress-activated cues that trigger organelle exchange. Mitochondrial transfer also exerts distinct, context-dependent influences on disease trajectories. It mitigates injury in neurological damage, ischemia-reperfusion conditions, immune dysfunction, aging, and inflammatory pain, largely by reprogramming mitochondrial function and reactive oxygen species (ROS) dynamics. Conversely, in cancer, mitochondrial acquisition enhances metabolic flexibility, invasiveness, and resistance to therapy. Current therapeutic approaches, including mitochondrial transplantation, EV-based delivery systems, and mitochondria-enhanced immune cells, highlight the translational potential of manipulating mitochondrial exchange, yet face challenges such as mitochondrial fragility, inefficient targeting, and immunogenicity. Deeper mechanistic insight into how mitochondrial transfer remodels redox signaling and metabolic adaptation will be essential for converting this biological process into next-generation organelle-level interventions for redox-driven disorders.
    Keywords:  Extracellular vesicles (EVs); Immunometabolism; Mitochondrial therapeutics; Mitochondrial transfer; Tunneling nanotubes (TNTs)
    DOI:  https://doi.org/10.1016/j.redox.2026.104019
  5. Nucleic Acids Res. 2026 Jan 14. pii: gkaf1390. [Epub ahead of print]54(2):
    Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.
    Simon Schrott, Ilaria Marafelli, Charlotte Gerle, Sebastian Bibinger, Lea Bertgen, Giada Marino, Serena Schwenkert, Romina Rathberger, Johannes M Herrmann, Christof Osman.
      Mitochondrial DNA (mtDNA) copy number regulation remains incompletely understood, despite its importance in cellular function. In Saccharomyces cerevisiae, Mrx6 belongs to the Pet20-domain-containing protein family, consisting of Mrx6, Pet20, and Sue1. Notably, absence of Mrx6 leads to increased mtDNA copy number. Here, we identify the C-terminus of Mrx6 as essential for its stability and interaction with the mitochondrial matrix protein Mam33. Deletion of Mam33 mimics the effect of Mrx6 loss, resulting in elevated mtDNA copy number. Bioinformatics, mutational analyses, and immunoprecipitation studies corroborate that a subcomplex of Mam33 and Mrx6 trimers interacts with the substrate recognition domain of the conserved mitochondrial Lon protease Pim1 through a bipartite domain in the Pet20 domain of Mrx6. Loss of Mrx6, its paralog Pet20, Mam33, or mutations disrupting the interaction between Mrx6 and Pim1 stabilize key proteins required for mtDNA maintenance, the RNA polymerase Rpo41 and the HMG-box-containing protein Cim1. We propose that Mrx6, alongside Pet20 and Mam33, regulates mtDNA copy number by modulating substrate degradation through Pim1. Additionally, Mrx6 loss alters Cim1's function, preventing the detrimental effect on mtDNA maintenance observed upon Cim1 overexpression. The presence of three Pet20-domain proteins in yeast implies broader roles of Lon protease substrate recognition beyond mtDNA regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf1390
  6. Neurology. 2026 Feb 10. 106(3): e214618
    What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
    Eduardo Benarroch.
      Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.
    DOI:  https://doi.org/10.1212/WNL.0000000000214618
  7. Clin Chim Acta. 2026 Jan 10. pii: S0009-8981(26)00002-1. [Epub ahead of print]583 120820
    Evaluation of MASSARRAY technique in detecting mitochondrial disease mutations.
    Nahuda Chetu, Preyaporn Onsod, Budsaba Rerkamnuaychoke, Teerapong Siriboonpiputtana, Takol Chareonsirisuthigul.
      Mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA), leading to impaired energy production, cellular dysfunction, and tissue damage. Accurate and efficient detection of mitochondrial DNA (mtDNA) mutations is crucial for diagnosis and patient management. This study aimed to evaluate the performance of MassARRAY in detecting mtDNA mutations compared to the routinely used MLPA technique. 34 EDTA blood samples from patients with suspected mitochondrial disorders were analyzed using MassARRAY and MLPA methods. MassARRAY was customized to detect 14 mtDNA loci, while MLPA targeted six fixed genetic loci. Both techniques detected five positive cases: three with the m.11778G > A mutation (8.82%) and two with the m.14484 T > C mutation (5.88%). Additionally, MassARRAY uniquely identified the m.12026 A > G mutation and a heteroplasmic m.12258C > A variant (2.94%). MassARRAY also demonstrated advantages in terms of rapid turnaround time (approximately 8 h) and assay flexibility. In conclusion, MassARRAY offers a highly accurate and efficient alternative for detecting mtDNA mutations, with the added benefit of customizable probes. However, sequencing confirmation is recommended for broader mutation coverage.
    Keywords:  Mitochondrial diseases; Multiplex MALDI-TOF mass spectrometry; Multiplex ligation-dependent probe amplification; mtDNA
    DOI:  https://doi.org/10.1016/j.cca.2026.120820
  8. Cell Mol Life Sci. 2026 Jan 12.
    A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
    Marlena Helms, Angelika B Harbauer.
      Neurons have adapted the transport and positioning of mitochondria to fit their extended shape and high energy needs. To sustain mitochondrial function, neurons developed systems that allow local biogenesis and adaption to locally regulate mitochondrial form and function. Likewise, fine-tuned degradative systems are required to protect the neurons from mitochondrial dysfunction. Throughout both domains of mitostasis, the local synthesis of the mitochondrial damage-induced kinase PINK1 emerges as a central player. Along with other nuclear encoded mitochondrial proteins, its mRNA associates with mitochondria to sustain mitochondrial function locally. It also regulates mitochondrial degradation, via regulation of proteases, the generation of mitochondria-derived vesicles and mitophagy. In this review, we provide a general overview of the mechanisms governing mitochondrial health in neurons, with a special focus on the role of PINK1 in this endeavor.
    Keywords:  Local translation; Mitochondrial proteases; Mitophagy; mRNA transport
    DOI:  https://doi.org/10.1007/s00018-025-06054-4
  9. Neurology. 2026 Feb 10. 106(3): e214401
    Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
    Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC)
       BACKGROUND AND OBJECTIVES: Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders.
    METHODS: A retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns.
    RESULTS: The study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions.
    DISCUSSION: This large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.
    DOI:  https://doi.org/10.1212/WNL.0000000000214401
  10. Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2505894123
    Towards CRISPR-based editing of the mitochondrial genome in yeast.
    Sifei Yin, Daniel F Jarosz, Alice Y Ting.
      Mitochondria, which evolved from symbiotic bacteria, possess their own genomes (mtDNA) and support independent transcription and translation within the organelle. Given the essential role of mtDNA in energy production, metabolism, as well as cellular homeostasis, and the high density of confirmed pathogenic mutations that map to mtDNA, there is a pressing need for versatile methods to study and manipulate this genome. Although CRISPR technology has revolutionized the editing of nuclear genomes, it has not been successfully extended to mtDNA, primarily due to the challenge of delivering single guide RNAs (sgRNAs) across both outer and inner mitochondrial membranes. Here we develop a survival-based reporter in Saccharomyces cerevisiae to screen for potential RNA import motifs. We identify a 40-nucleotide aptamer (IM83) that facilitates sgRNA entry into the mitochondrial matrix, enabling CRISPR editing by a mitochondrially-localized adenine base editor. We show that mitochondrial import of IM83 is ATP-dependent and enhanced by the tRNA synthetase Msk1. Further investigations identify barriers to efficient CRISPR editing of mtDNA, including loss of membrane potential associated with mitochondrial targeting of the base editor. These insights lay the groundwork for future improvements in CRISPR-based editing of mtDNA in eukaryotes.
    Keywords:  CRISPR editing; RNA technology; base editing; mitochondrial RNA import; mitochondrial gene editing
    DOI:  https://doi.org/10.1073/pnas.2505894123
  11. J Biol Chem. 2026 Jan 12. pii: S0021-9258(26)00026-8. [Epub ahead of print] 111156
    F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
    Anirban Chakraborty, Santi M Mandal, Mikita Mankevich, Rajam S Mani, Shandy Shahabi, Manohar Kodavati, Sravan Gopalkrishnashetty Sreenivasmurthy, Nisha Tapryal, Dale J Hamilton, Balaji Krishnan, Muralidhar L Hegde, Michael Weinfeld, Gourisankar Ghosh, Tapas Hazra.
      Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks, is a potential cause for its compromised functionality. Here we show that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly decreased in the mitochondrial extract of HD patients' brains due to a lower level of fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Such decrease in PNKP activity leads to persistent DNA strand breaks that are refractory to subsequent steps for repair completion. Both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria and PFKFB3 is part of a mitochondrial DNA repair complex containing HTT, PNKP, DNA Pol γ (POLG) and Lig IIIα. Notably, PNKP binds F2,6BP (Kd= 525±25 nM) and utilizes it as a cofactor. The levels of both F2,6BP and PFKFB3 are significantly decreased in the mitochondrial extract of HD mouse striatal neuronal cells and patients' brain. Activity of PNKP is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored its activity. Moreover, supplementation of F2,6BP in HD cells restored PFKFB3 level, mitochondrial genome integrity and partially restored mitochondrial membrane potential, mitochondrial respiration and prevented pathogenic aggregate formation. Importantly, F2,6BP supplementation significantly restored mitochondrial genome integrity in an HD Drosophila model. Our findings, therefore, suggest that F2,6BP-mediated restoration of PNKP activity could have a profound impact in ameliorating neurodegenerative symptoms in HD.
    Keywords:  DNA strand break repair; Huntington’s disease; PNKP; fructose-2,6-bisphosphate; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2026.111156
  12. Hepatol Commun. 2026 Feb 01. pii: e0885. [Epub ahead of print]10(2):
    Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets.
    Themis Thoudam, Ge Zeng, Hui Gao, Yanchao Jiang, Nazmul Huda, Zhihong Yang, Jing Ma, Suthat Liangpunsakul.
      Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA). Humanin, the first MDP to be discovered, functions as a cytoprotective factor, protecting cells from stress-induced apoptosis. Subsequent discoveries expanded this family to include Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1-6), which modulate mitochondrial bioenergetics and insulin sensitivity. MDPs play critical roles in liver homeostasis by maintaining mitochondrial function and metabolic balance. Intracellularly, they modulate mitochondrial activity, oxidative stress, and apoptosis, promoting hepatocyte survival. Extracellularly, they act in autocrine, paracrine, or endocrine manners, engaging receptors or signaling pathways to regulate nuclear gene expression and metabolic adaptation. Emerging evidence highlights their relevance in metabolic dysfunction-associated steatotic liver disease (MASLD). Humanin exerts hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism. MOTS-c activates AMPK, regulates nuclear gene expression, suppresses fibrotic and inflammatory signaling, and restores mitochondrial function in MASLD and fibrosis models. SHLPs, particularly SHLP2, enhance mitochondrial function and insulin sensitivity, supporting glucose homeostasis and mitigating oxidative stress. Collectively, MDPs establish a novel paradigm in mitochondrial signaling, extending mtDNA function beyond energy production. This review summarizes current insights into MDP biology and highlights its emerging therapeutic potential in chronic liver disease.
    Keywords:  Humanin; Mitochondrial Open-reading-frame of the Twelve S rRNA-c; SHLPs; liver disease; mitochondria-derived peptides; mitochondrial DNA
    DOI:  https://doi.org/10.1097/HC9.0000000000000885
  13. Pharmacol Res. 2026 Jan 10. pii: S1043-6618(26)00011-3. [Epub ahead of print]224 108096
    Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease.
    Andrea Mancini, Elisabetta Betterini, Matteo Bordi, Francesco Cecconi.
      Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid-liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion-purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.
    Keywords:  Cancer biology; Metabolons; Mitochondria metabolism; Nucleotide metabolism; Organelle contact sites; Purine synthesis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108096
  14. J Cell Biol. 2026 Apr 06. pii: e202505110. [Epub ahead of print]225(4):
    Potassium ion homeostasis modulates mitochondrial function.
    Adam James Waite, Beiduo Rao, Elizabeth Schinski, Nathaniel H Thayer, Manuel Hotz, Austin E Y T Lefebvre, Celeste Sandoval, Daniel E Gottschling.
      Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.
    DOI:  https://doi.org/10.1083/jcb.202505110
  15. Aging Med (Milton). 2025 Dec;8(6): 624-633
    Research Progress on Idebenone in Neurodegenerative Diseases.
    Yanqing Zhang, Yanhong Ren, Xiaoran Zhu, Tianhao Liu, Rundong Han, Yuqing Fang, Zhangning Zhao, Fei Mao, Yalin Wang, Xian Li, Xiuhua Li.
      In recent years, significant progress has been made in understanding the therapeutic potential of idebenone (IDE), a synthetic analogue of Coenzyme Q10, in neurodegenerative diseases (NDs). This review comprehensively examines the pharmacological properties of IDE and its emerging applications in various NDs, with particular emphasis on Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and Huntington's disease. We elucidate IDE's multifaceted neuroprotective mechanisms, including its potent antioxidant activity that reduces reactive oxygen species production, its ability to enhance mitochondrial bioenergetics, and its regulatory effects on cellular metabolism. Additionally, we critically evaluate current clinical research findings and discuss the translational potential of IDE in ND therapeutics. The accumulated evidence strongly supports IDE as a promising mitochondrial-targeted agent capable of mitigating disease symptoms and modifying disease progression in multiple neurodegenerative disorders. This review highlights both the current achievements and future directions for IDE-based interventions in ND treatment.
    Keywords:  antioxidants; idebenone; mitochondria; neurodegenerative diseases; neuroprotection
    DOI:  https://doi.org/10.1002/agm2.70047
  16. Nat Cell Biol. 2026 Jan 12.
    Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
    Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.
      The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.
    DOI:  https://doi.org/10.1038/s41556-025-01854-z
  17. J Transl Med. 2026 Jan 16. 24(1): 76
    Mitochondrial transfer: a Janus-faced force in health and disease.
    Yuan Hu, Wenqin Zhou, Lin Chen.
      
    Keywords:  Immune evasion; Infections; Intercellular communication; Mitochondrial transfer; Organelle therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-025-07649-y
  18. Apoptosis. 2026 Jan 10. 31(1): 24
    Pollutant-regulated mitophagy: new perspectives in environmental toxicology.
    Menglan Yan, Chunxia Huang, Shiqi Li, Wenjia Luo, Jiaqiang Wu, Xianhuan Zhou, Kangping Yang, Liang Yang.
      Environmental pollutants such as heavy metals, pesticides, air pollutants, and industrial chemicals pose serious threats to human health, in part by disrupting mitochondrial function. Mitophagy, a selective autophagic process that eliminates impaired mitochondria, is essential for maintaining mitochondrial and cellular homeostasis. Recent studies have shown that various pollutants can impair or dysregulate mitophagy, particularly through pathways such as PTEN-induced kinase 1 (PINK1)/Parkin-mediated mechanisms, leading to mitochondrial dysfunction, oxidative stress, inflammation, and ultimately contributing to diseases including neurodegeneration, cancer, and metabolic disorders. This review comprehensively summarizes the mechanisms by which different classes of environmental pollutants regulate mitophagy, the molecular signaling pathways involved, and the downstream effects on cellular health. Furthermore, this review also discusses current drugs and natural interventions that can alleviate pollutant-induced mitophagy dysfunction, such as melatonin, resveratrol, selenium, and stem cell therapy. By integrating the latest advances in environmental toxicology and mitochondrial biology, the review offers novel perspectives on the role of mitophagy in pollutant toxicity and highlights promising strategies for mitigating the adverse health effects of environmental exposures.
    Keywords:  Disease; Environmental pollutants; Mitophagy; Toxicology
    DOI:  https://doi.org/10.1007/s10495-025-02242-6
  19. BMC Med Res Methodol. 2026 Jan 16.
    PAtient-Centric epilepsy clinical trIal model For Improved health outcomes using Cannabidiol (PACIFIC study)-a methodology for developing patient-centred clinical trials in rare epilepsy syndromes.
    Linda Truong, Tegan Stettaford, Katrina Watt, Nafiseh Ghafournia, Pavel Anetko, Jiyoung Shin, Kris Pierce, John A Lawson, Jennifer H Martin.
       BACKGROUND: Clinical trials for rare epilepsies face substantial methodological and ethical challenges. Small and heterogeneous populations, coupled with limited validated outcome measures, often render traditional designs underpowered and unable to capture outcomes that are meaningful to patients and their families. Innovative approaches-such as decentralised, adaptive, and participatory designs-offer potential solutions but have rarely been systematically applied in this context.
    METHODS: We employed an exploratory three-phase sequential mixed-methods design to co-design a patient-centred clinical trial protocol for rare epilepsies in Australia. An expression-of-interest process recruited 40 participants, equally distributed across four advisory groups: patients, clinicians, researchers, and industry representatives. Phase 1 surveys collected demographic information, trial preferences, digital literacy, and perspectives on participation. Phase 2 comprised semi-structured interviews, analysed using reflexive thematic analysis, to identify themes relevant to trial design. In Phase 3, a consensus-driven process involving four structured online workshops with a multidisciplinary subcommittee translated these findings into a trial protocol recommendation.
    RESULTS: Four priorities emerged: (1) decentralised trial models to improve access and inclusion, particularly through home-based care; (2) embedding cultural safety and systems integration to support diversity; (3) prioritising outcomes beyond seizure reduction, including quality of life and patient-reported measures; and (4) improving communication and accessibility through digital innovation. These insights informed recommendations for an ethics-approved protocol emphasising inclusivity, feasibility, and real-world relevance.
    CONCLUSIONS: This study demonstrates the feasibility of participatory co-design in developing rare epilepsy trial protocols. Embedding patient perspectives and adopting innovative methodologies can enhance scientific rigour, build trust, and strengthen the clinical and policy impact of rare disease research.
    Keywords:  Clinical trial; Co-design; Developmental and epileptic encephalopathy; Mixed methods; Participatory research; Patient-centredness; Rare epilepsy
    DOI:  https://doi.org/10.1186/s12874-025-02757-1
  20. Comput Struct Biotechnol J. 2025 ;27 3929-3940
    Mitochondrial DNA common deletion in cancer: Emerging evidence and methodological challenges.
    Mun Kay Ho, Joshua W K Ho.
      The 4977 bp common deletion of the mitochondrial DNA (mtDNA-CD) is a large-scale deletion that has been frequently observed in various cancers in humans. The common deletion mutation affects 7 key genes encoding for several complex subunits essential to the mitochondrial oxidative phosphorylation system. In the last 20 years, the evidence for the presence of mtDNA-CD in cancer has been elusive. This review aims to examine the evidence of the molecular mechanism and prevalence of mtDNA-CD in different cancers, and to discuss methodological challenges in detecting the presence of mtDNA-CD from clinical samples, and the estimation of prevalence in cancers. This is an attempt to perform a comprehensive literature review and evaluation of experimental evidence to determine whether there is sufficient evidence to suggest a link between mtDNA-CD and cancer. Our results suggest there is a lack of evidence across all cancers. Source of potential discrepancies depends on the quality of the experimental methods, statistical analyses and sampling strategy. Emerging evidence indicates the presence of mtDNA-CD may be cell-type- and cancer-specific. With advances in experimental and analytical techniques, such as single cell genomic and transcriptomic sequencing, spatial omics profiling, and long-read sequencing, we expect to see more comprehensive research that can better clarify the role and prevalence of mtDNA-CD in cancer.
    Keywords:  Cancer biomarker; Genomic mutation; Large-scale deletion; Mitochondrial DNA (mtDNA); Structural variation
    DOI:  https://doi.org/10.1016/j.csbj.2025.09.010
  21. Immune Netw. 2025 Dec;25(6): e41
    Mitochondria Derived From iPSCs Control by Reciprocal Regulation of Th17/Treg and Anti-Fibrosis.
    Jin Seok Woo, Hanbi Lee, JooYeon Jhun, SeungCheon Yang, Yeon Su Lee, Yoo-Jin Shin, Sun Woo Lim, Bo-In Lee, Chul Woo Yang, Byung Ha Chung, Mi-La Cho.
      Several studies have reported the immunoregulatory effects of transplanting mitochondria from mesenchymal stem cells. However, whether similar effects can be achieved using mitochondria derived from human induced pluripotent stem cells (iPSCs; iMito) has not yet been investigated. Here, we examined the protective effects of iMito in a dextran sodium sulfate (DSS)-induced colitis mouse model. To address this, we investigated the effects both in vitro and in vivo. First, iMitos were transferred into mouse splenocytes, and the expression and secretion of IL-17 and FoxP3 were measured. Next, iMitos were transferred into mice with inflammatory bowel disease (IBD) induced by DSS. Intestinal tissues were assessed histologically, and immune cell infiltration was measured. In vitro, iMitos transfer increased mitochondrial function, evidenced by higher ATP synthesis. An immunomodulatory effect was observed, with decreased IL-17 and increased FoxP3 expression. In vivo, iMitos transplantation in IBD mice led to improvements in body weight and intestinal tissue damage; it decreased Th17 cells, increased Tregs, and reduced inflammatory cytokines and fibrosis markers. These data suggest the therapeutic potential of iMitos in treating human inflammatory diseases.
    Keywords:  Fibrosis; Human induced pluripotent stem cell; Inflammatory bowel disease; Mitochondrial transplantation; Th17/Treg homeostasis
    DOI:  https://doi.org/10.4110/in.2025.25.e41
  22. Immunol Rev. 2026 Jan;337(1): e70084
    Cellular Senescence, Inflammaging and Cardiovascular Disease.
    Lukas Zanders, Denada Arifaj, Julian U G Wagner, Stefanie Dimmeler.
      Aging is the most important yet unmodifiable risk factor for cardiovascular disease (CVD). As a result, targeting cardiovascular aging has emerged as a promising strategy to promote long-term cardiovascular health. This review summarizes current knowledge on the effects of aging within the cardiovascular system as well as systemic processes that modulate them. We highlight the roles of cellular senescence and the senescence-associated secretory phenotype (SASP), emphasizing their heterogeneous contributions to chronic low-grade inflammation and tissue remodeling-collectively termed inflammaging. Advances in biomarkers, animal models, and systems biology approaches have deepened our understanding of the interplay between senescence, inflammaging, and cardiovascular dysfunction, including the pivotal role of macrophages in senescent cell clearance. Therapeutic strategies are diverse, ranging from senolytic approaches designed to selectively eliminate senescent cells, to SASP modulation, and interventions targeting chronic inflammation and metabolic dysregulation. Of particular interest, drugs already in clinical use-such as metformin and other anti-diabetic agents-show beneficial effects on aging-related pathways, suggesting that their cardiovascular protection may in part reflect anti-aging properties. Despite these advances, therapies directly targeting senescence and inflammaging to reduce the global burden of CVD remain an urgent unmet need.
    Keywords:  cardiovascular disease; cellular senescence; heart failure; inflammaging; senolytic; senomorphic
    DOI:  https://doi.org/10.1111/imr.70084
  23. Physiology (Bethesda). 2026 Jan 16.
    Organelle dysfunction and TNT-mediated aggregate spreading in neurodegeneration.
    Valentine Thomas, Chiara Zurzolo.
      Organelle dysfunction is a central hallmark of neurodegenerative diseases (NDs), which are characterized by the pathological accumulation of misfolded proteins capable of inducing aggregation in healthy cells. This process generates a self-perpetuating cycle of protein misfolding and spreading across interconnected neuronal networks. In this review, we provide an integrated overview of organelle alterations associated with major NDs, emphasizing the pivotal roles of lysosomes, mitochondria, and the endoplasmic reticulum (ER) at the crossroads of proteostasis, metabolism, and stress signaling. We examine how defects in these organelles create conditions that favor aggregate formation and cellular vulnerability, with a focus on α-synuclein and Tau, the main aggregating proteins in Parkinson's and Alzheimer's diseases, respectively. We then explore mechanisms of intercellular protein transfer, highlighting the emerging role of tunneling nanotubes (TNTs). We discuss how organelle status influences TNT formation and cargo selection, and how TNTs may act as conduits for the propagation of pathogenic aggregates. Finally, we summarize the downstream consequences of TNT-mediated transfer in recipient cells, including alterations in the autophagy-lysosomal pathway, TFEB-dependent transcription, mitochondrial stress responses, calcium homeostasis, and inflammatory or senescent signaling. Together, these insights underscore the intertwined roles of organelle dysfunction and TNT-mediated communication in driving the progression of NDs and suggest new therapeutic avenues aimed at restoring organelle function and limiting aggregate spread.
    Keywords:  neurodegeneration; organelle dysfunction; protein aggregates; tunneling nanotubes
    DOI:  https://doi.org/10.1152/physiol.00048.2025
  24. Biochem Pharmacol. 2026 Jan 10. pii: S0006-2952(26)00026-2. [Epub ahead of print] 117695
    Targeting mitochondrial complexes for cancer therapy.
    Alaa M A Osman, Alya A Arabi.
      Mitochondrial Complexes I-IV in the electron transport chain (ETC) are strategic targets for cancer treatment since they provide the energy and biosynthetic demands of cancer cells. This review covers in silico, in vitro, and in vivo findings related to the inhibition of ETC complexes in order to block cancer cell survival. It covers details about bioenergetic disruption as well as innovative therapeutic strategies such as photodynamic therapy (PDT). This review, thus, serves as a guide for the development of novel small molecules and repurposed drugs for cancer treatment that target the ETC. In addition, this review shows how deep learning and AI-based nanotechnologies are being applied to predict the oxidative phosphorylation (OXPHOS) activity, identify ETC dependencies in cancer cells, and accelerate the discovery of mitochondrial complex-targeted anticancer drugs. It further explains how targeting ETC complexes can be implemented in precision medicine strategies.
    Keywords:  Artificial Intelligence; Cancer; Drug discovery; Electron transport chain; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.bcp.2026.117695
  25. BMB Rep. 2026 Jan 12. pii: 6696. [Epub ahead of print]
    Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.
    Hyun-Ji Ham, Jin-A Lee.
      Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.
  26. Aging Cell. 2026 Feb;25(2): e70372
    Fasting as Medicine: Mitochondrial and Endothelial Rejuvenation in Vascular Aging.
    Madison Milan, Eva Troyano-Rodriguez, Jennifer Ihuoma, Sharon Negri, Rakesh Rudraboina, Aleksandra Kosmider, Shantipriya Awasthi, Priya Balasubramanian, Shannon Conley, Andriy Yabluchanskiy, Anna Csiszar, Zoltan Ungvari, Rafael de Cabo, Stefano Tarantini.
      Aging drives a progressive decline in vascular health, undermining endothelial function, neurovascular coupling (NVC), and blood-brain barrier (BBB) integrity, three processes essential for maintaining cerebral perfusion and cognitive resilience. Central to these age-related deficits is mitochondrial dysfunction, which disrupts redox balance, bioenergetics, and nutrient-sensing pathways within vascular cells, thereby promoting oxidative stress, impaired mitophagy, mitochondrial fragmentation, and endothelial senescence. These molecular derangements are especially consequential in the brain's microvasculature, where the exquisite metabolic demands of neural tissue depend on intact endothelial signaling. As a result, cerebrovascular aging becomes a major driver of cognitive decline and vascular contributions to dementia. This review synthesizes current mechanistic insights into mitochondrial and endothelial pathways that shape vascular aging, with particular focus on the neurovascular unit. We further highlight emerging evidence that time-restricted feeding/eating (TRF/TRE), a circadian-aligned dietary intervention that limits food intake to a daily feeding window without reducing calories, can restore mitochondrial function, activate adaptive nutrient-sensing networks including AMPK and SIRT1, suppress mTOR signaling, and promote metabolic switching toward ketone synthesis and utilization. Through these mechanisms, TRF enhances endothelial resilience, preserves NVC and BBB integrity, and may counteract the cerebrovascular processes that accelerate cognitive aging. Understanding how TRF/TRE re-engages mitochondrial and vascular repair programs offers a translational framework for developing accessible, non-pharmacological strategies to extend healthspan and mitigate age-related cognitive impairment.
    Keywords:  aging; neuroinflammation; neuroprotection; nutritional interventions; oxidative stress
    DOI:  https://doi.org/10.1111/acel.70372
  27. Genet Med. 2026 Jan 09. pii: S1098-3600(26)00002-X. [Epub ahead of print] 101684
    A comprehensive approach to evaluating the clinical utility of genome sequencing in rare disease: A large prospective Canadian cohort.
    Care4Rare Canada Consortium
       PURPOSE: We characterized dimensions of clinical utility in a prospective, observational cohort of patients with rare diseases undergoing genome sequencing (GS).
    METHODS: Clinical utility data (diagnostic, clinical management and research recommended, avoided, or pursued for index cases and relatives) were collected from medical records and summarized using descriptive statistics. A multivariable regression model characterized factors associated with each type of utility, reported as odds ratios with 95% confidence intervals.
    RESULTS: Among 715 cases who underwent GS, results triggered diagnostic investigations in 17.5%, clinical management activities in 35.8%, research opportunities in 30.8%, and genetic counseling/testing for relatives in 19.0%. Results also limited diagnostic investigations in 87.9%. Regression analyses identified clinical, geographic, and ethnicity-related factors as significantly associated with utility. Diagnostic/potentially diagnostic results increased odds of changes in diagnostic investigations, management and genetic testing recommendations for relatives. Patients from larger sites had higher odds of management or research recommendations and patients of non-European ethnicity were less likely to pursue recommendations.
    CONCLUSIONS: Our findings provide evidence that GS has clinical utility beyond diagnostic care, including management, research, as well as familial care and preventing unnecessary medical activity. To determine which factors are associated with utility, multiple dimensions of care and broad sociodemographic factors warrant consideration.
    Keywords:  clinical utility; genomic sequencing; health policy; health services; rare diseases
    DOI:  https://doi.org/10.1016/j.gim.2026.101684
  28. Nat Biotechnol. 2026 Jan;44(1): 49-59
    Targeted delivery of genome editors in vivo.
    Wayne Ngo, Jamie L Y Wu, Kevin M Wasko, Jennifer A Doudna.
      Genome editing has revolutionized the treatment of genetic diseases, yet the difficulty of tissue-specific delivery currently limits applications of editing technology. In this Review, we discuss preclinical and clinical advances in delivering genome editors with both established and emerging delivery mechanisms. Targeted delivery promises to considerably expand the therapeutic applicability of genome editing, moving closer to the ideal of a precise 'magic bullet' that safely and effectively treats diverse genetic disorders.
    DOI:  https://doi.org/10.1038/s41587-025-02945-w
  29. Br J Dermatol. 2026 Jan 13. pii: ljag019. [Epub ahead of print]
    When Real-World Data Miss Rare Diseases.
    Philip Curman.
      
    DOI:  https://doi.org/10.1093/bjd/ljag019
  30. Exp Mol Med. 2026 Jan 15.
    Quality control and signaling pathways at stalled ribosomes.
    Weili Denyse Chang, Young-Jun Choe.
      Aberrant mRNAs can arise from errors in RNA processing or from various physicochemical insults. Ribosomes translating such faulty mRNAs may stall, producing incomplete and potentially toxic polypeptides. These aberrant translation products are eliminated by the ribosome-associated quality control pathway. Ribosome stalling also leads to ribosome collisions, which can activate signaling pathways that enable cells to adapt to stress or determine cell fate. Here, in this Review, we summarize the molecular mechanisms of ribosome stalling and the associated quality control and signaling pathways, and discuss their implications in disease and therapeutics.
    DOI:  https://doi.org/10.1038/s12276-025-01623-w
  31. Eur J Trauma Emerg Surg. 2026 Jan 13. 52(1): 18
    Assessment of circulating cell-free mitochondrial DNA as a damage associated molecular pattern in predicting severity and mortality of sepsis and septic shock patients.
    Bushra, Safia Begum, Shaik Iqbal Ahmed, Akbar Pasha, Ramesh Kande, Mohammed Affan Osman Khan, Aleem Ahmed Khan.
       BACKGROUND: Sepsis and septic shock are life-threatening conditions with high mortality, presenting challenges in predicting disease severity and outcomes. Cell-free mitochondrial DNA (mtDNA) has emerged as a potential mediator in sepsis pathogenesis, acting as a damage-associated molecular pattern (DAMP) that exacerbates inflammation. The present study aimed to assess cell-free mtDNA levels as predictors of mortality and disease severity, and to determine their correlation with established clinical markers.
    METHODS: A prospective study enrolled 150 participants, including healthy controls (n = 50) and patients (n = 100, of which 50 had sepsis and 50 had septic shock). Plasma cell-free mtDNA levels were quantified using RT-qPCR, and Receiver operating characteristic (ROC) curves were used to evaluate the predictive ability of cell-free mtDNA for 28-day mortality. The cell-free mtDNA correlated with clinical markers, including C-reactive protein (CRP), Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE II), Procalcitonin (PCT), neutrophil-to-lymphocyte ratio (NLR), and lactate.
    RESULTS: Cell-free mtDNA levels were significantly elevated in sepsis and septic shock patients compared to controls, and higher in septic shock compared to sepsis patients. Non-survivors exhibited significantly higher cell-free mtDNA levels than survivors across both sepsis and septic shock subgroups. Cell-free mtDNA demonstrated a superior predictive value for 28-day mortality, area under the curve (AUC = 0.865) compared to clinical markers (CRP, SOFA, PCT, NLR, and Lactate). Furthermore, cell-free mtDNA levels showed a positive correlation with CRP, followed by SOFA, NLR, and PCT.
    CONCLUSION: Elevated circulating cell-free mtDNA levels were associated with severity and mortality in sepsis and septic shock, and may act as a valuable molecular tool for predicting disease outcomes. The study's findings warrant further investigation into the potential of cell-free mtDNA as a future component of clinical management strategies in sepsis.
    Keywords:  Circulating cell-free mitochondrial DNA; DAMPs; Inflammation; Sepsis; Septic shock
    DOI:  https://doi.org/10.1007/s00068-025-03058-4
  32. Clin Transl Sci. 2026 Jan;19(1): e70464
    Pharmacotherapy Risks in Rare Genetic Diseases: Cross-Referencing ACMG Secondary Findings v3.2 List With Clinical Databases.
    Josiah D Allen, Benjamin Q Duong, Jordan Brady, Pamela Arn.
      Clinical genomics and pharmacogenomics have largely remained separate fields, though some genetic variants have overlapping disease risk and drug implications. However, the extent of this overlap is not well studied. To explore this gap, we cross-referenced genes from the American College of Medical Genetics Secondary Findings v3.2 list with genomic databases and drug labeling to identify gene-phenotype pairs with overlapping clinical genomics and pharmacogenomic implications. We searched GeneReviews and PharmGKB (now called ClinPGx) for each gene-phenotype pair and reviewed the FDALabel database contraindications or warnings. Targeted therapies for specific germline/somatic variants were excluded. PGx-trained pharmacists and a genetic counselor classified gene-phenotype pairs into three levels: Level 1 (Food and Drug Administration's or guideline-driven recommendations), Level 2 (potential pharmacotherapy implication), and Level 3 (no/weak interactions). Among 97 gene-phenotype pairs reviewed, 22 (23%) were Level 1, 31 (32%) were Level 2, and 44 (45%) were Level 3. Pharmacotherapy implications included risks inferred by disease pathology (e.g., anticoagulants and hereditary hemorrhagic telangiectasia) and less obvious associations (e.g., Marfan syndrome and fluoroquinolones). Unrecognized medication implications may pose patient safety risks. Greater research, information consolidation and dissemination, and multidisciplinary collaboration among clinical genomics specialists, pharmacogenomic specialists, and other practitioners are essential as genetic testing becomes routine in clinical care.
    Keywords:  clinical genomics; contraindications; multidisciplinary care; pharmacogenomics; pharmacy; rare disease; secondary findings
    DOI:  https://doi.org/10.1111/cts.70464
  33. Postgrad Med J. 2026 Jan 10. pii: qgaf191. [Epub ahead of print]
    Understanding and teaching rare diseases: from historical origins to modern classification.
    Donatella Lippi, Elena Varotto, Francesco M Galassi, Francesco Baldanzi.
      The concept of rare disease, formalized in the United States in the 1980s with the Orphan Drug Act, has historical and cultural roots dating back to the Renaissance. The definition of "rarity" has changed over time according to diagnostic tools, social contexts, and economic factors. With the advent of genetics, many new low-prevalence diseases have emerged, raising clinical and ethical challenges. Today, rare diseases require a multidisciplinary approach that also includes narrative medicine, in order to value the patient's experience and better understand the relationship between disease, illness, and society.
    Keywords:  medical education & training; medical history
    DOI:  https://doi.org/10.1093/postmj/qgaf191
  34. Handb Clin Neurol. 2026 ;pii: B978-0-323-90887-0.00005-5. [Epub ahead of print]214 27-44
    The history of paraneoplastic neurologic disorders of the CNS, PNS, and autonomic nervous systems: Perspective on the past toward a brighter future.
    Aditi Sharma, Tammy L Smith, John E Greenlee, Stacey L Clardy.
      Cases of paraneoplastic neurologic disease were described as early as the 1800s; despite two centuries of impressive progress in our understanding of immunity, autoimmunity, and paraneoplastic antibodies, we still have a lot to learn about these rare and devastating diseases. This chapter focuses on the history of paraneoplastic neurologic diseases of the central, peripheral, and autonomic nervous systems. Rather than attempting an exhaustive chronicle of every antibody discovered to date, we discuss key discoveries and concepts which laid the groundwork for our current understanding of paraneoplastic neurologic disease as a whole. The work of the pioneers described in this chapter, as well as many others, provides the foundation upon which future work in this field will be built. Reflecting on the incremental nature of scientific discovery, the critical observations which allowed for paradigm shifts, and the gaps in our current knowledge provides valuable lessons for future directions in this field.
    Keywords:  Antineuronal antibody; Autoimmune neurology; Onconeural antibodies; Paraneoplastic antibodies; Paraneoplastic neurologic disease; Paraneoplastic neurologic syndrome
    DOI:  https://doi.org/10.1016/B978-0-323-90887-0.00005-5
  35. Cell Chem Biol. 2026 Jan 15. pii: S2451-9456(25)00430-1. [Epub ahead of print]33(1): 7-9
    Adenosine signaling as a hub for the action of novel antidepressant strategies.
    Ana M Sebastião.
      In a study recently published in Nature, Yue et al.1 provide a causal relationship between mitochondrial metabolism, adenosine receptor signaling, and the mechanism of action for novel antidepressants. Their findings identify adenosine as a key driver of rapid-acting antidepressant effects and as a therapeutic target for major depressive disorder.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.12.014
  36. Anal Chem. 2026 Jan 15.
    mtDNApipe: A Pioneering Pipeline for High-Sensitivity Detection of Low-Frequency Mitochondrial DNA Mutations.
    Wenjie Guo, Shengjing Li, Tianlei Sun, Zhangwen Lei, Kaixiang Zhou, Lei Zhang, Xu Guo, Feng Zhou, Yang Liu, Jinliang Xing.
      Accurate detection of low-frequency mitochondrial DNA (mtDNA) mutations is essential for advancing molecular profiling, yet it is often confounded by sequencing artifacts, nuclear mitochondrial DNA (NUMTs), and oxidative damage-induced errors. Although unique molecular identifier (UMI)-based duplex sequencing can reduce such errors, its high cost and limited efficiency restrict its widespread use. Here, we present mtDNApipe, a bioinformatics pipeline tailored for capture-based mtDNA sequencing that integrates multiple layers of error suppression. The workflow combines stringent prealignment filtering to remove low-quality reads, overlap-based correction exploiting paired-end redundancy, and exclusion of soft-clipped reads to minimize NUMT interference. Additionally, an endogenous UMI (eUMI)-guided deduplication strategy corrects strand-specific damage, while terminal mutation filtering mitigates end-repair artifacts. When applied to technical replicates of peripheral blood mononuclear cells with low mtDNA copy numbers and paired fresh tumor tissues with high copy numbers, mtDNApipe reduced false positives by more than 80% in the low-frequency range while maintaining sensitivity. Notably, it achieved accuracy comparable to that of conventional UMI-based methods but without their cost and complexity. Compared with existing tools, mtDNApipe demonstrated superior robustness for detecting low-frequency heteroplasmy, offering a reliable and cost-effective solution for high-fidelity mtDNA mutation analysis with broad applications in biomarker discovery, molecular diagnostics, and analytical genomics.
    DOI:  https://doi.org/10.1021/acs.analchem.5c05068
  37. Aging Dis. 2026 Jan 09.
    Alternative Polyadenylation in Aging and Aging-Related Diseases.
    Mengqi Chen, Xiangyu Zhu, Lejia Hang, Zijie Yan, Li Xu, Fang Liu, Qiong Zhang, Jingjing Huang.
      Aging is a major risk factor for a wide range of chronic diseases. Elucidating the molecular mechanisms underlying aging-associated disorders is essential for developing effective preventive and therapeutic strategies. Recent research has unveiled the regulatory roles of non-coding genomic regions. Among these, alternative polyadenylation (APA), a conserved co-transcriptional mechanism, has emerged as a key modulator of gene expression, with an established involvement in various age-related pathologies. APA alters the length of the mRNA 3' untranslated region (3' UTR), thereby affecting mRNA stability, localization, translational efficiency, and ultimately protein expression. Notably, approximately 70% of human genes undergo APA-mediated regulation, underscoring its extensive influence on cellular function. This review summarizes the advances in exploring the role of APA in aging-related diseases, including musculoskeletal disorders, neurodegenerative diseases, cardiovascular and respiratory diseases. These findings can verify the potential of APA as a novel regulatory player in aging biology and a mechanistic contributor to the pathogenesis of age-associated diseases, highlighting its promise as a therapeutic target.
    DOI:  https://doi.org/10.14336/AD.2025.0882
  38. Nat Genet. 2026 Jan 13.
    The predicament of heritable confounders.
    Na Cai, Andy Dahl, Richard Border, Aditya Gorla, Jolien Rietkerk, Joel Mefford, Noah Zaitlen, Morten Dybdahl Krebs, Andrew J Schork, Kenneth Kendler, Jonathan Flint.
      Identifying significant associations between genetic loci and psychiatric disorders is dependent on very large sample sizes. Methods for diagnosing diseases on this scale, such as the use of self-assessment questionnaires and data from electronic health records, incorporate heritable variation unrelated to the disease of interest into the diagnosis. Consequently, genetic mapping will identify loci unrelated to the target disease while missing some that are related, and genetic correlations cannot be used to infer the genetic relationships between diseases and between cohorts. Furthermore, shared biases between different disorders appear as shared etiology. As sample sizes grow, such confounders propagate, and findings based on their presence are replicated and extended. Here, we draw attention to the problem, make suggestions for flagging affected cohorts, and discuss future data collection and machine learning approaches to mitigate the effects of heritable confounders in psychiatric disorders.
    DOI:  https://doi.org/10.1038/s41588-025-02465-y
  39. Handb Clin Neurol. 2026 ;pii: B978-0-323-90887-0.00017-1. [Epub ahead of print]214 291-307
    Immunotherapies in autoimmune movement disorders and cerebellar ataxia.
    Benjamin Vlad, Bettina Balint.
      The spectrum of autoimmune movement disorders is very broad with regard to clinical presentations, associated antibodies, and underlying immunopathophysiology. Early and adequate immunotherapy is key in the management to achieve good outcomes, avoid deterioration, or even death. The rarity of these disorders, however, entails a lack of gold-standard treatment trials we could base our management decisions upon. Here, we summarize existing knowledge about the treatment of autoimmune movement disorders and cerebellar ataxias with neuronal antibodies. We start with a brief introduction of the basic paradigms of neuronal antibody-associated autoimmunity, and of the principles of immune therapy generally applied in antibody-related neurologic disorders, to then discuss in more detail the main movement disorders and cerebellar ataxia related-antibody syndromes and their treatment.
    Keywords:  Antibodies; Autoimmune ataxia; Autoimmune movement disorders; Immunotherapy; Therapy; Treatment
    DOI:  https://doi.org/10.1016/B978-0-323-90887-0.00017-1
  40. Cell Prolif. 2026 Jan 11. e70161
    Vascularised Brain Organoids: Engineering Strategies and Neurobiological Applications.
    Yeajin Song, Hyejin Jo, Seokchan Jeong, Inseon Kim, Seunghun S Lee.
      Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This deficiency restricts organoid size, contributes to necrotic core formation, and hampers their functional maturation. Introducing vascularization offers a compelling solution-it enhances nutrient delivery, supports neurogenesis, and fosters the development of interfaces that resemble the blood-brain barrier (BBB). In this review, we explore how vascularization enhances the structural and physiological relevance of brain organoids and its growing significance in disease modelling and therapeutic screening. We examine current methodologies for engineering vascularized brain organoids (vBOs), including co-culturing with endothelial cells (ECs), transcriptional programming, tissue fusion techniques, microfluidic perfusion systems, and 3D bioprinting. These strategies vary in complexity, scalability, and the extent to which they achieve vascular integration. Functionally, vBOs demonstrate improved oxygen diffusion, enhanced synaptic development, and more robust barrier properties. Such advances enable modelling of complex neurovascular conditions like stroke, glioblastoma, and BBB dysfunction. Moreover, vBOs are emerging as valuable tools in developmental studies and personalised medicine, supporting patient-derived modelling and large-scale drug testing in BBB-relevant contexts. Despite these advances, replicating the structural complexity, functionality, and long-term stability of native vasculature remains challenging. We discuss current limitations and highlight innovative approaches, including the use of next-generation biomaterials and dynamic perfusion technologies. Ultimately, vBOs mark a significant step towards creating physiologically accurate in vitro models of the human brain-offering new opportunities for neuroscience research, drug development, and regenerative medicine.
    Keywords:  blood–brain barrier (BBB); neurovascular disease modelling; perfusion and microfluidic systems; regenerative medicine and cell therapy; vascularized brain organoids
    DOI:  https://doi.org/10.1111/cpr.70161
  41. Biochem Biophys Rep. 2025 Dec;44 102263
    Oenological tannins mitigate rotenone-induced mitochondrial impairments and oxidative stress, with concomitant detection of urolithin A in the brain.
    Olga Wojciechowska, Michaël Jourdes, Mirosław Andrusiewicz, Małgorzata Pokrzywa, Marta Karaźniewicz-Łada, Jadwiga Jodynis-Liebert, Pierre-Louis Teissedre, Małgorzata Kujawska.
      Mitochondria are key organelles that supply energy to the brain, and their dysfunction contributes to neurotoxicity induced by environmental toxins such as rotenone. Recently, oenological tannins (OTs) and their colonic metabolite, urolithin A (UA), have been emphasized due to their potential neuroprotective activity. However, their role in counteracting toxin-induced mitochondrial impairments remains unclear. Therefore, this study aimed to investigate the administration of OTs to rotenone (ROT)-induced mitochondrial dysfunction and oxidative stress, key contributors to neurotoxicity. We measured mitochondrial membrane potential (MMP), the activity of mitochondrial complex I (Grishchuk et al.), and aldehyde dehydrogenase 2 (ALDH2) to assess mitochondria and protein carbonyl (PC) levels. We also checked the presence of UA in the brain. Our results indicate that the OTs treatment restored MMP, increased MCI and ALDH2 activity, and decreased PC content in ROT-induced rats. Furthermore, we confirmed the presence of UA in the brains of the animals. While its exact contribution to the observed mitochondrial effects remains undetermined, this finding suggests a potential role of the gut-derived metabolite in neuroprotection. Thus, we conclude that OTs administration attenuates mitochondria-related neurotoxicity. We call for further mechanistic studies and the putative contribution of metabolites, including UA, to the demonstrated mitoprotective effect of OTs treatment.
    Keywords:  Ellagitannins; Mitochondria; Mitochondrial complex I; Mitochondrial membrane potential; Oxidative stress; Protein oxidation
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102263
  42. AIMS Neurosci. 2025 ;12(4): 444-513
    Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.
    Saviana Antonella Barbati, Giuseppe Carota, Konstantinos Partsinevelos, Lucia Di Pietro, Anna Privitera, Vincenzo Cardaci, Andrea Graziani, Renata Mangione, Giuseppe Lazzarino, Barbara Tavazzi, Valentina Di Pietro, Emiliano Maiani, Francesco Bellia, Angela Maria Amorini, Giacomo Lazzarino, Shahid Pervez Baba, Giuseppe Caruso.
      Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.
    Keywords:  Alzheimer's disease; Parkinson's disease; animal models; carnosine; carnosinemia; cellular and molecular mechanisms; in vivo studies; stroke
    DOI:  https://doi.org/10.3934/Neuroscience.2025025
  43. Mediators Inflamm. 2026 ;2026 7600668
    Sirtuin 4 Knockout Aggravates Sepsis-Induced Acute Liver Injury by Enhancing Mitochondrial Fission and Mitophagy in Hepatocytes.
    Na Li, Dan Ma, Suxin Luo, An He, Shuting Chang.
       Background: Sepsis leads to multiorgan damage, with the liver being the main target. Sirtuin 4 (Sirt4) plays a regulatory role in mitochondrial function and metabolism, but its mechanism in liver injury caused by sepsis remains unclear.
    Methods: The mouse model of liver injury caused by sepsis was established by cecal ligation and puncture (CLP) surgery. The degree of liver injury in wild-type (WT) and Sirt4 gene total knockout (Sirt4-KO) mice was compared by serum AST, alanine aminotransferase (ALT), and histological analysis. The expression of mitophagy and mitochondrial dynamic indicators was detected by biochemical experiments.
    Results: Liver injury in Sirt4-KO mice was more severe than that in WT mice after CLP, manifested as significant upregulation of mitophagy and mitochondrial dynamics imbalance. Mechanistically, Sirt4 deficiency increases mitochondrial fission and mitophagy, thereby leading to cellular damage.
    Conclusions: Sirt4 knockout (KO) aggravates liver injury in sepsis through increasing mitochondrial fission and mitophagy, which indicates a promising direction for future clinical treatment.
    Keywords:  DRP1; Parkin; mitophagy; sepsis-induced liver injury; sirtuin 4
    DOI:  https://doi.org/10.1155/mi/7600668
  44. Bioconjug Chem. 2026 Jan 16.
    Metabolic GLUT1 Priming with Disulfide-Stabilized Micelles Enables Noninvasive mRNA Delivery across the Blood-Brain Barrier.
    Yanhua Li, Xia Cheng, Yue Wang, Zhen Li, Xiyi Chen, Yan Zhao, Qixian Chen, Weidong Le.
      The blood-brain barrier (BBB) remains the single most obstructive bottleneck to mRNA therapeutics for central nervous system (CNS) disorders. Here we introduce a metabolically primed, redox-locked nanoplatform that converts the brain's glucose addiction into a gate-cracking key. A disulfide-stabilized, glucose-decorated block-cationic copolymer self-assembles with mRNA into 36 nm micelles (ζ potential approximately +4.5 mV) that withstand serum nucleases and polyanionic assault yet disassemble on cytosolic glutathione. Fasting-induced GLUT1 upregulation (4.2-fold) is exploited as a transiently overexpressed "receptor"; a subsequent glycemic spike drives receptor-mediated transcytosis, yielding 160-fold higher cerebral mRNA accumulation versus untargeted controls. Single-cell intravital imaging confirms parenchymal penetration within 120 min and pan-brain GFP expression. The strategy affords spatiotemporally sharp CNS transfection without BBB disruption or systemic toxicity, offering a generalizable, nonviral avenue for genomic medicine of neurological diseases.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.5c00621
  45. Free Radic Biol Med. 2026 Jan 12. pii: S0891-5849(26)00027-4. [Epub ahead of print]
    Mitochondrial DNA 6mA Methylation by METTL4 Drives Neuroinflammation via cGAS-STING Activation in Vascular Cognitive Impairment.
    Zhe Gong, Ziyi Chen, Shuixian Sang, Lingfei Yang, Hongzhuo Qin, Qingsheng Li, Yanjie Jia.
       BACKGROUND: Vascular cognitive impairment (VCI) is strongly associated with mitochondrial dysfunction, yet the underlying molecular mechanisms connecting mitochondrial impairment to neuroinflammation remain elusive. While mitochondrial epigenetic modifications are emerging as key regulators of cellular metabolism, the role of mitochondrial DNA (mtDNA) N6-methyladenine (6mA) modification and its writer enzyme METTL4 in VCI pathogenesis has not been established.
    METHODS: Using complementary in vitro (oxygen-glucose deprivation, OGD) and in vivo (chronic cerebral hypoperfusion, CCH) models of VCI, we systematically investigated METTL4-mediated mtDNA epigenetic regulation. Approaches included RNA sequencing (RNA-seq), mitochondrial functional assays, reactive oxygen species (ROS) measurement, and comprehensive analysis of cGAS-STING-mediated neuroinflammatory responses.
    RESULTS: We identified mitochondrial-specific enrichment of METTL4 in hippocampal neurons, with significantly elevated mtDNA 6mA levels following CCH. Mechanistically, OGD-induced METTL4 preferentially methylated the light-strand promoter region of mtDNA, leading to: (1) impaired electron transport chain (ETC) activity, (2) excessive ROS production, and (3) oxidized mtDNA leakage. These mitochondrial abnormalities robustly activated the cGAS-STING neuroinflammatory pathway. Genetic inhibition of METTL4 normalized 6mA levels, restored mitochondrial gene expression profiles, and significantly improved cognitive function in VCI models.
    CONCLUSION: Our study delineates a complete METTL4-mtDNA 6mA-mitochondrial dysfunction-neuroinflammation axis in VCI pathogenesis. These findings not only provide novel insights into the epigenetic control of neuroinflammation but also position METTL4 as a promising therapeutic target for mitigating cerebrovascular-related cognitive decline.
    Keywords:  METTL4; cGAS-STING pathway; hippocampal neuron; mitochondrial dysfunction; mtDNA 6mA; vascular cognitive impairment
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.019
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