bims-polgdi Biomed News
on POLG disease
Issue of 2025–11–23
fifty-five papers selected by
Luca Bolliger, lxBio
  1. Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.
  2. Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.
  3. Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
  4. Targeted deletions in human mitochondrial DNA engineered by Type V CRISPR-Cas12a system.
  5. Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
  6. Accelerate the discovery of genetic variants in mitochondrial diseases with Variant prIOritization using Latent spAce.
  7. Elucidating the Localization and Interactome of Mitochondrial Microproteins.
  8. CRISPR/Cas9-mediated editing of MIC13 in human induced pluripotent stem cells: A model for mitochondrial hepato-encephalopathy.
  9. Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells.
  10. Caloric restriction enhances inheritance of wild-type mitochondrial DNA in Saccharomyces cerevisiae.
  11. Study Designs and Crafting Endpoints for Gene Therapy Development Programs in Rare Disease: A Narrative Review.
  12. Mitochondrial dysfunction induced by E-cigarettes.
  13. Mitochondrial transfer from human embryonic stem cell-derived mature cardiomyocytes to mesenchymal stem cells.
  14. The mitochondrial nexus: Dysfunction, inhibition, and therapeutic frontiers in lung disease.
  15. Assessing Mitochondrial Respiration of In Vitro Models for the Study of Immune-Related Diseases Using a Seahorse Analyzer.
  16. Caenorhabditis elegans as a Model System for Environmental Mitotoxicants.
  17. Retrograde mitochondrial transport regulates mitochondrial biogenesis in zebrafish neurons.
  18. Mitochondrial variation in Taiwan Biobank reveals ancestry structure and trait associations.
  19. Targeting the Powerhouse: A Critical Review of Mitochondrial Inhibitors as a Therapeutic Strategy in Lung Cancer.
  20. An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
  21. Association of peripheral blood mitochondrial DNA gene variation and methylation levels with rheumatoid arthritis.
  22. MTERF1 Regulates Podocyte Mitochondrial DNA Replication Impairment and Mitochondrial Dysfunction in Diabetic Nephropathy through the AMPK/mTOR Pathway.
  23. A Scoping Review of POLG-Related Cerebellar Ataxia: Insights and Clinical Perspectives.
  24. Mitochondrial cristae remodeling: Mechanisms, functions, and pathology.
  25. Mitochondrial NAD+ gradient sustained by membrane potential and transport.
  26. Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
  27. Expanding research and care for Leigh syndrome: efforts of a patient-led advocacy organization.
  28. Mesenchymal Stromal Cells: Bridging the Gaps in Hematologic Disease Therapy.
  29. Extracellular mitochondrial DNA activates complement and is associated with complement activation in patients with out-of-hospital cardiac arrest.
  30. Brain organoids: a new paradigm for studying human neuropsychiatric disorders.
  31. Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.
  32. The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
  33. Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
  34. Epigenetic pharmacology in aging: from mechanisms to therapies for age-related disorders.
  35. The mtDNA-ZBP1 axis in alzheimer's disease: Mechanisms, pathogenesis, and therapeutic implications.
  36. Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids.
  37. RareLink: scalable REDCap-based framework for rare disease interoperability linking international registries to FHIR and Phenopackets.
  38. Computational design of a high-precision mitochondrial DNA cytosine base editor.
  39. PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.
  40. Surface Problem: Unveiling Extracellular Vesicles Surface Markers and Their Implications for Central Nervous System Diseases' Diagnosis and Treatment.
  41. Aging as the wound that fails to heal: a bioenergetic continuum of resolution failure.
  42. Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors.
  43. Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.
  44. In Their Own Words: Creating Connections Through Narrative Medicine.
  45. Fontaine progeroid syndrome with neonatal mitochondrial disease.
  46. Imaging brain inflammation and blood brain barrier permeability in neurological and psychiatric diseases: a review.
  47. Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.
  48. Rare but relevant: genetic liver disease in the general medical setting.
  49. Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.
  50. A 12-Week Strength Training Improves Mitochondrial Respiration, H2O2 Emission and Skeletal Muscle Integrity in Women With Myotonic Dystrophy Type 1.
  51. Quantification and characterization of extracellular vesicles by flow cytometry.
  52. Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval.
  53. Mitochondria-targeted strategies in tumor immunity.
  54. Digitally Assessed Long COVID Symptomatology Is Associated With Lymphocyte Mitochondrial Dysfunction and Altered Immune Potential.
  55. Across Barriers: Blood-Brain and Gut Barrier Signaling in Psychiatric Disorders.
  1. BMB Rep. 2025 Nov 20. pii: 6418. [Epub ahead of print]
    Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.
    Dohee Kim, Seo-Eun Lee, JuHyuen Cha, Jun Ho Lee, Young Cheol Kang, Sang-Yeon Lee.
      This study examined therapeutic potential of mitochondrial transplantation using PN-101, a mitochondria preparation derived from human umbilical cord mesenchymal stem cells (UCMSCs), to address SSBP1-related mitochondrial DNA (mtDNA) depletion syndrome. Patient-derived fibroblasts harboring a heterozygous SSBP1 mutation (c.272G＞A:p.Arg91Gln) were treated with PN-101. Its successful uptake and integration into these cells were confirmed. Subsequent analyses revealed that PN-101 treatment significantly increased mtDNA copy numbers in a time- and dose-dependent manner, elevated the expression of key oxidative phosphorylation proteins, and enhanced overall mitochondrial bioenergetics. Taken together, these results provide strong evidence that mitochondrial transplantation holds promise as a therapeutic strategy for primary mitochondrial diseases, including those involving SSBP1 mutations.
  2. J Mol Neurosci. 2025 Nov 19. 75(4): 154
    Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.
    Yingxue Li, Dongjuan Wang, Maobin Zhou, Haoxuan Sun, Siqi Hong, Li Jiang, Yi Guo.
      MT-ATP6 mitochondrial diseases are a group of disorders inherited from the maternal lineage caused by pathogenic variants in the MT-ATP6 gene, which encodes the a subunit of mitochondrial complex V (ATP synthase) in the electron transport chain. In this study, statistical analysis of 69 mitochondrial disease patients with complete blood metabolic screening at our center demonstrated that hypocitrullinemia exhibited 58% sensitivity (7/12) and 100% specificity (57/57) for diagnosing MT-ATP6 mitochondrial diseases. For detecting the m.8993T > G variant, the diagnostic sensitivity reached 78% (7/9) with maintained 100% specificity (60/60). Among the 7 patients with hypocitrullinemia, one had mtDNA large segment deletion syndrome involving MT-ATP6, and the other 6 had MT-ATP6 mitochondrial diseases due to the m.8993T > G variant. Hypocitrullinemia was initially detected in 3 patients during newborn screening and persisted in follow-up evaluations. A literature review identified 42 cases with MT-ATP6 variants exhibiting hypocitrullinemia, of whom 21 were diagnosed with decreased citrulline during newborn screening. We propose that hypocitrullinemia may serve as an early, characteristic serum biomarker for MT-ATP6 mitochondrial diseases, particularly aiding in the early diagnosis of the m.8993T > G variant. It also exhibits high specificity for diagnosing MT-ATP6 mitochondrial diseases and the m.8993T > G variant. Timely interventions, such as proactive diagnosis of pathogenic variants and administration of mitochondrial cofactors and citrulline, can mitigate the risk of decompensation and improve long-term prognosis.
    Keywords:   MT-ATP6 ; Biomarker; Hypocitrullinemia; Leigh syndrome; m.8993T > G
    DOI:  https://doi.org/10.1007/s12031-025-02440-6
  3. Int Rev Immunol. 2025 Nov 17. 1-30
    Mitochondria in the immune system: Therapeutic potential from mitochondria transfer.
    Thao Hoang Nhu Le, Van Thi Tuong Nguyen.
      Mitochondria serve as the powerhouses of living cells, supplying energy and essential building blocks for cellular activities. The immune system exhibits a dynamic and active characteristic within the body, wherein immune cells are constantly activated and primed for pathogens without causing harmful effects on the self-body. These characteristics necessitate that immune cells function effectively and correctly, supported by a sufficient energy supply and metabolism from the mitochondria. Mitochondrial dysfunction leads to immune dysregulation, resulting in inappropriate inflammation, autoimmunity, immunodeficiency, and hypersensitive responses, all of which contribute to the development of illness and disease. Recent studies on mitochondrial transfer in immune cells indicate that mitochondrial replacement could emerge as a promising tool for rectifying immune cell function. This review will emphasize the role of mitochondria in various immune cell types and explore how mitochondrial dysfunction can result in pathogenesis in different conditions. We also discuss the potential application of mitochondrial transfer and transplantation to- and from immune cells in the context of health and disease.
    Keywords:  Immunology; immunometabolism; mesenchymal stem cells; metabolism; mitochondria transfer
    DOI:  https://doi.org/10.1080/08830185.2025.2577986
  4. NAR Mol Med. 2025 Apr;2(2): ugaf021
    Targeted deletions in human mitochondrial DNA engineered by Type V CRISPR-Cas12a system.
    Natalia Nikitchina, Anne-Marie Heckel, Nikita Shebanov, Ilya Mazunin, Ivan Tarassov, Nina Entelis.
      Mutations in mitochondrial DNA (mtDNA) contribute to various neuromuscular diseases, with severity depending on heteroplasmy level when mutant and wild-type mtDNA coexist within the same cell. Developing methods to model mtDNA dysfunction is crucial for experimental therapies. Here, we adapted the Type V CRISPR-AsCas12a system, which recognizes AT-rich PAM sequences, for targeted editing of human mtDNA. We demonstrated that mitochondrial targeting sequence (MTS) from Neurospora crassa ATPase subunit 9 efficiently addressed the AsCas12a effector nuclease into human mitochondria. When programmed with two CRISPR RNAs (crRNAs) targeting distant regions of mtDNA, the mito-AsCas12a can cleave mtDNA, enabling generation of deletions in cultured human cells. Next generation sequencing of the deletions boundaries confirmed mtDNA ligation after the cleavage by the mitoCRISPR-AsCas12a system. Therefore, we provide experimental data proving that a CRISPR system has potential to be used for precise mtDNA manipulation, offering a promising tool for generating predefined deletions in mtDNA and creating cellular models of mitochondrial disorders.
    DOI:  https://doi.org/10.1093/narmme/ugaf021
  5. J Transl Med. 2025 Nov 19. 23(1): 1321
    Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance.
    Cristina Algieri, Salvatore Nesci, Francesca Oppedisano.
      Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine.
    Keywords:  Complex diseases; Immunity; Inflammation; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1186/s12967-025-07392-4
  6. Brief Bioinform. 2025 Nov 01. pii: bbaf612. [Epub ahead of print]26(6):
    Accelerate the discovery of genetic variants in mitochondrial diseases with Variant prIOritization using Latent spAce.
    Justine Labory, Youssef Boulaimen, Jasmine Singh, Samira Ait-El-Mkadem Saadi, Véronique Paquis-Flucklinger, Sylvie Bannwarth, Silvia Bottini.
      Interpreting variants from whole-exome sequencing remains a major challenge, particularly for heterogeneous disorders such as mitochondrial diseases (MDs). To address this, we have developed Variant prIoritizatiOn using Latent spAce (VIOLA), a pipeline designed to help find a diagnosis for complex cases. VIOLA uses a variational autoencoder to embed functional annotations into a low-dimensional space, followed by DBSCAN-based outlier detection to identify potential pathogenic variants. Filtering steps and phenotype integration via HPO terms are then applied. The VIOLA score (Vscore) combines variant outlierness, transcriptomic co-expression data, and MD-specific annotations. Two rankings are derived: the VIOLA rank (all variants) and the ARrank (variants compatible with autosomal recessive inheritance). The VIOLA Aggregated score (VAscore) merges Vscore with Exomiser's pathogenicity score. Applied to 20 patients (four diagnosed), VIOLA reduced the variant list by >99% and ranked causal variants within the top 5 using ARrank, outperforming existing methods. Overall, VIOLA is a patient-specific strategy for variant prioritization, helping to resolve challenging MD cases and uncover novel disease mechanisms.
    Keywords:  exome sequencing; machine learning; mitochondrial diseases; multi-omics; variant prioritization
    DOI:  https://doi.org/10.1093/bib/bbaf612
  7. Methods Mol Biol. 2026 ;2992 213-228
    Elucidating the Localization and Interactome of Mitochondrial Microproteins.
    Jiemin Nah, Pooja Sridharan, Lena Ho.
      A large number of novel microproteins discovered to date are nuclear encoded, mitochondrial proteins, pointing to their widespread roles in metabolic regulation. In this chapter, we provide a workflow of how to verify if a candidate microprotein is localized to the mitochondria, its submitochondrial localization (i.e., outer, inner membrane, or matrix) and how to determine its interactome in order to elucidate its molecular function.
    Keywords:  Microproteins; Mitochondria; OXPHOS
    DOI:  https://doi.org/10.1007/978-1-0716-5013-4_15
  8. Stem Cell Res. 2025 Nov 10. pii: S1873-5061(25)00220-X. [Epub ahead of print]89 103870
    CRISPR/Cas9-mediated editing of MIC13 in human induced pluripotent stem cells: A model for mitochondrial hepato-encephalopathy.
    Haribaskar Ramachandran, Alexander Becker, Jochen Dobner, Barbara Hildebrandt, Felix Distelmaier, Andrea Rossi, Ruchika Anand.
      MIC13 is essential for cristae formation and functions as a key component of the large mitochondrial multi subunit MICOS complex. Mutations in MIC13 causes severe mitochondrial disease called mitochondrial hepato-encephalopathy. In this study, we describe the generation of a human induced pluripotent stem cell (iPSC) line carrying a patient-specific MIC13 mutation, introduced using a CRISPR/Cas knock-in approach. The resulting iPSC line will provide a valuable model to study the pediatric severe mitochondrial disease and to determine the pathological mechanisms as well as to facilitate the identification of potential therapeutic targets in the future.
    DOI:  https://doi.org/10.1016/j.scr.2025.103870
  9. Trends Cell Biol. 2025 Nov 15. pii: S0962-8924(25)00245-4. [Epub ahead of print]
    Mitochondrial transfer at the crossroads of cancer, stromal, and immune cells.
    Takamasa Ishino, Yu Inutsuka, Hideki Ikeda, Yosuke Togashi.
      Mitochondria are organelles that are essential for their multiple roles in cell biology, including energy metabolism. Accumulating evidence has revealed that intercellular mitochondrial transfer occurs within the tumor microenvironment (TME). The mitochondrial transfer among the TME components can profoundly affect tumor progression, immune surveillance, and stromal remodeling. Importantly, cancer cells function not only as recipients but also as donors of mitochondria, underscoring the bidirectional nature of this process. This review summarizes the multifaceted roles of mitochondria in cancer cells, immune cells, and stromal cells, with particular emphasis on emerging insights into mitochondrial transfer. In addition, the current implications of mitochondria-targeting therapies and future challenges in this evolving field are highlighted.
    Keywords:  antitumor immunity; cancer; mitochondria; mitochondrial transfer
    DOI:  https://doi.org/10.1016/j.tcb.2025.10.004
  10. Sci Rep. 2025 Nov 17. 15(1): 40201
    Caloric restriction enhances inheritance of wild-type mitochondrial DNA in Saccharomyces cerevisiae.
    Wenjuan Zhu, Minoru Yoshida, Feng Ling.
      In Saccharomyces cerevisiae, an asymmetrical division model, mitochondrial (mt) DNA typically exists in a homoplasmic state, but mutations frequently occur. Rolling-circle replication, mediated by the mtDNA recombinase Mhr1p, forms tandem concatemers that are selectively transmitted to budding cells. In crosses between haploids with wild-type (ρ+) and hypersuppressive (HS) ρ- mtDNA, ρ- progeny are predominantly produced due to the replicative advantage of mtDNA with large deletions. We investigated the effects of caloric restriction (CR; 0.5% glucose medium) on mitochondrial distribution and found that ρ+ mtDNA-mitochondria are pre-selected in zygotes and transmitted into buds prior to mitochondrial fusion. This process, termed ρ+ mtDNA-mitochondrial preselection and transmission (ρ+ mtDNA-MPT), was validated by confocal imaging and flow cytometry analyses. The rate of ρ+ progeny increased under CR conditions compared to glucose-abundant media, suggesting that CR enhances ρ+ mtDNA-MPT and promotes the formation of wild-type mtDNA homoplasmy via an Mhr1p-dependent mechanism, which dominates mtDNA inheritance.
    Keywords:  Heteroplasmy; Homoplasmy; Hypersuppresiveness; Mitochondria; Nonmedial budding.; Preselection; mtDNA
    DOI:  https://doi.org/10.1038/s41598-025-23888-x
  11. Adv Ther. 2025 Nov 21.
    Study Designs and Crafting Endpoints for Gene Therapy Development Programs in Rare Disease: A Narrative Review.
    on behalf of the Rare Disease Clinical Outcome Assessment Consortium
      Gene therapies are emerging as a promising strategy for the treatment of rare genetic diseases, for which treatment options are often limited and do not address the underlying disease mechanisms. However, there are significant challenges for gene therapy programs, including defining a suitable first-in-human cohort and selecting endpoints with appropriate variability, sensitivity, reliability, and clinical meaningfulness; a systematic framework for the assessment and approval of these treatments is lacking. In this review, we share insights from 12 clinical development programs that culminated in recent approvals of gene therapies for rare genetic diseases (2016-2023). These approvals highlight useful strategies for navigating the unique challenges of gene therapy trials, including early and frequent engagement with regulatory bodies, incorporating the patient voice, selecting meaningful clinical outcome assessments and suitable controls, and leveraging well-matched real-world data to understand long-term efficacy, durability, and safety. By systematically documenting and analyzing detailed examples in this review, it becomes possible to derive data-driven solutions that can inform the design of future studies. Such solutions may diverge from prior assumptions or preconceptions but can provide a more evidence-based foundation for improving trial efficiency, and ultimately accelerate the development of urgently needed therapies for patients with rare genetic diseases.
    Keywords:  Clinical development; Clinical outcome assessments; Clinical trials; Endpoints; Gene therapy; Genetic disorders; Marketing authorization; Rare diseases; Regulatory approval; Study design
    DOI:  https://doi.org/10.1007/s12325-025-03385-3
  12. Toxicology. 2025 Nov 14. pii: S0300-483X(25)00298-7. [Epub ahead of print]519 154339
    Mitochondrial dysfunction induced by E-cigarettes.
    Ardie Barry Sailis, Muhamad Alfakri Bin Mat Noh, Bey Fen Leo, Farid Nazer Faruqu, Anne Yee, Maw Shin Sim.
      E-cigarette use has been linked to mitochondrial dysfunction through exposure to reactive oxygen species (ROS), toxic aldehydes, metals, and flavoring agents. These constituents can damage mitochondrial DNA, impair oxidative phosphorylation, and disrupt calcium homeostasis, resulting in oxidative stress, inflammation, and programmed cell death. Mitochondrial impairment contributes to many systemic disorders, including respiratory, cardiovascular, and metabolic conditions. Preclinical findings suggest altered mitochondrial morphology, reduced adenosine triphosphate (ATP) production, and increased ROS, all of which can contribute to mitochondrial dysfunction following e-cigarette exposure. Certain flavorings and metals intensify these effects. While early human data suggest systemic mitochondrial stress, most research remains in vitro or animal-based. This review identifies mitochondrial dysfunction as a key mechanism in e-cigarette toxicity and calls for longitudinal research to elucidate its long-term health consequences.
    Keywords:  electronic cigarette; electronic nicotine delivery systems; mitochondrial diseases; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.tox.2025.154339
  13. BMB Rep. 2025 Nov 20. pii: 6458. [Epub ahead of print]
    Mitochondrial transfer from human embryonic stem cell-derived mature cardiomyocytes to mesenchymal stem cells.
    Ye Seul Jeong, Dasol Kim, Yoon Ji Jung, Jung Won Yoon, Yong Seong Kwon, Seong-Jang Kim, Jae Ho Kim.
      Mitochondria are crucial for energy metabolism and their dysfunction is implicated in the development of various human diseases. Direct mitochondrial transplantation has shown potential in reversing mitochondrial dysfunction in recipient cells. Mesenchymal stem cells (MSCs) present a promising approach as donor cells for such transplantation. We have previously demonstrated that tomatidine, a natural steroidal alkaloid, promotes the differentiation of human embryonic stem cells (hESCs) into mature cardiomyocytes by enhancing mitochondrial quantity and function. In this study, we assessed the capacity of hESCderived cardiomyocytes (hESC-CMs) and MSCs as donor cells for mitochondrial transplantation. Mitochondria were extracted from MSCs, immature hESC-CMs, and tomatidine-treated mature hESC-CMs. Treating MSCs with mitochondria derived from mature hESC-CMs led to a marked increase in mitochondrial protein levels, such as COX IV and MIC60, in the recipient MSCs, in comparison to those receiving mitochondria from immature hESC-CMs or MSCs. Transplantation of mature hESC-CM-derived mitochondria significantly enhanced the proliferation of recipient MSCs. These findings indicate that mature hESC-CMs are highly effective as donor cells for mitochondrial transplantation in addressing mitochondrial dysfunction.
  14. Respir Med. 2025 Nov 13. pii: S0954-6111(25)00569-4. [Epub ahead of print]250 108506
    The mitochondrial nexus: Dysfunction, inhibition, and therapeutic frontiers in lung disease.
    Woo Hyun Park.
      Mitochondria are increasingly recognized as central arbiters of cellular fate, placing them at the nexus of pulmonary health and disease. Beyond their canonical role in adenosine triphosphate (ATP) synthesis, these organelles are critical hubs for redox signaling, metabolic homeostasis, and programmed cell death. Mitochondrial dysfunction-a multifaceted condition characterized by impaired bioenergetics, excessive reactive oxygen species (ROS) production, aberrant dynamics, and defective quality control via mitophagy-is a unifying pathogenic feature in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary arterial hypertension (PAH). This dysfunction is also a critical determinant of severity in acute conditions like acute lung injury (ALI) and COVID-19 and is a key mechanistic driver of Long COVID. This review synthesizes the core mechanisms of mitochondrial impairment, delineates their specific contributions to this spectrum of pulmonary pathologies, and discusses the burgeoning field of mitochondria-targeted therapeutics. Strategies ranging from targeted antioxidants and metabolic modulators to novel regenerative approaches like mitochondrial transplantation are highlighted, with an expanded discussion on their limitations, challenges, and clinical implications. By framing mitochondrial integrity as a critical determinant of pulmonary disease, we underscore a pivotal axis for future diagnostic and therapeutic innovation.
    Keywords:  Lung disease; Metabolic reprogramming; Mitochondria; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.rmed.2025.108506
  15. Methods Mol Biol. 2026 ;2990 145-156
    Assessing Mitochondrial Respiration of In Vitro Models for the Study of Immune-Related Diseases Using a Seahorse Analyzer.
    Chloé Chivé, Arnaud Tête.
      Energy metabolism, particularly mitochondrial function, has emerged as a key regulator of the immune response and plays a significant role in the pathophysiology of inflammatory diseases. Studying mitochondrial parameters is therefore crucial in understanding these pathologies. This protocol outlines the evaluation of mitochondrial respiration parameters using a Seahorse Analyzer. With the growing use of innovative models that better mimic human physiology, such as cell cultures in inserts, this chapter provides a detailed guide to Seahorse analysis for this specific type of culture.
    Keywords:  Cell culture models; ETC; Metabolism; Mitochondria; OXPHOS
    DOI:  https://doi.org/10.1007/978-1-0716-4997-8_12
  16. Annu Rev Pharmacol Toxicol. 2025 Nov 21.
    Caenorhabditis elegans as a Model System for Environmental Mitotoxicants.
    Akinleye Akinrinde, Luis Andres Sanchez, Silvia Maglioni, Natascia Ventura.
      Environmental pollutants such as heavy metals, pesticides, and plastic nanoparticles pose significant risks to human, animal, and environmental health. New approach methodologies complying with the 3R principles (replace, reduce, refine) are essential for advancing the molecular basis of pollutant-induced toxicity, thus improving risk assessment, disease prevention, and therapies. Thanks to its remarkable features, the multicellular organism Caenorhabditis elegans offers unique opportunities to meet this goal. Mitochondria, central hubs in cellular homeostasis, are particularly vulnerable to pollutants, orchestrating stress responses that progress to toxicity and disease. C. elegans represents a powerful models to study these effects, offering conserved systems with quantifiable endpoints. While previous studies have mainly focused on environmental stressors inducing DNA damage, this review explores C. elegans's end points of relevance for mitotoxicology, highlighting advantages and limitations of the system as an alternative approach for in vivo environmental-induced mitochondrial toxicology and diseases.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-062124-012254
  17. bioRxiv. 2025 Oct 01. pii: 2025.09.29.679307. [Epub ahead of print]
    Retrograde mitochondrial transport regulates mitochondrial biogenesis in zebrafish neurons.
    Angelica E Lang, Chris Stein, Catherine M Drerup.
      To maintain a healthy mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because the majority of mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires nuclear sensing of mitochondrial population health and function. This can be a challenge in a large, compartmentalized cell like a neuron in which a large portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with mitochondrial gene expression. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.
    DOI:  https://doi.org/10.1101/2025.09.29.679307
  18. iScience. 2025 Nov 21. 28(11): 113746
    Mitochondrial variation in Taiwan Biobank reveals ancestry structure and trait associations.
    Ting-Hsuan Chou, Pei-Miao Chien, Pin-Xuan Chen, Ni-Chung Lee, Hurng-Yi Wang, Yi-Cheng Chang, Chien-Yu Chen, Pei-Lung Chen, Jacob Shu-Jui Hsu.
      Mitochondrial DNA (mtDNA) variation contributes to human health, but its role in the Taiwanese population remains largely unexplored. Here, we comprehensively analyzed mtDNA variation in the Taiwan Biobank (TWB) by genotyping 1,492 individuals using whole-genome sequencing and imputing variants for 101,473 participants from microarray data. We identified 23 pathogenic mtDNA variants, with approximately 1 in 180 individuals carrying such variants. Analyses of mitochondrial genetic diversity revealed subtle differentiation among maternal ancestry groups. A mitochondrial genome-wide association study across 86 traits identified novel links between MT-ND2 variants and high myopia, as well as 14 variants associated with renal function biomarkers. Notably, renal-associated variants clustered into two groups: ancestral variants of macrohaplogroup M associated with reduced renal function and B4b sub-haplogroup variants linked to improved function. These findings highlight the value of population-specific mtDNA studies in advancing our understanding of mitochondrial genetics and health.
    Keywords:  Biological sciences; Genomic analysis; Genomics; Population
    DOI:  https://doi.org/10.1016/j.isci.2025.113746
  19. Eur J Pharmacol. 2025 Nov 18. pii: S0014-2999(25)01136-7. [Epub ahead of print] 178382
    Targeting the Powerhouse: A Critical Review of Mitochondrial Inhibitors as a Therapeutic Strategy in Lung Cancer.
    Woo Hyun Park.
      Lung cancer therapy is constrained by profound intrinsic and acquired resistance to targeted therapies and immunotherapy. To overcome this, a new therapeutic paradigm is emerging that targets the unique metabolic and survival dependencies of cancer cells. Mitochondria, the central hubs of metabolism, cell death, and signaling, represent a critical vulnerability. This review provides a new conceptual framework for understanding and targeting mitochondrial pathways in lung cancer. First, this review outlines the key "mitochondrial hallmarks" of lung cancer that create therapeutic windows, emphasizing the critical role of metabolic heterogeneity. Second, it provides a novel, mechanism-based classification of mitochondrial inhibitors into four major classes: (1) electron transport chain (ETC) inhibitors, (2) metabolic enzyme modulators, (3) apoptosis pathway modulators, and (4) mitochondrial quality control (MQC) disruptors. Third, this review critically analyzes the molecular mechanisms by which these inhibitors activate regulated cell death pathways (apoptosis, ferroptosis) and, most importantly, their potential in overcoming therapeutic resistance to standard-of-care. Fourth, it explores the mechanisms of mitochondrial crosstalk within the tumor microenvironment (TME), including intercellular transfer via tunneling nanotubes. Finally, this review presents a systematic review of the clinical landscape, synthesizing data from preclinical models and ongoing clinical trials. This review concludes by highlighting key limitations and future perspectives, positioning MQC and the mitochondrial unfolded protein response (UPRmt) as next-generation targets to improve patient outcomes.
    Keywords:  Ferroptosis; Lung Cancer; Mitochondria; Mitochondrial Inhibitors; Mitochondrial Quality Control (MQC); Therapeutic Resistance
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178382
  20. Nat Commun. 2025 Nov 20. 16(1): 10222
    An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
    Eloïse Marques, Stephen P Burr, Alva M Casey, Richard J Stopforth, Chak Shun Yu, Keira Turner, Dane M Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J Tyrrell, Robbin Kramer, Yamini M Kanse, Chinmayi Pednekar, Chris A Powell, James B Stewart, Julien Prudent, Michael P Murphy, Michal Minczuk, Valerie B O'Donnell, Clare E Bryant, Patrick F Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G Ryan.
      Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.
    DOI:  https://doi.org/10.1038/s41467-025-65023-4
  21. Clin Immunol. 2025 Nov 17. pii: S1521-6616(25)00216-5. [Epub ahead of print]282 110641
    Association of peripheral blood mitochondrial DNA gene variation and methylation levels with rheumatoid arthritis.
    Qian Huang, Xue-Qian Cai, Zhi-Qiang Li, Yan Liu, Hai-Feng Pan.
       OBJECTIVE: Mitochondrial dysfunction is closely related to the pathogenesis of various autoimmune diseases, and mitochondrial DNA (mtDNA) gene variations are associated with the susceptibility to autoimmune diseases. This study aimed to investigate association between mtDNA genetic variants, methylation levels and rheumatoid arthritis (RA).
    METHOD: We performed mtDNA whole genome sequencing in 32 RA patients and 32 controls, and then validated 8 mtDNA variants using the SNaPshot™ multiplex technique in 452 RA patients and 457 controls. The methylation levels of 4 mtDNA genes were measured in 108 RA patients and 107 controls by MethylTarget technique.
    RESULTS: We found that ND5 gene m.12705 T genotype, tRNA-Pro gene m.16304C genotype, tRNA-Pro gene m.16319 A genotype were significantly associated with RA susceptibility in entire population and female population. Moreover, the increased frequency of m.12705 T and the decreased frequency of m.16304C were significantly related to anti-CCP positive in RA patients. While tRNA-Pro gene m.16092 T > C, m.16189 T > C, RNR2 gene m.2706 T > G, ND2 gene m.4833 A > G, m.5108 T > C showed no association with the risk of RA. When compared to controls, the methylation levels of ND5, RNR2, ND2 genes were significantly decreased in RA patients. In addition, ND5, RNR2 methylation levels were linked to erythrocyte sedimentation rate, and m.12705C > T variant significantly influenced ND5 methylation level among RA patients.
    CONCLUSION: Multiple mtDNA variants in ND5, tRNA-Pro genes and methylation levels of ND5, RNR2, ND2 genes were significantly associated with genetic susceptibility to RA in Chinese population.
    Keywords:  Genetic variation; Methylation; Mitochondrial DNA; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.clim.2025.110641
  22. Ann Clin Lab Sci. 2025 Sep;55(5): 663-671
    MTERF1 Regulates Podocyte Mitochondrial DNA Replication Impairment and Mitochondrial Dysfunction in Diabetic Nephropathy through the AMPK/mTOR Pathway.
    Haiying Tao, Ling'an Yu.
       OBJECTIVE: This study was carried out with an objective to clarify the mechanism of mitochondrial transcription termination factor 1 (MTERF1) in regulating mitochondrial DNA (mtDNA) replication and mitochondrial function of podocytes in diabetic nephropathy (DN).
    METHODS: To establish a type I diabetes model, C57BL/6J mice were injected intraperitoneally with streptozotocin (STZ). Eight weeks after STZ injection, blood glucose levels and renal function were assessed in mice. Mouse renal tissues were analyzed via hematoxylin-eosin, periodic acid-Schiff, and TdT-mediated dUTP nick-end labeling staining. Immunohistochemistry/Western blot were employed for the detection of MTERF1 expression. MPC-5 cells were treated with high glucose (HG) (30 mM) to establish the cellular model. MTERF1-overexpressing MPC-5 cells were constructed and treated with HG and the AMP-activated protein kinase (AMPK) inhibitor compound C (CC) for 24 h. Cell apoptosis was assessed by flow cytometry, cell viability by the cell counting kit-8 assay, mtDNA copy number by real-time quantitative PCR, adenosine triphosphate (ATP) production by ultraviolet spectrophotometric method, mitochondrial reactive oxygen species (mtROS) by MitoSox, and mitochondrial membrane potential (MMP) by JC-1. MTERF1 protein expression and AMPK/mammalian target of rapamycin (mTOR) signaling pathway activity were measured via Western blot.
    RESULTS: The model group (relative to the control group) exhibited a significant rise in blood glucose, urine volume, urinary albumin, and urine albumin-creatinine ratio, along with significantly aggravated glomerular injury and markedly increased glycogen deposition and decreased MTERF1 expression in mouse renal tissue. In in vitro experiments, compared with the normal glucose (NG) group, the HG group showed increased apoptosis and reduced cell activity, accompanied by significantly decreased MTERF1 protein expression, mtDNA copy number, and ATP content. Compared to the HG+oe-NC group, the HG+oe-MTERF1 group showed significant increases in mtDNA copy number, ATP content, MMP, and AMPK/mTOR signaling pathway activity, while demonstrating decreased mtROS production. The HG+oe-MTERF1+CC group exhibited significant reductions in mtDNA copy number, ATP production, and AMPK/mTOR signaling pathway activity compared to the HG+oe-MTERF1 group, but displayed elevated mtROS levels.
    CONCLUSION: Over-expression of MTERF1 can alleviate HG-induced damage of mtDNA replication and mitochondrial dysfunction in podocytes via activating the AMPK/mTOR signaling pathway, thus improving DN.
    Keywords:  AMPK/mTOR signaling pathway; MTERF1; diabetic nephropathy; mitochondrial dysfunction
  23. Tremor Other Hyperkinet Mov (N Y). 2025 ;15 55
    A Scoping Review of POLG-Related Cerebellar Ataxia: Insights and Clinical Perspectives.
    Stefania Kalampokini, Iraklis Keramidiotis, Stylianos Ravanidis, Piergiorgio Lochner, Vasilios K Kimiskidis, Georgios M Hadjigeorgiou.
       Background: Cerebellar ataxia is one of the most common movement disorders in mitochondrial disease, with POLG mutations being a frequent cause. This scoping review aimed to summarize current knowledge regarding cerebellar ataxia due to POLG mutations, focusing on epidemiological, clinical, radiological features and genotype-phenotype correlations.
    Methods: We searched PubMed and Web of Science databases for all articles published in English till September 2025 describing cases of POLG-related cerebellar ataxia.
    Results: In homozygous or compound heterozygous POLG mutation carriers, cerebellar ataxia seems to be progressive, and can initiate from either the bulbar muscles, trunk, or limbs. Age at onset varies greatly, ranging from birth to the early 70s. The most common variants in POLG-related cerebellar ataxia are W748S and A476T, localized in the linker region of POLG gene. Cerebellar ataxia due to POLG mutations can present in combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy (including status epilepticus), headache, other hyperkinetic movement disorders such as myoclonus and tremor, cognitive or affective disorders. Brain imaging commonly reveals atrophy of the vermis or cerebellar hemispheres, cortical atrophy, and/or bilateral T2/FLAIR lesions in both white matter and deep brain nuclei, including inferior olivary nuclei.
    Conclusion: POLG-related ataxia should be included in the differential diagnosis of slowly progressive cerebellar ataxias. POLG-related disease comprises a continuum of clinical features; the combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy, hyperkinetic movement disorders, as well as characteristic imaging findings, can aid the diagnosis of this underdiagnosed entity. These findings contribute to a better characterization of the phenotype-genotype relationship in the extended pool of POLG-related mitochondrial diseases.
    Highlights: This review summarizes current knowledge regarding cerebellar ataxia due to POLG mutations. A slowly progressive cerebellar ataxia in combination with sensory neuropathy, progressive external ophthalmoplegia, epilepsy, myoclonus, and characteristic imaging findings, including cerebellar atrophy, bilateral lesions in deep brain nuclei (thalami, olivary nuclei) should raise suspicion for POLG-related disease.
    Keywords:  POLG mutation; POLG-related ataxia; cerebellar ataxia; movement disorders; phenotype-genotype
    DOI:  https://doi.org/10.5334/tohm.1027
  24. Cell Insight. 2025 Dec;4(6): 100285
    Mitochondrial cristae remodeling: Mechanisms, functions, and pathology.
    Jianglong Yu, Yuanchun Luo, Jiacheng Lin, Zhuofan Li, Zheng Fang, He He, Chaojun Yan, Zhiyin Song.
      Mitochondrial cristae are the principal sites of oxidative phosphorylation and are central to mitochondria-dependent energy metabolism. Rather than static folds, cristae are dynamic bioenergetic compartments that remodel in response to physiological and stress cues. During remodeling, their number, length, width, lateral alignment, curvature/stiffness, and the geometry of crista junctions (CJs) can change. Depending on cellular context, cristae may increase in abundance, tighten or widen, and exhibit opening or closure of CJs, with corresponding effects on respiratory-chain organization and supercomplex assembly. Key regulators include OPA1 (and its proteolytic processing), the MICOS complex that scaffolds CJs, F1Fo-ATP synthase dimerization/oligomerization that shapes high-curvature ridges, and cardiolipin, which stabilizes inner-membrane architecture. Abnormal cristae compromise electron transport, ATP production, and mitochondrial metabolism, contributing to neurodegeneration and metabolic disease etc. In this review, we synthesize current insights into the molecular control of cristae ultrastructure and its impact on mitochondrial metabolism, delineate structural features and quantitative readouts, and highlight mechanisms that govern cristae remodeling under physiological and stress conditions, with an emphasis on diseases arising from aberrant crista architecture.
    Keywords:  Cardiolipin; Cristae remodeling; F1Fo-ATP synthase; MICOS complex; OPA1; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.cellin.2025.100285
  25. Sci Adv. 2025 Nov 21. 11(47): eaea7460
    Mitochondrial NAD+ gradient sustained by membrane potential and transport.
    Shivansh Goyal, Scott N Lyons, Xiaolu A Cambronne.
      SLC25A51 is required for the replenishment of free nicotinamide adenine dinucleotide (oxidized form) (NAD+) into mammalian mitochondria. However, it is not known how SLC25A51 imports this anionic molecule to sustain elevated NAD+ concentrations in the matrix. Understanding this would reveal regulatory mechanisms used to maintain critical bioenergetic gradients for cellular respiration, oxidative mitochondrial reactions, and mitochondrial adenosine triphosphate (ATP) production. In this work, mutational analyses and localized NAD+ biosensors revealed that the mitochondrial membrane potential (ΔΨm) works in concert with charged residues in the carrier's inner pore to enable sustained import of NAD+ against its electrochemical gradient into the matrix. Dissipation of the ΔΨm or mutation of select residues in SLC25A51 led to equilibration of NAD+ from the matrix. Corroborating data were obtained with the structurally distinct mitochondrial NAD+ carrier from Saccharomyces cerevisiae (ScNdt1p) and mitochondrial ATP transport suggesting a shared mechanism of charge compensation and electrogenic transport in these mitochondrial carrier family members.
    DOI:  https://doi.org/10.1126/sciadv.aea7460
  26. Exp Physiol. 2025 Nov 19.
    Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
    Anastasiya Kuznyetsova, David A Hood.
      Skeletal muscle plays an important role in whole-body health, quality of life and regulation of metabolism. The maintenance of a healthy mitochondrial pool is imperative for the preservation of skeletal muscle quality and is mediated through mitochondrial quality control consisting of mitochondrial turnover mediated by a balance between organelle synthesis and degradation. The selective tagging and removal of dysfunctional mitochondria is essential for maintaining mitochondrial quality control and is termed mitophagy. The mechanisms of the initial stages of mitophagy involving the recognition and tagging of mitochondria within skeletal muscle are well established, but our understanding of the terminal step involving organelle degradation mediated via lysosomes is in its infancy. An assessment of the proteolytic functions to facilitate the removal and breakdown of dysfunctional mitochondria is crucial for our understanding of the mechanisms of mitophagy, which is essential for maintaining skeletal muscle health. The aim of this review is to address the current knowledge surrounding mitophagy and lysosomal function, alongside distinct physiological conditions, such as ageing, exercise and disuse, that have varying effects on mitophagy and lysosomal adaptations within skeletal muscle.
    Keywords:  Parkin; adaptation; lysosomes; mitophagy; skeletal muscle; transcription factor EB
    DOI:  https://doi.org/10.1113/EP093041
  27. Res Involv Engagem. 2025 Nov 20. 11(1): 137
    Expanding research and care for Leigh syndrome: efforts of a patient-led advocacy organization.
    Sophia Zilber, Melinda Burnworth, Titilola Afolabi, Jonathan R Brestoff, Michal Minczuk, Alejandro Rodriguez Luis, Qinglan Ling, Alessandro Prigione, Isabella Tolle, Ibrahim Elsharkawi, Ethan Perlstein, Danielle Boyce, Simon Johnson, Kasey Woleben.
      
    Keywords:  Gene therapy; Leigh syndrome; Mitochondrial disease; Patient advocacy; Rare disease
    DOI:  https://doi.org/10.1186/s40900-025-00808-x
  28. Stem Cell Rev Rep. 2025 Nov 18.
    Mesenchymal Stromal Cells: Bridging the Gaps in Hematologic Disease Therapy.
    Xumeng Zhao, Xi Ming, Jiaying Wu, Xiaojian Zhu, Yi Xiao.
      Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in hematologic diseases by modulating immune responses, supporting hematopoiesis, and remodeling the bone marrow microenvironment. Clinically, MSCs have been explored for graft-versus-host disease and hematopoietic stem cell transplantation support, while their applications in hematologic malignancies, including acute myeloid leukemia, multiple myeloma, and myelodysplastic syndromes, remain under investigation. However, therapeutic heterogeneity, safety concerns, and standardization challenges limit their clinical translation. Recent advances in MSC-derived extracellular vesicles, gene modification technologies, and integrative combination strategies have expanded the therapeutic landscape, enabling more precise and targeted modulation of immune responses and tumor microenvironments. Moreover, disease-specific evidence highlights the dual roles of MSCs-acting either as therapeutic agents or as contributors to disease progression-depending on stromal plasticity and niche conditioning. This review provides a comprehensive and mechanistic synthesis of MSC functions across both malignant and non-malignant hematologic disorders, integrating preclinical and clinical findings in immunoregulation, hematopoietic recovery, anti-fibrosis, and microenvironmental reprogramming. In addition, we critically evaluate emerging strategies to overcome translational bottlenecks, including inter-donor variability, lack of predictive potency markers, and the need for scalable, standardized manufacturing protocols. By bridging foundational mechanisms with translational potential, this review offers forward-looking perspectives to guide future optimization and clinical integration of MSC-based therapies in hematology.
    Keywords:  Extracellular vesicles; Hematologic diseases; Hematopoietic stem cell transplantation; Immunomodulation; Mesenchymal stromal cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12015-025-11011-6
  29. Sci Rep. 2025 Nov 20. 15(1): 41000
    Extracellular mitochondrial DNA activates complement and is associated with complement activation in patients with out-of-hospital cardiac arrest.
    Eline de Boer, Anne-Lise Strandmoe, Marina Sokolova, Trond M Michelsen, Huy Q Quach, Viktoriia Chaban, Espen R Nakstad, Geir Ø Andersen, May-Kristin S Torp, Kåre-Olav Stensløkken, Tom E Mollnes, Søren E Pischke.
      Synthetic analogues of mitochondrial DNA (mtDNA) have been reported as potent complement system activators. This study investigated the impact of endogenous mtDNA on complement activation. mtDNA and nuclear DNA (nDNA) were extracted from human placental tissue and complement activation was determined using ELISA. When incubated in lepirudin-anticoagulated human blood and plasma, increasing concentrations of mtDNA, but not nDNA, resulted in dose- and time-dependent increases in C3bc, C3bBbP and soluble C5b-9 (sC5b-9). In a clinical context, mtDNA, nDNA, and complement levels of 55 resuscitated out-of-hospital cardiac arrest (OHCA) patients were determined using qPCR and ELISA. C3bc and sC5b-9 correlated significantly with mtDNA and nDNA in OHCA patients. We conclude that mtDNA, but not nDNA, triggers in vitro complement activation, which holds significance in a clinical context in OHCA patients. This novel mode of human complement activation might explain pathophysiological mechanisms of sterile inflammation and could be relevant for innovative therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41598-025-24705-1
  30. Front Neurosci. 2025 ;19 1699814
    Brain organoids: a new paradigm for studying human neuropsychiatric disorders.
    Yi Sun, Wei Pan.
      Understanding human brain development and dysfunction is a major goal in neurobiology. Compared with traditional 2D models and animal models, brain organoids technology based on induced pluripotent stem cell (iPSC) constructs can more accurately recapitulate the developmental process of the human brain and simulate the characteristic phenotypes of neurological diseases in recent years. This technology is expected to change our understanding of human brain development, while providing a fresh perspective on elucidating the pathogenesis of inherited and acquired brain diseases. This article reviews the development and recent advances in brain organoids, explores their use in neuropsychiatric disorders, from neurodevelopmental to neurodegenerative and psychiatric diseases, while also outlining the challenges facing the technology. We conclude that these advances not only enhance our understanding of human-specific brain development and disease mechanisms, but also accelerate the translation of brain organoid technology into personalized medicine and drug discovery.
    Keywords:  brain development; brain organoids; neurodegenerative disorders; neurodevelopmental disorders; organoid assembly; psychiatric disorders
    DOI:  https://doi.org/10.3389/fnins.2025.1699814
  31. Cell Regen. 2025 Nov 16. 14(1): 45
    Modulating mitochondrial metabolism: a neuroprotective mechanism for hypoxic-ischemic preconditioning.
    Wenxin Li, Guo Shao, Ruifang Qi.
      Hypoxia-ischemia plays a role in the physiological and pathological processes of various diseases and presents a common challenge for humans under extreme environmental conditions. Neurons are particularly sensitive to hypoxia-ischemia, and prolonged exposure may lead to irreversible brain damage. The primary mechanisms underlying this damage include energy depletion, mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis. Mitochondria serve as primary organelles for adenosine triphosphate (ATP) production, and mitochondrial dysfunction plays a crucial role in mediating hypoxic pathophysiological processes. Hypoxic-ischemic preconditioning (H/IPC) is an endogenous cellular protective mechanism that reduces the damage caused by lethal hypoxic stressors. In this review, we summarize the potential role of H/IPC and its protective effects on mitochondrial quality control and function. This perspective offers a new approach for treating diseases caused by hypoxia-ischemia.
    Keywords:  Hypoxia; Hypoxic/ischemic preconditioning; Ischemia; Mitochondrial; Neuroprotection
    DOI:  https://doi.org/10.1186/s13619-025-00268-4
  32. Mitochondrion. 2025 Nov 16. pii: S1567-7249(25)00096-0. [Epub ahead of print] 102099
    The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
    Jakob D Busch, Thomas Schöndorf, Dusanka Milenkovic, Xinping Li, Rolf Wibom, Joana F Silva-Rodrigues, Roberta Filograna, Camilla Koolmeister, Nils-Göran Larsson, Diana Rubalcava-Gracia.
      The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.
    Keywords:  Cytochrome c oxidase; Mitochondria; Mitoribosomes; OXPHOS; mtDNA
    DOI:  https://doi.org/10.1016/j.mito.2025.102099
  33. Mol Cell Biol. 2025 Nov 18. 1-16
    Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
    Himangshu S Bose, William E Burak, Randy M Whittal.
      Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN2) scaffolds raft-like microdomains in the trans-Golgi network, endosomes, and plasma membrane. We found that ERLIN2 assists in rolling cholesterol trafficking-associated lipid vesicles by facilitating the intermediate folding of cholesterol trafficker steroidogenic acute regulatory protein (StAR) from the ER to MAM prior to delivery to the outer mitochondrial membrane. Each ERLIN2-StAR interaction is short. The absence of ERLIN2 ablates mitochondrial cholesterol transport. Over time, StAR association with ERLIN2 increases from the ER to MAM, thereby enhancing mitochondrial cholesterol transport. Thus, ERLIN2 is central for regulating mitochondrial cholesterol trafficking required for mitochondrial steroid metabolism.
    Keywords:  Steroids; cholesterol; endoplasmic reticulum; mitochondria associated-ER membrane (MAM); pregnenolone; steroidogenic acute regulatory protein (StAR)
    DOI:  https://doi.org/10.1080/10985549.2025.2583172
  34. Front Pharmacol. 2025 ;16 1699296
    Epigenetic pharmacology in aging: from mechanisms to therapies for age-related disorders.
    Haikuan Yu, Taojin Feng, Chengcheng Zhang, Zhouguang Jiao, Wenkai Fan, Rongxian Jiang, Dewen Kong, Fubing Li.
      Aging is a multidimensional process regulated by the interplay of genetic and environmental factors, with epigenetic alterations serving as a central regulatory hub. Aberrant DNA methylation patterns, dysregulation of histone-modifying enzymes (e.g., SIRT1, EZH2), and non-coding RNA-mediated mechanisms collectively remodel gene expression networks, impacting critical pathways such as cellular senescence and mitochondrial homeostasis. This establishes an "environment-epigenome-disease" causal axis, closely associated with pathologies including β-amyloid deposition in Alzheimer's disease, atherosclerosis, immunosenescence, osteoporosis, sarcopenia, and tumorigenesis. Capitalizing on the reversible nature of epigenetic modifications, pharmacological epigenetics has emerged as a cutting-edge field for intervening in aging and age-related diseases. Targeting key epigenetic modifiers such as DNA methyltransferases and histone deacetylases enables the modulation of disease-associated epigenetic states, providing a promising avenue for therapeutic intervention in aging and age-related diseases. This review synthesizes the molecular mechanisms of epigenetic regulation in aging, their role in age-related diseases, and advances in pharmacological epigenetics-from basic research to clinical translation. It further situates key challenges such as target specificity, long-term safety, and tissue-specific delivery within a translational framework, aiming to inform strategies for the diagnosis and intervention of age-related conditions.
    Keywords:  DNA methylation; age-related diseases; aging; epigenetic modifiers; epigenetics; histone modification; non-coding RNA; pharmacological epigenetics
    DOI:  https://doi.org/10.3389/fphar.2025.1699296
  35. Int Immunopharmacol. 2025 Nov 16. pii: S1567-5769(25)01841-7. [Epub ahead of print]168(Pt 1): 115853
    The mtDNA-ZBP1 axis in alzheimer's disease: Mechanisms, pathogenesis, and therapeutic implications.
    Yue Chen, Yan Liu, Hong Hu, Shenghong Li.
      Alzheimer's disease (AD) is a neurodegenerative disorder, particularly prevalent in the elderly. Recent research has focused on the interplay between mitochondrial dysfunction and neuroinflammation, with the mtDNA-ZBP1 axis identified as a critical pathway linking mitochondrial function, immune response, and cell death in AD pathogenesis. Upon release into the cytoplasm, mitochondrial DNA (mtDNA) is recognized by ZBP1, triggering immune responses, inflammation, and cell death. As a central node linking mitochondrial damage, neuroinflammation, and neuronal death, ZBP1 has garnered increasing attention as both a pathogenic mechanism and a potential therapeutic target in AD. However, a comprehensive review of the mtDNA-ZBP1 axis in AD pathology and pharmacology remains lacking. This review discusses the role of the mtDNA-ZBP1 axis in AD, emphasizing how mtDNA and ZBP1 interact to activate immune responses and cell death pathways. We underscore the synergistic contribution of mitochondrial dysfunction and chronic neuroinflammation to AD progression. Additionally, we explore therapeutic strategies targeting the mtDNA-ZBP1 axis, including ZBP1 inhibitors and mtDNA stabilizers. While these strategies have shown promise in animal models, their clinical potential requires further validation. Finally, we discuss future research directions, aiming to address current challenges and advance mtDNA-ZBP1-targeted therapies toward clinical application.
    Keywords:  Alzheimer's disease; Cell death; Inflammation; mtDNA-ZBP1 axis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115853
  36. bioRxiv. 2025 Oct 02. pii: 2025.10.01.679889. [Epub ahead of print]
    Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids.
    Tienju Wang, Yanting Chen, Jing Tian, Khloud Emam, Lan Guo, Tao Ma, Heng Du.
      Patients with Alzheimer's disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a bona fide pathology to promote AD development. In this study, by meta-analysis of publicly available proteomics analysis of post-mortem frontal lobe tissues from four large cohorts of patients with AD we identified loss of key CCO subunits including mitochondrial DNA (mtDNA)-encoded COX1 and COX3 as well as nuclear DNA (nDNA)-encoded COX5A, COX6B1, COX7C, COX8A, and NDUFA4 in patients with AD. Further biochemical analysis using post-mortem frontal lobe tissues showed lowered CCO activity of neuronal mitochondria from patients with AD, suggesting CCO vulnerability and its potential association with amyloidosis in AD. Lastly, in addition to the inverse relationship between neuronal CCO activity and brain amyloidosis in the tested AD cohort, pharmacological inhibition of CCO promoted amyloid production and elevated beta-secretase 1 (BACE1) activity in cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) from one nonAD and one AD subject. The simplest interpretation of the results is that CCO dysfunction in the frontal lobe is a phenotypic mitochondrial change accompanying AD, which may contribute to the development of brain amyloidosis.
    DOI:  https://doi.org/10.1101/2025.10.01.679889
  37. NPJ Genom Med. 2025 Nov 18. 10(1): 72
    RareLink: scalable REDCap-based framework for rare disease interoperability linking international registries to FHIR and Phenopackets.
    Adam S L Graefe, Filip Rehburg, Samer Alkarkoukly, Daniel Danis, Ana Grönke, Miriam R Hübner, Alexander Bartschke, Thomas Debertshäuser, Sophie A I Klopfenstein, Julian Saß, Julia Fleck, Mirko Rehberg, Jana Zschüntzsch, Elisabeth F Nyoungui, Tatiana Kalashnikova, Luis Murguía-Favela, Beata Derfalvi, Nicola A M Wright, Shahida Moosa, Soichi Ogishima, Oliver Semler, Susanna Wiegand, Peter Kühnen, Christopher J Mungall, Melissa A Haendel, Peter N Robinson, Sylvia Thun, Oya Beyan.
      While Research Electronic Data Capture (REDCap) is widely adopted in rare disease research, its unconstrained data format often lacks native interoperability with global health standards, limiting secondary use. We developed RareLink, an open-source framework implementing our published ontology-based rare disease common data model. It enables standardised data exchange between REDCap, international registries, and downstream analysis tools by linking Global Alliance for Genomics and Health Phenopackets and Health Level 7 Fast Healthcare Interoperability Resources (FHIR) instances conforming to International Patient Summary and Genomics Reporting profiles. RareLink was developed in three phases across Germany, Canada, South Africa, and Japan for registry and data analysis purposes. We defined a simulated Kabuki syndrome cohort and demonstrated data export to Phenopackets and FHIR. RareLink can enhance the clinical utility of REDCap through its global applicability, supporting equitable rare disease research. Broader adoption and coordination with international entities are thus essential to realise its full potential.
    DOI:  https://doi.org/10.1038/s41525-025-00534-z
  38. Nat Struct Mol Biol. 2025 Nov 17.
    Computational design of a high-precision mitochondrial DNA cytosine base editor.
    Li Mi, Yu-Xuan Li, Xinchen Lv, Zi-Li Wan, Xu Liu, Kairan Zhang, Huican Li, Yue Yao, Leping Zhang, Zhe Xu, Xingyu Zhuang, Kunqian Ji, Min Jiang, Yangming Wang, Peilong Lu.
      Bystander editing remains a major limitation of current base editors, hindering their precision and therapeutic potential. Here, we present a de novo protein design strategy that creates a structurally rigid interface between a DNA-binding TALE domain and a cytosine deaminase, forming a unified editing module termed TALE-oriented deaminase (TOD). Cryo-EM analysis of TOD-DNA complexes confirms that this precise spatial architecture tightly restricts the deaminase activity window, thereby minimizing unwanted deamination. To further enhance editing specificity, we develop a split version, termed DdCBE-TOD, which virtually eliminates off-target editing. As a proof of concept, we apply DdCBE-TOD to generate a mitochondrial disease mouse model and to correct a pathogenic mutation associated with MERRF syndrome in patient-derived cells, achieving single-nucleotide precision. This work introduces a generalizable and computationally guided approach for ultra-precise base editing, offering a promising platform for both mechanistic studies and therapeutic correction of single-nucleotide mutations.
    DOI:  https://doi.org/10.1038/s41594-025-01714-2
  39. Database (Oxford). 2025 Jan 18. pii: baaf076. [Epub ahead of print]2025
    PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.
    Lev Tsarin, Polina V Shcherbakova.
      Human POLE and POLD1 genes encode DNA polymerases responsible for genome replication and proofreading of DNA synthesis errors. Germline and somatic POLE/POLD1 mutations compromising the polymerase fidelity cause cancers with high mutational burden. Ultramutation is associated with a better prognosis and immunotherapy response, highlighting the need to define tumour POLE/POLD1 status unambiguously. Prior studies assessed the functional significance of numerous POLE/POLD1 variants in experimental models. However, the data remain scattered and difficult to evaluate by non-specialists, limiting their utility for research and clinical applications. Through manual literature curation, we integrated data from functional studies of clinically relevant POLE and POLD1 variants into PolED, a publicly available database (https://poled-db.org). PolED compiles information on variant effects in biochemical assays, yeast, mammalian cells, and mouse tumour models along with supporting references. It also includes a concise summary of functional significance for each variant. PolED aims to assist in clinical decision-making, guide personalized therapy, and promote further research.
    DOI:  https://doi.org/10.1093/database/baaf076
  40. Mol Neurobiol. 2025 Nov 21. 63(1): 127
    Surface Problem: Unveiling Extracellular Vesicles Surface Markers and Their Implications for Central Nervous System Diseases' Diagnosis and Treatment.
    Stanislav Gruzdev, Alexander Yakovlev.
      Extracellular vesicles (EVs) are a broad category of small vesicles released by cells in the central nervous system (CNS) that facilitate intercellular communication and contribute to various diseases. In neuroscience, one of the most important and well-characterized EV subtypes is exosomes. However, current issues with EV nomenclature make it difficult to draw firm conclusions due to variability in usage across different studies. One solution to overcome this challenge is to use established markers for isolating different types of CNS-derived EVs. This article provides an up-to-date list of potential EV markers, focusing on surface markers. We discuss the role of EVs in CNS diseases and explore each candidate's potential to be used as a specific EV surface marker. We also highlight how non-adherence to EV nomenclature leads to confusion and misuse of EV markers. Additional challenges in EV research, such as isolation methods and the lack of comparative studies between plasma and tissue-derived EVs, are discussed. Providing a list of new possible CNS-derived EV marker candidates can lead to more precise isolation and description of EVs, thereby enhancing our understanding of EV signaling and advancing our knowledge of neurological diseases.
    Keywords:  Biomarker; Exosomes; Extracellular vesicles; L1CAM; Surface markers; Surfaceome
    DOI:  https://doi.org/10.1007/s12035-025-05487-z
  41. Biogerontology. 2025 Nov 20. 27(1): 7
    Aging as the wound that fails to heal: a bioenergetic continuum of resolution failure.
    Torsak Tippairote, Pruettithada Hoonkaew, Aunchisa Suksawang, Prayfan Tippairote.
      Aging may be conceptualized as a wound that fails to heal, characterized by persistent, unresolved inflammation. Building on Ogrodnik's "unhealed wound" model, this Perspective extends the Exposure-Related Malnutrition (ERM) framework to propose a bioenergetic interpretation of aging. ERM links chronic stress adaptation, nutrient misallocation, and mitochondrial insufficiency to sustained bioenergetic debt that impedes the transition from catabolic containment to anabolic repair. Across tissues, this energetic shortfall manifests as metabolic inflexibility, lipid-droplet accumulation, and a continuum of adaptive mitochondrial dysfunction that remains reversible until the threshold of senescence-the terminal stage of unresolved adaptation. Recognizing bioenergetic availability as the principal determinant of regenerative success reframes mitochondrial dysfunction and senescence not as primary causes of aging but as downstream consequences of chronic energetic exhaustion. Within this continuum, aging reflects a progressive loss of rhythmic catabolic-anabolic cycling that supports metabolic adaptation. Transient metabolic stress normally induces hormetic activation followed by anabolic recovery, but when this oscillation fails, adaptive hormesis gives way to maladaptive exhaustion. Aging thus emerges from the erosion of bioenergetic rhythm-a transition from recovery with renewal to endurance without repair.
    Keywords:  Aging; Energy metabolism; Exposure-related malnutrition (ERM); Metabolic adaptation; Regeneration; Wound healing
    DOI:  https://doi.org/10.1007/s10522-025-10356-2
  42. Stem Cell Reports. 2025 Nov 20. pii: S2213-6711(25)00324-8. [Epub ahead of print] 102720
    Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors.
    Eunkyu Sung, Shohei Murakami, Masanobu Morita, Tomoaki Ida, Takaaki Akaike, Hozumi Motohashi.
      Recent studies highlight the critical role of mitochondria in hematopoiesis, especially in stem cell function and erythroid maturation. To explore mitochondrial contributions to cell lineage commitment of hematopoietic progenitors, we utilized Cars2-mutant mice, an ideal model for this purpose. CARS2, a mitochondrial isoform of cysteinyl-tRNA synthetase, has cysteine persulfide synthase (CPERS) activity. Our new mouse model, with reduced CPERS activity, showed that the Cars2 mutation led to mitochondrial inhibition and anemia by suppressing erythroid commitment in megakaryocyte-erythroid progenitors (MEPs). This suppression was reproduced using mitochondrial electron transport chain inhibitors. We identified two distinct MEP populations based on the mitochondrial content: mitochondria-rich MEPs favored erythroid differentiation, while the mitochondria-poor MEPs favored megakaryocyte differentiation. These findings reveal critical contributions of mitochondria to the MEP lineage selection, acting as a "mitochondrial navigation" for lineage commitment.
    Keywords:  CARS2; MEP; differentiation; erythropoesis; megakaryocyte; megakaryocyte-erythroid progenitor; mitochondria; mouse; persulfide; sulfur metabolism
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102720
  43. Cell Death Dis. 2025 Nov 21.
    Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.
    Evan Woo, Faiza Tasnim, Hibiki Kawamata, Giovanni Manfredi, Csaba Konrad.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons, leading to fatal muscle paralysis. Familial forms of ALS (fALS) account for approximately 10% of cases. Alterations of mitochondrial functions have been proposed to contribute to disease pathogenesis. Here, we employed a direct conversion (DC) technique to generate induced motor neurons (iMN) from skin fibroblasts to investigate mitochondrial phenotypes in a patient-derived disease relevant cell culture system. We converted 7 control fibroblast lines and 17 lines harboring the following fALS mutations, SOD1A4V, TDP-43N352S, FUSR521G, CHCHD10R15L, and C9orf72 repeat expansion. We developed new machine learning approaches to identify iMN, analyze their mitochondrial function, and follow their fate longitudinally. Mitochondrial and energetic abnormalities were observed, but not all fALS iMN lines exhibited the same alterations. SOD1A4V, C9orf72, and TDP-43N352S iMN had increased mitochondrial membrane potential, while in CHCHD10R15L cells membrane potential was decreased. TDP-43N352S iMN displayed changes in mitochondrial morphology and increased motility. SOD1A4V, TDP-43N352S, and CHCHD10R15L iMN had increased oxygen consumption rates and altered extracellular acidification rates. FUSR521G mutants had decreased ATP/ADP ratio, suggesting impaired energy metabolism. SOD1A4V, C9orf72, and TDP-43N352S had increased, while FUSR521G had decreased mitochondrial reactive oxygen species production. We tested the viability of iMN and found decreases in survival in SOD1A4V, C9orf72, and FUSR521G, which were corrected by small molecules that target mitochondrial stress and worsened by bioenergetic stressors. Together, our findings reinforce the role of mitochondrial dysfunction in ALS and indicate that fibroblast-derived iMN may be useful to study fALS metabolic alterations. Strengths of the DC iMN approach include low cost, speed of transformation, and the preservation of epigenetic modifications. However, further refinement of the fibroblasts DC iMN technique is still needed to improve transformation efficiency, reproducibility, the relatively short lifespan of iMN, and the senescence of the parental fibroblasts.
    DOI:  https://doi.org/10.1038/s41419-025-08126-6
  44. J Patient Exp. 2025 ;12 23743735251400013
    In Their Own Words: Creating Connections Through Narrative Medicine.
    Sneha Mantri, Lissa Kapust, Jillian Goober, David K Simon.
      People with Parkinson's disease (PwP) often report feeling unheard or hurried through clinical visits, without the opportunity to share their unique illness story. Simultaneously, clinicians report increasing dissatisfaction with efficiency pressures that disincentivize active listening and patient-centered communication. This research brief outlines a guided short-form journaling activity, the 55-word story, for PwP to share their stories in a format that can be received by busy clinicians. Three cohorts of 10 to 13 PwP completed the program, with virtual meetings over four consecutive weeks, led by a facilitator trained in both narrative medicine and movement disorders. By the end of each cohort, nearly all (31/35 participants, 88.6%) reported an improved relationship with their neurologist, communication skills, clarity about goals and values, and/or increased community with other PwP. Further, 32/35 (91.4%) reported an intention to share their 55-word story with health providers, friends, or family. An online guided journaling activity was feasible, enjoyable, and successful at improving the well-being of PwP. This model can be used at other institutions or with other chronic illnesses.
    Keywords:  clinician–patient relationship; communication; community engagement; patient engagement; patient experience; patient/relationship-centered
    DOI:  https://doi.org/10.1177/23743735251400013
  45. Hum Genome Var. 2025 Nov 21. 12(1): 26
    Fontaine progeroid syndrome with neonatal mitochondrial disease.
    Mitsuhiko Riko, Daiki Kawamoto, Kentaro Hirayama, Tomoya Tsuchihashi, Takayuki Suzuki, Takuya Sugimoto, Yasushi Okazaki, Kei Murayama, Daisuke Tokuhara.
      Fontaine progeroid syndrome (FPS) is a rare condition characterized by abnormalities in SLC25A24. Some instances of FPS have been reported to be fatal early in life. Here we present the first case of mitochondrial disease diagnosed with FPS in Japan. The diagnosis was based on the presence of the heterozygous known pathogenic variant of SLC25A24, NM_013386.5: c.649C>T and decreased activity of mitochondrial respiratory chain enzyme activity.
    DOI:  https://doi.org/10.1038/s41439-025-00331-1
  46. J Neuroinflammation. 2025 Nov 19. 22(1): 275
    Imaging brain inflammation and blood brain barrier permeability in neurological and psychiatric diseases: a review.
    Zanetta Kovbasyuk, Eden Tefera, Chenyang Li, Steven H Baete, Claude Steriade.
      Neuroinflammation involving glial cell activation and BBB dysfunction has increasingly been recognized as a key feature of neuropsychiatric disorders. In vivo imaging methods, particularly translocator protein positron emission tomography (TSPO-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), have advanced our understanding of glial activation and BBB permeability in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's disease, schizophrenia, and depression. We present key findings from the clinical application of these imaging modalities and highlight critical methodological challenges-including variability in study protocols, tracer selection, input function derivation, and parameter estimation-that currently limit cross-study comparability and clinical translation. TSPO-PET and DCE-MRI provide valuable clinical insights on the inflammatory mechanisms contributing to CNS disease at various disease stages. Future methodological standardization, co-localization studies, and longitudinal multi-modal applications will be crucial for using these tools as markers of disease in the context of immune interventions in at-risk populations.
    DOI:  https://doi.org/10.1186/s12974-025-03598-x
  47. Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2505046122
    Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.
    Firoz Akhter, Asma Akhter, Xiongwei Zhu, Hillary Schiff, Arianna Maffei, Justin T Douglas, Qifa Zhou, Zhen Zhao, Donghui Zhu.
      Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer's-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.
    Keywords:  Alzheimer’s disease; glycated amyloid-beta; innate immunity; mitochondrial DNA
    DOI:  https://doi.org/10.1073/pnas.2505046122
  48. Clin Med (Lond). 2025 Nov 19. pii: S1470-2118(25)00253-2. [Epub ahead of print] 100535
    Rare but relevant: genetic liver disease in the general medical setting.
    Sammi Allounia, Aftab Alab.
      Genetic liver diseases are individually rare but collectively significant causes of chronic liver dysfunction in adults. Conditions such as Wilson disease (WD), hereditary haemochromatosis (HC), and alpha-1 antitrypsin deficiency (A1ATD) often present with vague or non-specific features, including fatigue, abnormal liver enzymes, or extrahepatic manifestations. These features are easily misattributed to more common hepatic or systemic conditions, particularly in acute or general medical settings. Early recognition and investigation are crucial, as targeted treatments can prevent progression to end-stage liver disease, and timely referral enables cascade testing for at-risk relatives. With increasing access to genomic testing through systems such as the NHS Genomic Medicine Service (GMS) in England, generalists play a key role in integrating genomics into routine care. This article provides a practical update on recognising, investigating, and managing rare genetic liver conditions, aiming to support earlier diagnosis, better patient outcomes, and improved use of genomic services in frontline practice.
    Keywords:  Alpha-1 antitrypsin deficiency; Genetic liver disease; Genomic medicine; Hereditary hemochromatosis; Wilson disease
    DOI:  https://doi.org/10.1016/j.clinme.2025.100535
  49. Turk J Biol. 2025 ;49(5): 635-659
    Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.
    Teslime Özge Şahin, Özge Cemali, Merve Özdemir, Şerife Ayten, Duygu Ağagündüz.
       Background/aim: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.
    Materials and methods: A literature search of the Web of Science, PubMed, and ScienceDirect databases was conducted to evaluate the therapeutic potential of flavonoids and phenolic compounds against neurodegenerative diseases. The search terms included "polyphenols", "flavonoids", and related compounds, along with "Alzheimer's", "Parkinson's", "Huntington's", and "Amyotrophic lateral sclerosis". Eligible studies included clinical trials, randomized controlled trials, and in vitro and in vivo research published in English. Priority was given to studies from the last decade, although older but significant publications were also included.
    Results: The findings of multiple studies report the ability of flavonoid compounds such as quercetin, myricetin, apigenin, and epigallocatechin gallate (EGCG) to modulate critical signaling pathways, reduce oxidative stress, prevent the accumulation of neurotoxic proteins, and support mitochondrial function. These bioactive molecules have exhibited significant potential in slowing disease progression and preserving neuronal integrity. Their therapeutic application, however, has been limited by their poor bioavailability, low stability, and rapid metabolism.
    Conclusion: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.
    Keywords:  Antioxidants; neuroinflammation; neuroprotection; phytotherapy
    DOI:  https://doi.org/10.55730/1300-0152.2767
  50. Acta Physiol (Oxf). 2025 Dec;241(12): e70135
    A 12-Week Strength Training Improves Mitochondrial Respiration, H2O2 Emission and Skeletal Muscle Integrity in Women With Myotonic Dystrophy Type 1.
    Vincent Marcangeli, Laura Girard-Côté, Valeria Di Leo, Marie-Pier Roussel, Conor Lawless, Olivier Charest, Anteneh Argaw, Maude Dulac, Guy Hajj-Boutros, José A Morais, Amy Vincent, Gilles Gouspillou, Jean-Philippe Leduc-Gaudet, Elise Duchesne.
       BACKGROUND: Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK gene, causing the accumulation of toxic RNA that sequesters RNA-binding proteins. Clinically, DM1 is characterized by progressive muscle weakness and atrophy, resulting in reduced physical capacity and quality of life. Recent evidence implicates mitochondrial dysfunction in DM1 pathophysiology. While aerobic exercise has been shown to improve skeletal muscle and mitochondrial health in individuals with DM1, the benefits of strength training remain unexplored.
    OBJECTIVES: We investigated the effects of a 12-week strength training program on mitochondrial respiration, reactive oxygen species (ROS) production and muscle integrity in women with DM1.
    METHODS: Vastus lateralis muscle biopsies were collected pre- and post-training in participants with DM1 and once in unaffected/untrained individuals. Mitochondrial respiration and hydrogen peroxide emission (marker of ROS production) were assessed in permeabilized myofibers, while OXPHOS protein contents were quantified by immunoblotting and immunofluorescence. Markers of myofiber denervation (NCAM+) and integrity (centrally located myonuclei, damaged laminin, nuclear clumps) were assessed on histological sections.
    RESULTS: At baseline, DM1 participants exhibited lower mitochondrial respiration compared to unaffected individuals. Strength training significantly improved mitochondrial respiration and content in DM1 participants. At baseline, absolute ROS production was lower, while ROS production normalized to oxygen consumption (free radical leak) was higher, in DM1. Histological signs of denervation and altered muscle integrity were observed. Strength training partially normalized mitochondrial free radical leak and restored some markers of myofiber integrity.
    CONCLUSION: Collectively, our results indicate that strength training enhances mitochondrial health and improves myofiber integrity in women with DM1.
    Keywords:  ROS; exercise; mitochondria; mitochondrial function; mitochondrial respiration; myotonic dystrophy; neuromuscular disease; oxidative phosphorylation defects; resistance training
    DOI:  https://doi.org/10.1111/apha.70135
  51. Curr Top Membr. 2025 ;pii: S1063-5823(25)00033-X. [Epub ahead of print]96 277-315
    Quantification and characterization of extracellular vesicles by flow cytometry.
    Ekaterina Petrovich-Kopitman, Joshua A Welsh, Shimrit Adutler-Lieber, Avraham Dayan, Ziv Porat.
      Extracellular vesicles (EVs) are nano-sized, membrane-surrounded vesicles released by cells under both physiological and pathological conditions. Due to their small size and heterogeneity, comprehensive characterization of EVs remains technically challenging. Among the various analytical tools developed, flow cytometry stands out as a highly versatile and scalable platform, offering high-throughput analysis, multiparametric phenotyping, and quantitative detection. However, conventional flow cytometers are typically designed for cell-sized particles (0.5-40 µm) and require specific optimizations to reliably detect and analyze EVs, which are significantly smaller and result in weaker signals. These optimizations include instrument settings, sample handling and labelling strategies as well as acquisition protocols. Robust calibration and the use of appropriate controls are essential to ensure data accuracy and reproducibility across platforms. In this chapter, we outline the principles, technical considerations, and advantages of applying flow cytometry and imaging flow cytometry to EV research. We also highlight representative applications in both scientific and clinical contexts and discuss future directions for the field.
    Keywords:  Cell sorting; Extracellular vesicles; Flow cytometry; Imaging flow cytometry
    DOI:  https://doi.org/10.1016/bs.ctm.2025.09.002
  52. Drug Discov Ther. 2025 Nov 20.
    Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval.
    Chenru Zhao, Xuemei Zhuang, Jianjun Gao.
      Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by tafazzin mutations that impair cardiolipin remodeling, leading to mitochondrial dysfunction and symptoms such as cardiomyopathy, myopathy, and neutropenia. On September 19, 2025, the U.S. Food and Drug Administration (FDA) granted accelerated approval to elamipretide, the first therapy directly targeting the mitochondrial etiology of BTHS. Elamipretide binds to cardiolipin on the inner mitochondrial membrane, stabilizing respiratory chain supercomplexes, enhancing electron transport efficiency, and reducing reactive oxygen species production. In a randomized, double-blind, placebo-controlled, crossover trial, elamipretide resulted in no significant improvement in the 6-minute walk test or fatigue scores; however, sustained benefits were observed during a 168-week open-label extension. The most common adverse events were mild injection-site reactions. As a condition of accelerated approval, a confirmatory trial is required. Elamipretide represents a promising therapy addressing an unmet medical need in BTHS and provides a foundation for future mitochondria-targeted treatments.
    Keywords:  Barth syndrome; X-linked mitochondrial disorder; elamipretide; mitochondria-targeted therapeutic drugs
    DOI:  https://doi.org/10.5582/ddt.2025.01111
  53. Front Immunol. 2025 ;16 1646138
    Mitochondria-targeted strategies in tumor immunity.
    Xudong Cheng, Yian Wang, Bryon Johnson, Ming You.
      Mitochondria, as regulators of cellular energy production and metabolism, play a crucial role in tumor growth and survival. Tumors are reprogrammed to accommodate rapid proliferation through the Warburg effect. This reprogramming leads to the accumulation of metabolites such as lactate and ketone bodies, thereby lowering the pH of the tumor microenvironment, inhibiting the activity of effector T cells and NK cells, while promoting the infiltration of regulatory T cells and MDSCs, forming an immunosuppressive microenvironment. ROS produced by mitochondria can affect immune cell function by modulating their signaling pathways. Mitochondria also release DAMPs, which activate the antigen-presenting capacity of dendritic cells and initiate anti-tumor immune responses. Currently, various methods have been employed, such as DLCs modifications and mitochondrial targeted delivery, which enable drugs to penetrate the lipid bilayer and enter the mitochondria, thereby helping to reduce immunosuppression in the tumor microenvironment. In this review, we will discuss the impact of mitochondria on tumor immunity, strategies to target tumor cell mitochondria, and progress on the discovery of mitochondria-targeted drugs to enhance tumor immunity, providing potential directions for developing new cancer therapeutic strategies.
    Keywords:  TME; cancer; immunotherapy; mitochondria targeted; triphenylphosphonium
    DOI:  https://doi.org/10.3389/fimmu.2025.1646138
  54. Open Forum Infect Dis. 2025 Nov;12(11): ofaf447
    Digitally Assessed Long COVID Symptomatology Is Associated With Lymphocyte Mitochondrial Dysfunction and Altered Immune Potential.
    Vasile Mihai Sularea, Liam Townsend, Cian Reid, Andreea V Atanasescu, Adam H Dyer, Federica Giangrazi, Roman Rocha Lawrence, Manoj Sivan, Barry Moran, Derek G Doherty, Niall P Conlon, Aideen Long, Cliona O'Farrelly.
       Background: Postacute sequelae of SARS-CoV-2 infection, also known as long COVID (LC), is a complex and heterogenous condition affecting millions worldwide with a poorly understood underlying pathology. Although metabolic dysregulations have been described in LC, it remains unclear whether circulating immune cells exhibit immunometabolic alterations.
    Methods: We conducted a detailed clinical, immunologic, and mitochondrial analysis on 27 patients with LC and 27 who recovered from COVID-19 and were healthy. Symptom burden and severity were assessed and quantified via a digital platform with the modified COVID-19 Yorkshire Rehabilitation Scale. Mitochondrial function of circulating immune cell populations (lymphocytes and monocytes) was analyzed by measuring mitochondrial mass and mitochondrial membrane potential. Production of 11 cytokines after whole blood stimulation with bacterial and viral agonists was measured by multiplex immunoassay. Relationships between mitochondrial and immune parameters with LC symptoms were investigated.
    Results: Patients with LC exhibited significant symptom burden, with worsening across all symptom domains as compared with their health state before SARS-CoV-2 infection. They also had a decreased mitochondrial membrane potential of CD56bright natural killer cells, particularly in patients experiencing dizziness, whereas reduced mitochondrial membrane potential in CD4+ lymphocytes was found in patients with worsening breathlessness. Upon LPS stimulation, patients with LC demonstrated significantly lower IFN-γ production. In response to viral ligand R848, impaired IFN-β and IL-10 responses were associated with worsening cough and executive functions.
    Conclusions: Symptom severity in LC is associated with immune cell mitochondrial dysfunction and altered cytokine responses, highlighting potential disease biomarkers and targets for future therapeutic strategies.
    Keywords:  Immunometabolism; Long COVID; Lymphocyte; Mitochondria; Natural Killer cell
    DOI:  https://doi.org/10.1093/ofid/ofaf447
  55. J Neurochem. 2025 Nov;169(11): e70282
    Across Barriers: Blood-Brain and Gut Barrier Signaling in Psychiatric Disorders.
    Luisa Bandeira Binder, Laura Menegatti Bevilacqua, Flora Gro Lorentzen Thomassen, Manon Lebel, Benjamin A H Jensen, Caroline Menard.
      Psychiatric disorders affect millions of people worldwide. Despite widespread use of conventional treatments targeting monoaminergic systems, remission rates remain low, and many individuals experience treatment resistance or relapse. Consequently, there has been growing interest in the involvement of other systems, with exacerbated immune responses and barrier alterations reported in clinical settings and preclinical models. Indeed, emerging evidence supports disruption of the blood-brain barrier (BBB) and intestinal barrier in the etiology and progression of psychiatric conditions, notably major depression, bipolar disorder, and generalized anxiety. The BBB is a highly selective structure whose integrity is maintained by endothelial cells, astrocytes, pericytes, and cellular adhesion molecules. Loss of BBB integrity has been increasingly recognized not only as a marker of psychiatric disorders but also as a contributing factor in their development. The BBB and intestinal barrier share anatomical features and functions, especially with the gut-vascular barrier, which remains understudied. Intestinal barrier dysfunction is a hallmark of inflammatory bowel disease (IBD), a condition with a high rate of comorbidity with psychiatric disorders. Both barriers are characterized by similar cellular components and signaling pathways regulating permeability. Psychological stress, a major risk factor for psychiatric conditions and IBD, renders the BBB and intestinal barrier hyperpermeable, feeding a vicious cycle of exacerbated inflammation and ultimately, mood changes as discussed here. We highlight key signaling pathways linked to barrier development and function, including Wnt/β-catenin, VEGF, and FGF-2, and argue that they may contribute to the pathophysiology of mental disorders and IBD, and could be targeted to develop innovative diagnostic tools and treatments. Key limitations and knowledge gaps are reviewed. To sum up, barrier-related alterations have long been reported in clinical studies in psychiatry and are now receiving increasing attention at the mechanistic level, as they may be relevant to uncovering new therapeutic targets beyond traditional monoamine-focused treatments.
    Keywords:  anxiety; blood–brain barrier; depression; gut–brain axis; gut–vascular barrier; stress
    DOI:  https://doi.org/10.1111/jnc.70282
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