bims-polgdi Biomed News
on POLG disease
Issue of 2025–05–25
28 papers selected by
Luca Bolliger, lxBio



  1. J Transl Med. 2025 May 21. 23(1): 568
      With the discovery of intercellular mitochondrial transfer, the intricate mitochondrial regulatory networks on stem cell fate have aroused intense academic interest. Apart from capturing freely released mitochondria from donor cells, stem cells are able to receive mitochondria through tunneling nanotubes (TNTs), gap junctional channels (GJCs) and extracellular vesicles (EVs), especially when undergoing stressful conditions such as inflammation, hypoxia, chemotherapy drug exposure, and irradiation. Stem cells that are potentiated by exogenous mitochondria show enhanced potential for proliferation, differentiation, and immunomodulation. The well-tolerated nature of either autogenous or allogenous mitochondria when locally injected in the human ischemic heart has validated the safety and therapeutic potential of mitochondrial transplantation. In children diagnosed with mitochondrial DNA deletion syndrome, functional improvements have been observed when empowering their hematopoietic stem cells with maternally derived mitochondria. Apart from the widely investigated applications of mitochondrial transfer in ischemia-reperfusion injury, neurodegenerative diseases and mitochondrial diseases etc., therapeutic potentials of mitochondrial transfer in tissue repair and regeneration are equally noteworthy, though there has been no systematic summary in this regard.This review analyzed the research and development trends of mitochondrial transfer in stem cells and regenerative medicine over the past decade from a bibliometric perspective, introduced the concept and associated mechanisms of mitochondrial transfer, summarized the regulations of intercellular mitochondrial transfer on stem cell fate. Finally, the therapeutic application of mitochondrial transplantation in diseases and tissue regeneration has been reviewed, including recent clinical studies related to mitochondrial transplantation.Mitochondrial transfer shows promise in modifying and reshaping the cellular properties of stem cells, making them more conducive to regeneration. Mesenchymal stem cells (MSCs)-derived mitochondria have shown multifaceted potential in promoting the revitalization and regeneration of cardiac, cutaneous, muscular, neuronal tissue. This review integrates novel research findings on mitochondrial transfer in stem cell biology and regenerative medicine, emphasizing the crucial translational value of mitochondrial transfer in regeneration. It serves to underscore the significant impact of mitochondrial transfer and provides a valuable reference for further exploration in this field.
    Keywords:  Mitochondrial therapeutics; Mitochondrial transfer; Regenerative medicine; Stem cell fate; Tissue repair
    DOI:  https://doi.org/10.1186/s12967-025-06472-9
  2. Mol Biol Rep. 2025 May 20. 52(1): 470
      Epilepsy is a common neurological disorder that is increasingly recognized for its significant association with mitochondrial dysfunction. This review explores the intricate relationship between mitochondrial dysfunction and epilepsy, highlighting the molecular mechanisms, diagnostic strategies, and therapeutic approaches involved. Mitochondrial abnormalities, including defects in the electron transport chain, impaired mitochondrial dynamics, disrupted autophagy, and increased oxidative stress, are implicated in epilepsy pathogenesis. The molecular mechanisms involve respiratory chain impairments, fission-fusion imbalances, inadequate mitophagy, and oxidative stress-induced neuronal excitability. The diagnosis of mitochondrial epilepsy requires a multifaceted approach, combining clinical assessment, biochemical testing, imaging, and genetic analysis, with a particular focus on mtDNA mutations. Therapeutic strategies include antiepileptic drugs with variable mitochondrial effects, the ketogenic diet, and emerging potential approaches such as antioxidants and mitochondrial-targeted therapies. Despite advances in understanding and treatment, challenges persist due to the complexity of mtDNA mutations and treatment resistance. Future directions involve gene-editing technologies, mitochondrial transplantation, and induced pluripotent stem cells, which hold promise for addressing the underlying defects and improving epilepsy management.
    Keywords:  Epilepsy; Ketogenic diet; Mitochondria; Mutation; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-025-10577-1
  3. Curr Osteoporos Rep. 2025 May 22. 23(1): 22
       PURPOSE OF REVIEW: Mechanical loading of bone is an important physical stimulus for bone tissue remodeling and adaptation. It is transmitted from the extracellular matrix all the way to the osteocyte nucleus via the extracellular matrix-integrin-cytoskeleton-nucleus system. Mitochondria are integral in sensing of mechanical loads to allow the cell to adapt to its environment. This review provides a background of mitochondrial distribution in osteocytes especially during mechanical loading, discussing the importance of mitochondrial distribution in osteocyte mechanosensitivity and mechanotransduction.
    RECENT FINDINGS: Mitochondria throughout the osteocyte are highly dynamic and provide essential metabolic and signal functions to regulate osteocyte morphology and function. They undergo the processes of fission and fusion accompanied by mitochondrial DNA distribution. The mitochondrial network structure and function in osteocytes can be regulated by mechanical loading. Interestingly, mitochondria can be transmitted by osteocytes into adjacent cells to communicate with them via tunneling nanotubes, migrasomes, and blebbisomes, causing changes in cell morphology and/or function. Mitochondrial distribution in or out osteocytes can be rearranged by physical and (bio)chemical signals via fission and fusion, as well as tunneling nanotubes, migrasomes, and blebbisomes. Mechanical loading-induced changes in mitochondria may drive signaling pathways of cell function in aging and diseases. More insights into interactions between neighbouring osteocytes and between osteocytes and other cell types would facilitate the development of new strategies to apply mitochondrial therapy for bone-related diseases.
    Keywords:  Cell communication; Mechanical loading; Mechanotransduction; Mitochondria; Mitochondrial distribution; Osteocytes
    DOI:  https://doi.org/10.1007/s11914-025-00918-1
  4. Open Biol. 2025 May;15(5): 240331
      Understanding and treating disease depend upon our knowledge of how the body works. The biomedical approach to disease describes health purely in terms of biological factors, with a focus on the genome as the molecular basis for cellular function and dysfunction in disease. However, the eukaryotic cell has evolved as a partnership between prokaryotic cells with mitochondria being crucial to this relationship. Aside from their role as bioenergetic and biosynthetic hubs, mitochondria are also involved in cell signalling and cell fate pathways, playing a multifaceted role in cell function and health. Crucially, mitochondria are implicated in most diseases. Perhaps then, visualizing biomedical function on the backdrop of endosymbiosis may provide another viewpoint for explaining and treating disease.
    Keywords:  endosymbiosis; eukaryotic cell; genome; human disease; mitochondria
    DOI:  https://doi.org/10.1098/rsob.240331
  5. Nat Commun. 2025 May 23. 16(1): 4782
      DNA polymerase γ (POLγ), responsible for mitochondrial DNA replication, consists of a catalytic POLγA subunit and two accessory POLγB subunits. Mutations in POLG, which encodes POLγA, lead to various mitochondrial diseases. We investigated the most common POLG mutations (A467T, W748S, G848S, Y955C) by characterizing human and mouse POLγ variants. Our data reveal that these mutations significantly impair POLγ activities, with mouse variants exhibiting milder defects. Cryogenic electron microscopy highlighted structural differences between human and mouse POLγ, particularly in the POLγB subunit, which may explain the higher activity of mouse POLγ and the reduced severity of mutations in mice. We further generated a panel of mouse models mirroring common human POLG mutations, providing crucial insights into the pathogenesis of POLG-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POLγB in modulating the severity of POLG mutations.
    DOI:  https://doi.org/10.1038/s41467-025-60059-y
  6. Metabolism. 2025 May 17. pii: S0026-0495(25)00169-6. [Epub ahead of print]170 156300
      Cellular metabolism has a key role in the pathogenesis of human disease. Mitochondria are the organelles that generate most of the energy needed for a cell to function and drive cellular metabolism. Understanding the link between metabolic and mitochondrial function can be challenging due to the variation in methods used to measure mitochondrial function and heterogeneity in mitochondria, cells, tissues, and end organs. Mitochondrial dysfunction can be determined at both the cellular and tissue levels using several methods, such as assessment of cellular bioenergetics, levels of mitochondrial DNA (mtDNA), mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mito-ROS), and levels of mitochondrial enzymes. Recent advances involving novel radiotracers in combination with PET imaging have allowed for the determination of mitochondrial function in vivo with high specificity. Understanding the barriers in existing methodologies used to study mitochondrial function may help further establish the assessment of mitochondrial function as a biologically and clinically relevant biomarker for human disease severity and prognosis. Herein, we critically review the existing literature regarding the strengths and limitations of methods that determine mitochondrial function, and we subsequently discuss how emerging research methods have begun to overcome some of these hurdles. We conclude that a combination of techniques, including respirometry and mitochondrial membrane potential assessment, is necessary to understand the complexity and biological and clinical relevance of mitochondrial function in human disease.
    Keywords:  Biomarkers; Human disease; Metabolism; Mitochondria; Mitrochondrial function
    DOI:  https://doi.org/10.1016/j.metabol.2025.156300
  7. Mol Biol Rep. 2025 May 21. 52(1): 479
      The COVID-19 pandemic, caused by SARS-CoV-2, posed a tremendous challenge to healthcare systems globally. Severe COVID-19 infection was reported to be associated with altered immunometabolism and cytokine storms, contributing to poor clinical outcomes and in many cases resulting in mortality. Despite promising preclinical results, many drugs have failed to show efficacy in clinical trials, highlighting the need for novel approaches to combat the virus and its severe manifestations. Mitochondria, crucial for aerobic respiration, play a pivotal role in modulating immunometabolism and neuronal function, making their compromised capability as central pathological mechanism contributing to the development of neurological complications in COVID-19. Dysregulated mitochondrial dynamics can lead to uncontrolled immune responses, underscoring the importance of mitochondrial regulation in shaping clinical outcomes. Aging further accelerates mitochondrial dysfunction, compounding immune dysregulation and neurodegeneration, making older adults particularly vulnerable to severe COVID-19 and its neurological sequelae. COVID-19 infection impairs mitochondrial oxidative phosphorylation, contributing to the long-term neurological complications associated with the disease. Additionally, recent reports also suggest that up to 30% of COVID-19 patients experience lingering neurological issues, thereby highlighting the critical need for further research into mitochondrial pathways to mitigate long-tern neurological consequences of Covid-19. This review examines the role of mitochondrial dysfunction in COVID-19-induced neurological complications, its connection to aging, and potential biomarkers for clinical diagnostics. It also discusses therapeutic strategies aimed at maintaining mitochondrial integrity to improve COVID-19 outcomes.
    Keywords:  Aging; Biomarkers; COVID-19; Mitochondrial dynamics; Mitochondrial dysfunction; Neurological symptoms
    DOI:  https://doi.org/10.1007/s11033-025-10586-0
  8. Nat Commun. 2025 May 20. 16(1): 4640
      Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.
    DOI:  https://doi.org/10.1038/s41467-025-59907-8
  9. Cell Commun Signal. 2025 May 20. 23(1): 232
      Mitochondria are traditionally known as the cells' powerhouses; however, their roles go far beyond energy suppliers. They are involved in intracellular signaling and thus play a crucial role in shaping cells' destiny and functionality, including immune cells. Mitochondria can be actively exchanged between immune and non-immune cells via mechanisms such as nanotubes and extracellular vesicles. The mitochondria transfer from immune cells to different cells is associated with physiological and pathological processes, including inflammatory disorders, cardiovascular diseases, diabetes, and cancer. On the other hand, mitochondrial transfer from mesenchymal stem cells, bone marrow-derived stem cells, and adipocytes to immune cells significantly affects their functions. Mitochondrial transfer can prevent exhaustion/senescence in immune cells through intracellular signaling pathways and metabolic reprogramming. Thus, it is emerging as a promising therapeutic strategy for immune system diseases, especially those involving inflammation and autoimmune components. Transferring healthy mitochondria into damaged or dysfunctional cells can restore mitochondrial function, which is crucial for cellular energy production, immune regulation, and inflammation control. Also, mitochondrial transfer may enhance the potential of current therapeutic immune cell-based therapies such as CAR-T cell therapy.
    Keywords:  Immune system; Immunometabolism; Immunotherapy; Mitochondria; Mitochondria Transfer; Organelle therapy
    DOI:  https://doi.org/10.1186/s12964-025-02237-5
  10. Cell. 2025 May 15. pii: S0092-8674(25)00296-X. [Epub ahead of print]188(10): 2561-2566
      Human DNA is unavoidably present in metagenomic analyses of human microbiomes. While current protocols remove human DNA before submission to public repositories, mitochondrial DNA (mtDNA) has been overlooked and frequently persists. We discuss the privacy risks and research opportunities associated with mtDNA, urging consideration by the scientific, ethics, and legal communities.
    DOI:  https://doi.org/10.1016/j.cell.2025.03.023
  11. CNS Neurosci Ther. 2025 May;31(5): e70378
       BACKGROUND: Neurodegenerative diseases pose significant health challenges in the 21st century, with increasing morbidity and mortality, particularly among the elderly population. One of the key factors contributing to the pathogenesis of these diseases is the disrupted crosstalk between mitochondria and the endoplasmic reticulum. Mitochondria-associated membranes (MAMs), which are regions where the ER interfaces with mitochondria, serve as crucial platforms facilitating communication between these organelles.
    OBJECTIVES: This review focuses on the structural composition and functions of MAMs and highlights their roles. Additionally, in this review, we summarize the relationship between MAM dysfunction and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and others. The involvement of key proteins such as Sig-1R, IP3R, and VAPB in maintaining ER-mitochondrial communication and their dysfunction in neurodegenerative diseases is emphasized.
    CONCLUSION: Through analyzing the effects of MAM on neurodegenerative diseases, we provide the newest insights and potential therapeutic targets for the treatment of these debilitating conditions.
    Keywords:  Alzheimers' disease; Ca2+ homeostasis; IP3R; Parkinson's disease; Sig‐1R; VAPB; mitochondria‐associated membranes; neurodegenerative disease
    DOI:  https://doi.org/10.1111/cns.70378
  12. Adv Sci (Weinh). 2025 May 23. e01612
      The aberrant cellular senescence in chronic wounds presents a significant barrier to healing. Mitochondrial dysfunction is critical in initiating and maintaining cellular senescence, underscoring therapeutic potential in restoring mitochondrial function by delivering healthy mitochondria to wound cells. However, approaches for delivering mitochondria to achieve optimized wound repair remain lacking. Herein, enucleated MSCs-derived microvesicles containing functional mitochondria (Mito@euMVs) via simple extrusion are developed. By controlling the size of microvesicles within a small micron-scale range, the mitochondrial encapsulation efficiency is optimized. Mito@euMVs effectively delivered mitochondria into fibroblasts and HUVECs, inhibiting and rejuvenating hyperglycemia-induced cellular senescence. To enhance the clinical applicability, soluble PVA microneedle patches for the transdermal Mito@euMVs delivery are utilized. In diabetic rats with pressure sores, the senescence-inhibiting and -rescuing properties of Mito@euMVs are further validated, along with their therapeutic efficacy, demonstrating their potential for chronic wound repair. Moreover, as a versatile delivery vehicle for mitochondria, Mito@euMVs hold promising for treating mitochondrial dysfunction and aging-related conditions.
    Keywords:  cellular senescence; diabetic pressure sore; enucleated mesenchymal stem cells; mitochondrial transfer
    DOI:  https://doi.org/10.1002/advs.202501612
  13. Seizure. 2025 May 10. pii: S1059-1311(25)00121-9. [Epub ahead of print]
      Epilepsy is a common and severe neurological manifestation of primary mitochondrial disease, affecting approximately 60 % of paediatric patients and 20 % of adult patients. Many of the mitochondrial epilepsies, particularly those presenting in childhood, are refractory to anti-epileptic treatment. Moreover, these conditions are typically characterised by severe neurodegeneration and closely associated with neurological decline and premature death. Indeed, there persists an urgent need to delineate the mechanisms underpinning mitochondrial epilepsy in order to develop effective treatments. In this review, we provide an overview of currently available in vitro models of the mitochondrial epilepsies. Such models offer opportunities to characterise early disease pathophysiology and interrogate novel mitochondrial-targeting and anti-epileptic treatments, with an overall aim to modulate seizure associated pathology and activity for the mitochondrial epilepsies. We discuss the use of acute cortical and subcortical brain slice preparations, obtained from both neurosurgical patients and rodents, for modelling the common neuropathophysiological features of mitochondrial epilepsy. We also review the use of induced pluripotent stem cell derived neural and glial culture models, and the development of three-dimensional cerebral organoids, generated from fibroblasts obtained from patients with primary mitochondrial disease. Human-derived, disease-relevant in vitro model systems which recapitulate the complexity and pathological features observed in patient brain tissues are crucial to help bridge the gap between animal models and patients living with mitochondrial epilepsy.
    Keywords:  Alpers’ syndrome; MELAS; MERRF; Oxidative phosphorylation (OXPHOS); POLG; mtDNA
    DOI:  https://doi.org/10.1016/j.seizure.2025.05.005
  14. Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710
      The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.
    Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115710
  15. Front Cell Dev Biol. 2025 ;13 1593207
      The ability to reprogram mature, differentiated cells into induced pluripotent stem cells (iPSCs) using exogenous pluripotency factors opened up unprecedented opportunities for their application in biomedicine. iPSCs are already successfully used in cell and regenerative therapy, as various drug discovery platforms and for in vitro disease modeling. However, even though already 20 years have passed since their discovery, the production of iPSC-based therapies is still associated with a number of hurdles due to low reprogramming efficiency, the complexity of accurate characterization of the resulting colonies, and the concerns associated with the safety of this approach. However, significant progress in many areas of molecular biology facilitated the production, characterization, and thorough assessment of the safety profile of iPSCs. The number of iPSC-based studies has been steadily increasing in recent years, leading to the accumulation of significant knowledge in this area. In this review, we aimed to provide a comprehensive analysis of methods used for reprogramming and subsequent characterization of iPSCs, discussed barriers towards achieving these goals, and various approaches to improve the efficiency of reprogramming of different cell populations. In addition, we focused on the analysis of iPSC application in preclinical and clinical studies. The accumulated breadth of data helps to draw conclusions about the future of this technology in biomedicine.
    Keywords:  cell reprogramming; cell therapy; iPSC; in vitro disease modeling; induced pluripotent stem cells; regenerative medicine; transcription factors; viral delivery
    DOI:  https://doi.org/10.3389/fcell.2025.1593207
  16. Cold Spring Harb Perspect Biol. 2025 May 19. pii: a041849. [Epub ahead of print]
      Mitochondria are the masters of evolutionary tinkering, which can be exemplified by both the remarkable variability of the mitochondrial genome architectures and numerous noncanonical features involved in the mitochondrial gene expression. Evolutionary experimentation in these living test tubes is facilitated by their polyploid nature and resulted in a number of surprising oddities identified in various eukaryotic lineages. Excellent examples of these peculiarities are provided by mitochondrial genetic systems of unicellular fungi classified as the budding yeasts. Perhaps the most perplexing eccentricity found in yeast mitochondria are the bypassing elements (byps) residing in the reading frames of protein-coding genes. Ribosomes ignore byps during translation by means of programmed translational bypassing. Massive occurrence of these coding gaps in certain yeast species raises the questions on their evolutionary origin and mobility as well as the molecular mechanism of translational bypassing.
    DOI:  https://doi.org/10.1101/cshperspect.a041849
  17. Oncol Rev. 2025 ;19 1567860
      Mitochondrial "powerhouses" play a central function in cellular metabolism and energy generation. Their dysregulation is directly correlated with a myriad of diseases, among them cancer. The serine protease ClpP, accompanied by its cochaperone ClpX, is a principal homeostatic regulator in mitochondrial function by degrading aberrant proteins in order to preserve mitochondrial integrity. Recently, evidence suggests ClpP is overexpressed in many cancer cells and, as such, is an appealing target for drug therapy. In this review, current information about the structure, physiological function, and therapeutic promise of mitochondrial ClpP in oncology is summarized. We provide an overview about the mechanistic rationale behind ClpP agonists as novel anticancer drugs, their regulation in cell signal transduction, and the major challenge in the creation of small molecules that specifically activate human ClpP, but not bacterial ClpP. The review highlights the therapeutic promise of ClpP agonists as a novel approach in cancer therapy, presenting their prospective potential for cancer treatment by focusing on an unexplored mitochondrial target.
    Keywords:  ClpP protease; cancer biology tumor targeting; cellular signaling; mitochondrial dysfunction; targeted cancer therapy
    DOI:  https://doi.org/10.3389/or.2025.1567860
  18. Genome Med. 2025 May 22. 17(1): 58
    MitoMDT Diagnostic Network for Genomics and Omics
       BACKGROUND: Only half of individuals with suspected rare diseases receive a genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate care, restores reproductive confidence and reduces the number of potentially unnecessary interventions. A major barrier is the lack of disease agnostic functional tests suitable for implementation in routine diagnostics that can provide evidence supporting pathogenicity of novel variants, especially those refractory to RNA sequencing.
    METHODS: Focusing on mitochondrial disease, we describe an untargeted mass-spectrometry based proteomics pipeline that can quantify proteins encoded by > 50% of Mendelian disease genes and > 80% of known mitochondrial disease genes in clinically relevant sample types, including peripheral blood mononuclear cells (PBMCs). In total we profiled > 90 individuals including undiagnosed individuals suspected of mitochondrial disease and a supporting cohort of disease controls harbouring pathogenic variants in nuclear and mitochondrial genes. Proteomics data were benchmarked against pathology accredited respiratory chain enzymology to assess the performance of proteomics as a functional test. Proteomics testing was subsequently applied to individuals with suspected mitochondrial disease, including a critically ill infant with a view toward rapid interpretation of variants identified in ultra-rapid genome sequencing.
    RESULTS: Proteomics testing provided evidence to support variant pathogenicity in 83% of individuals in a cohort with confirmed mitochondrial disease, outperforming clinical respiratory chain enzymology. Freely available bioinformatic tools and criteria developed for this study ( https://rdms.app/ ) allow mitochondrial dysfunction to be identified in proteomics data with high confidence. Application of proteomics to undiagnosed individuals led to 6 additional diagnoses, including a mitochondrial phenocopy disorder, highlighting the disease agnostic nature of proteomics. Use of PBMCs as a sample type allowed rapid return of proteomics data supporting pathogenicity of novel variants identified through ultra-rapid genome sequencing in as little as 54 h.
    CONCLUSIONS: This study provides a framework to support the integration of a single untargeted proteomics test into routine diagnostic practice for the diagnosis of mitochondrial and potentially other rare genetic disorders in clinically actionable timelines, offering a paradigm shift for the functional validation of genetic variants.
    Keywords:  Genetic diagnostics; Mendelian disease; Proteomics; Ultra-rapid genome sequencing; Variant prioritisation
    DOI:  https://doi.org/10.1186/s13073-025-01467-z
  19. J Assist Reprod Genet. 2025 May 22.
       PURPOSE: To evaluate the value of mtDNA copy number measurement in spent culture medium of blastocysts for predicting the chance of implantation following single blastocyst transfer (SBT).
    METHODS: Copy numbers of mtDNA and genomic DNA (gDNA) were determined using multiplex PCR and NGS and modeled to predict implantation following SBT using a generalized linear model (GLM), generalized additive model (GAM), and extreme gradient boosting (XGBoost). The predictive power of the models was demonstrated and compared with the area under the receiver operating characteristic curve (AUC-ROC).
    RESULTS: Neither the mtDNA copy number nor the mtDNA/gDNA provided meaningful discriminatory power for prediction in GLM and GAM models. However, higher gDNA quartiles were associated with a negative correlation with pregnancy (OR 0.92, 95% CI 0.85, 1) and an interaction with mtDNA, suggesting that gDNA should not be used to normalize mtDNA copy number. An XGBoost model, which considered both mtDNA and gDNA values, demonstrated an AUC of 0.837 (95% CI 0.800, 0.874).
    CONCLUSIONS: The mtDNA copy number in spent medium alone may not be a reliable predictor of pregnancy, and dividing mtDNA by gDNA could distort the outcome. Alternatively, a model that makes full use of the interaction of the values may improve the prediction power.
    Keywords:  Assisted reproductive technology; Cell-free mitochondrial DNA; Predicting model; Single blastocyst transfer; Spent medium
    DOI:  https://doi.org/10.1007/s10815-025-03507-4
  20. Stem Cell Rev Rep. 2025 May 17.
      The advent of intestinal organoids, three-dimensional structures derived from stem cells, has significantly advanced the field of biology by providing robust in vitro models that closely mimic the architecture and functionality of the human intestine. These organoids, generated from induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), or adult stem cells, possess remarkable capabilities for self-renewal, differentiation into diverse intestinal cell types, and functional recapitulation of physiological processes, including nutrient absorption, epithelial barrier integrity, and host-microbe interactions. The utility of intestinal organoids has been extensively demonstrated in disease modeling, drug screening, and personalized medicine. Notable examples include iPSC-derived organoids, which have been effectively employed to model enteric infections, and ESC-derived organoids, which have provided critical insights into fetal intestinal development. Patient-derived organoids have emerged as powerful tools for investigating personalized therapeutics and regenerative interventions for conditions such as inflammatory bowel disease (IBD), cystic fibrosis, and colorectal cancer. Preclinical studies involving transplantation of human intestinal organoids into murine models have shown promising outcomes, including functional integration, epithelial restoration, and immune system interactions. Despite these advancements, several challenges persist, particularly in achieving reproducibility, scalability, and maturation of organoids, which hinder their widespread clinical translation. Addressing these limitations requires the establishment of standardized protocols for organoid generation, culture, storage, and analysis to ensure reproducibility and comparability of findings across studies. Nevertheless, intestinal organoids hold immense promise for transforming our understanding of gastrointestinal pathophysiology, enhancing drug development pipelines, and advancing personalized medicine. By bridging the gap between preclinical research and clinical applications, these organoids represent a paradigm shift in the exploration of novel therapeutic strategies and the investigation of gut-associated diseases.
    Keywords:  Colorectal cancer; Cystic fibrosis; Disease modeling; Drug screening; Embryonic stem cells; Epithelial restoration; Induced pluripotent stem cells; Inflammatory bowel disease; Intestinal organoids; Personalized medicine; Regenerative therapy; Stem cell-derived models
    DOI:  https://doi.org/10.1007/s12015-025-10893-w
  21. Transl Neurodegener. 2025 May 19. 14(1): 23
      There is increasing interest in nose-to-brain delivery as an innovative drug delivery strategy for neurodegenerative disorders such as Parkinson's or Alzheimer's disease. The unique anatomy of the nose-brain interface facilitates direct drug transport via the olfactory and trigeminal pathways to the brain, bypassing the blood-brain barrier. Different administration techniques as well as advanced drug formulations like targeted nanoparticles and thermoresponsive systems have been explored to improve the delivery efficiency and the therapeutic efficacy. This review provides an up-to-date perspective on this fast-developing field, and discusses different studies on safety and pharmacokinetic properties. A thorough evaluation of preclinical and clinical studies reveals both promises and challenges of this delivery method, highlighting approved drugs for the treatment of epilepsy and migraine that successfully utilize intranasal routes. The current landscape of research on nose-to-brain delivery is critically discussed, and a rationale is provided for ongoing research to optimize therapeutic strategies.
    Keywords:  Alzheimer's; Intranasal; N2B; Nanoparticle; Neurodegenerative disease; Parkinson's
    DOI:  https://doi.org/10.1186/s40035-025-00481-w
  22. Trends Mol Med. 2025 May 19. pii: S1471-4914(25)00106-6. [Epub ahead of print]
      Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality is often impaired under pathological conditions. Emerging evidence identifies mitochondria as key regulators of NK cell metabolism, fitness, and fate. This review examines how mitochondrial dysfunction impacts on NK cell activity in cancer, viral infections, and inflammatory disorders. We discuss strategies to target mitochondrial architecture, dynamics, and function as potential therapies to restore NK cell fitness. Finally, we highlight unanswered questions and future directions to better understand mitochondrial regulation in NK cells and its implications for therapeutic development.
    Keywords:  HIV; cellular therapies; immunometabolism; mitochondria; natural killer cells; oncology
    DOI:  https://doi.org/10.1016/j.molmed.2025.04.004
  23. Orphanet J Rare Dis. 2025 May 17. 20(1): 235
       BACKGROUND: Endocrine dysfunctions are commonly associated with mitochondrial diseases. This study aimed to investigate clinical characteristics and outcomes of endocrine manifestations in patients with mitochondrial diseases.
    METHODS: This study included 54 patients from 47 families with mitochondrial diseases who were genetically confirmed; 49 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), four with Pearson syndrome, and one with Kearns-Sayre syndrome (KSS). Clinical and endocrine findings were retrospectively reviewed.
    RESULTS: The median age at diagnosis was 18.5 years (range, 0.1 - 49 years). In 49 patients with MELAS, the mean height and weight standard deviation scores were - 2.0 ± 1.3 and - 2.6 ± 1.6, respectively, with 44.9% (n = 22) of the patients exhibiting short stature at diagnosis. Twenty-three (46.9%) patients with MELAS were diagnosed with diabetes mellitus (DM) at a median age of 26 years (range, 12 - 50 years). Interestingly, papillary thyroid cancer was observed in 10.2% of patients (n = 5) with MELAS at a mean age of 34.1 ± 6.9 years. One patient with MELAS and one with KSS exhibited hypoparathyroidism. Patients with Pearson syndrome and KSS exhibited more severe short stature. Adrenal insufficiency was noted in 50% of the patients with Pearson syndrome.
    CONCLUSIONS: In 20% of patients with MELAS, endocrine dysfunctions including having a short stature, DM, and hypoparathyroidism preceded the onset of neurological manifestations. Papillary thyroid cancer occurred in 10% of patients with MELAS. Patients with Pearson syndrome and KSS showed profound growth retardation and multisystem dysfunctions, such as chronic kidney disease and neurological defects, which contributed to increased mortality.
    Keywords:  Adrenal insufficiency; Diabetes mellitus; Hypoparathyroidism; Kearns–Sayre syndrome; Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes; Pearson syndrome
    DOI:  https://doi.org/10.1186/s13023-025-03773-6
  24. Front Cell Dev Biol. 2025 ;13 1538377
      Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's and Huntington's diseases as well as ataxias and fronto-temporal disorders are all characterized by the progressive accumulation of protein aggregates (amyloids) into inclusions bodies. In addition, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of some of these disease-relevant proteins to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. Abnormal secretion and levels of EVs are closely related to the pathogenesis of neurodegenerative diseases and contribute to disease progression. Numerous studies have proposed EVs as therapeutic targets or biomarkers for neurodegenerative diseases. In this review, we summarize and discuss the role of small heat shock proteins (sHSPs) and autophagy in cellular quality control and turn-over of the major aggregation-prone proteins associated to neurodegenerative disorders. We also highlight the advanced research progress on mechanisms regulating unconventional secretion, secretory autophagy and EVs biogenesis and their contribution in the pathological processes underlining these diseases. Finally, we outline the latest research on the roles of EVs in neurodegenerative diseases and their potential diagnostic and therapeutic significance for the treatment of these clinically relevant conditions.
    Keywords:  autophagy; extracellular vesicles and exosomes; neurodegenerative diseases; protein misfolding; protein oligomerization and aggregation; small heat shock proteins; unconventional protein secretion
    DOI:  https://doi.org/10.3389/fcell.2025.1538377
  25. Nat Struct Mol Biol. 2025 May;32(5): 780-789
      The variety of modifications decorating various RNA species has prompted researchers to study messenger RNA (mRNA) modifications that are likely to have, like N6-methyladenosine (m6A), important biological functions. Yet tackling these modifications has proved more complicated than anticipated. In this Perspective, we discuss two major obstacles to progress in epitranscriptomic research: the low abundance of most mRNA modification and the nonspecificity of many mRNA modifiers. We then shift our focus to the removal of mRNA modifications and their upstream regulation, emphasizing the context-dependent nature of epitranscriptomic regulation. We illustrate how specific modifications, such as N1-methyladenosine (m1A) and pseudouridine, are enriched in distinct environments, most notably within mitochondria and in certain physiopathological conditions. By focusing on biological settings in which non-m6A modifications are more abundant, we could deepen our understanding of their precise roles in gene regulation.
    DOI:  https://doi.org/10.1038/s41594-025-01548-y
  26. J Vis Exp. 2025 May 02.
      Organoid technology has allowed us to generate a variety of human organ-like mini structures, such as for the liver, brain, and intestine, in vitro. The remarkable advances in organoid models have recently opened a new experimental era for various applications in disease modeling, developmental biology, and drug discovery. Adult stem cells or induced pluripotent stem cell (iPSC)-derived liver organoids govern the generation of hepatocytes to use for diverse applications. Here, we present a robust and reproducible protocol for generating hepatic organoids from pluripotent stem cells. This protocol is applicable to healthy and patient-derived cells. To achieve 3D endoderm-derived hepatic organoids (eHEPOs), iPSCs were directly first differentiated into endodermal cells, and then FACS-enriched EpCAM-positive (EpCAM+) cells were used to establish hepatic organoids using the expansion medium. We provide a fast and efficient method to generate hepatic organoids within 2 weeks. The generated organoids mimic the essential properties and functions of hepatocytes, such as albumin secretion, glycogen storage, and cytochrome P450 enzyme activity. Besides the liver-specific gene expression similarities, eHEPOs comprise polarized epithelial cells with bile canaliculi in between. In addition, eHEPOs can be expanded and serial passages long term (1 year) without losing their capacity to differentiate into mature hepatocytes. Thus, eHEPOs provide an alternative source to produce functional hepatocytes.
    DOI:  https://doi.org/10.3791/65027
  27. PLoS One. 2025 ;20(5): e0324177
      Pediatric neurological disorders are a diverse group of conditions affecting the nervous system in children, often challenging to diagnose due to their nonspecific and overlapping clinical features. Advances in molecular diagnostics, particularly whole exome sequencing (WES), have significantly improved the identification of genetic causes, enabling precise diagnoses and personalized treatments. This study explores the application of WES in diagnosing pediatric neurological disorders within Moroccan childrens with undiagnosed or challenging pediatric neurological conditions to uncover genetic causes of complex pediatric neurological conditions unresolvable by traditional diagnostic methods. The study included 188 pediatric patients with complex neurological conditions from the Children's Hospital of Rabat who underwent exome sequencing to investigate suspected genetic causes. WES revealed a diagnostic yield of 45%, identifying conditions such as intellectual disabilities, hereditary metabolic disorders and epilepsies. It also uncovered neurodevelopmental and neurodegenerative disorders, neuromuscular diseases, and genetic syndromes. A total of 157 variants were detected: 34% were classified as pathogenic, 28.5% as likely pathogenic, and 37.5% as variants of uncertain significance (VUS). These findings underscore the utility of WES as a robust diagnostic tool, providing insights into genetic causes and enabling tailored treatment strategies. They also highlight the importance of expanding genetic research to improve diagnostic accuracy and clinical management of pediatric neurological disorders.
    DOI:  https://doi.org/10.1371/journal.pone.0324177
  28. Redox Biol. 2025 May 13. pii: S2213-2317(25)00191-0. [Epub ahead of print]84 103678
      Cytosolic thioredoxin (Trx) is a critical redox protein that converts protein disulfides to thiols via catalytic activity of thioredoxin reductase-1 (TrxR1) and NADPH. Thioredoxin-2 (Trx2) is a mitochondria-localized isoform. It is generally believed that Trx and Trx2 perform similar functions within the cytosol and mitochondria respectively. Here, we demonstrate that cytosolic Trx shuttles into mitochondria in the presence of normal levels of Trx2 in physiological state and higher levels of Trx translocate to mitochondria in oxidative stress conditions such as exposure to high concentrations of oxygen. This shuttle is required to maintain mitochondrial structure and function during physiological and oxidative stress conditions. Further, reduced Trx (Trx-SH) shuttle into mitochondria to protect against the downregulation of several mitochondrially coded genes and proteins of respiratory chain complexes in oxidative stress. Translocation of Trx occurs only in the reduced state as oxidized or cysteine mutant Trx is unable to translocate to the mitochondria. Accumulation of mitochondrial DNA damage product 8-Oxo-dG in hyperoxia is decreased in the presence of higher levels of cytosolic Trx within the mitochondrion. Collectively, our data demonstrate that shuttling of reduced cytosolic Trx into mitochondria protects against mitochondrial DNA damage, decreased gene and protein expression of respiratory chain complexes and mitochondrial dysfunction resulting in restoration of their native function and cell survival in physiological and oxidative stress conditions.
    DOI:  https://doi.org/10.1016/j.redox.2025.103678