bims-polgdi 2025-11-09 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–11–09
38 papers selected by
Luca Bolliger, lxBio

Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.
Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.
Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
Mitochondrial Leigh syndrome: the state of the art.
Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).
Size control: Tune the mitochondrial volume to time your cell division!
Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.
Mitochondrial quality control in neurodegenerative diseases: from molecular mechanisms to natural product therapies.
Calmodulinopathies: The Need for a Registry.
Mitochondrial quality control disorder: a potential mechanism of male infertility.
Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
Natural products that suppress 2-deoxy-d-glucose-induced cell death as potential drug seeds for mitochondrial diseases.
CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.
Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.
Surface-Engineered Mitochondria with Targeting Potential for Endothelial Repair.
Cell Free Regenerative Extracellular Vesicle Therapy for Ocular Diseases.
From preservation to repair: Mitochondrial transplantation as a paradigm shift in organ transplantation.
Network pharmacology of natural alkaloids: Rewiring the vicious cycle of mitochondrial dysfunction.
Advances in Induced Pluripotent Stem Cell Reprogramming and Its Application in Amyotrophic Lateral Sclerosis: A Review.
Integrating allostasis and emerging technologies to study complex diseases.
Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
Protocol for mitochondria lipid encapsulation using a dual-tube system for mitochondria transfer therapy.
The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.
Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
Imaging patterns of paediatric CNS mitochondrial disorders.
Inter-Organ Crosstalk and Regulatory Mechanisms of Skeletal Muscle-Derived Extracellular Vesicles in Systemic Metabolic Homeostasis.
National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey.
Cellular senescence and cell therapy in cardiovascular diseases.
Removal of Toxic Metabolites-Chelation: Manganese Disorders.
Stem cell-based interventions for epilepsy: Current progress and future promise.
Recent Advances in Organelle-Targeted Drug Delivery: Precision Medicine at the Subcellular Level.
Efficient mitochondrial DNA editing in rabbits with engineered sTALED base editors.
Advancing epigenetic signatures as functional biomarkers in rare diseases.
Ultra-High-Throughput Viscoelastic Squeezing for Mechanoporation and Efficient Intercellular Delivery.
Insights into the Versatile Role of Extracellular Vesicles in the Treatment of CNS Disorders.
Self-completed patient-reported outcome measures in adults with epilepsy: A review.
Navigating Drug Discovery for Myhre Syndrome: The Complexity of a Multisystemic Rare Disease.
Regulation of mitochondria functions by Mycobacterium tuberculosis infection.

Biol Pharm Bull. 2025 ;48(11): 1652-1666

Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.

Itsumi Sato, Masahiro Shiraishi, Kaede Norota, Kaoru Shiraki, Yuma Yamada.

  Mitochondria are essential for cellular functions, including ATP production, calcium homeostasis, oxidative stress regulation, and apoptosis. Mitochondrial dysfunction is associated with a variety of diseases, including neurodegenerative disorders, skeletal muscle diseases, and mitochondrial diseases. This review explores the latest mitochondrial-targeted therapeutic approaches across the following key perspectives: (1) technological innovations in mitochondrial transplantation, focusing on tunnel nanotubes and extracellular vesicles; (2) the role of mitochondria in skeletal muscle diseases and therapeutic activation strategies; (3) advances in mitochondrial enhancement techniques within cell therapy, particularly in pediatric applications; and (4) the latest treatment modalities for mitochondrial diseases, such as gene and cell therapies. Taken together, these strategies demonstrate the transformative potential of mitochondrial targeting in cell- and organelle-specific medicine. Additionally, the MITO-Porter system is highlighted as an innovative drug delivery platform contributing to these advances.

Keywords:  cell therapy; drug delivery system; mitochondria; mitochondrial disease; organelle medicine; skeletal muscle disease

DOI:  https://doi.org/10.1248/bpb.b25-00218
Wellcome Open Res. 2023 ;8 33

Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.

Jonathan Meyrick, Renae J Stefanetti, Linda Errington, Robert McFarland, Gráinne S Gorman, Nichola Z Lax.

   Introduction: Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma ( POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to employ systematic approaches, wherever possible, to investigate the cellular and animal models used in POLG-related research and assess how well they help us understand disease mechanisms in patients.
Methods: Four databases were searched from inception to May 31 st, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model.
Results: A total of 55 articles, including seven model organisms (Human, yeast [ Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Caenorhabditis elegans, and Zebrafish) with 258 distinct variants were included. Of these, 69% (N=38/55) of articles recapitulated mitochondrial DNA (mtDNA) depletion, 33% (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7/55) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders.
Discussion: While some evidence is available to support the ability of POLG-related disease models to recapitulate molecular mechanisms and phenotypes, much is of limited quality, with inconsistencies evident across the literature. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease.
PROSPERO registration: CRD42021234883.

Keywords:  POLG; epilepsy; mitochondria; mtDNA; neurological manifestations; preclinical

DOI:  https://doi.org/10.12688/wellcomeopenres.18637.2
Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):

Proteolytic cleavage activates the mitochondrial isoform of TOP3A.

Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.

The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.

DOI: https://doi.org/10.1093/nar/gkaf1140
Arch Pediatr. 2025 Nov 05. pii: S0929-693X(25)00182-4. [Epub ahead of print]

Mitochondrial Leigh syndrome: the state of the art.

Gauthier Toutain, Célia Hoebeke, Marguerite Gastaldi, Mathieu Milh, Brigitte Chabrol.

   BACKGROUND: Leigh syndrome or subacute necrotizing encephalomyelopathy was first recognized as a neuropathological entity in 1951. It is a progressive neurological disease characterized by neuroradiological lesions, particularly in the brainstem and basal ganglia. Leigh's syndrome is a pan-ethnic disorder with onset usually in infancy or early childhood. Over the last six decades, this complex neurodegenerative disorder has been shown to comprise >100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This article reviews clinical, radiological, biochemical and genetic aspects of the disorder.
OBJECTIVES: this overview provides a better understanding of this rare mitochondrial disease by identifying its clinical, radiological and genetic manifestations in order to improve early diagnosis, patient follow-up and genetic counseling.
METHODOLOGY: systematic literature review RESULTS: Leigh syndromes present with childhood developmental regression, a loss of previously achieved developmental milestones. Numerous non-neurological manifestations of Leigh syndrome have been reported, many of which are related to the underlying genetic defects. These include cardiomyopathy, renal tubulopathy, gastrointestinal and endocrine dysfunction, and liver disease. Known genetic causes, including defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon CONCLUSION: Management of mitochondrial diseases must be multidisciplinary, and in collaboration with a center of reference (CRMR) or a center of competence (CCMR) with expertise in mitochondrial diseases.

Keywords:  Central nervous system; Genetic; Itochondrial DNA; Leigh syndrome; Metabolic disease; Mitochondrial disease; Neurodegeneration; Neuroimaging; Nuclear DNA; OXPHOS; Treatment

DOI:  https://doi.org/10.1016/j.arcped.2025.04.007
Ann Med Surg (Lond). 2025 Oct;87(10): 6904-6905

Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).

Amna Rahman, Muneeb Faiz, Maliha Khalid, Muhammad Talha, Aminath Waafira.

  Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial disorder primarily driven by mutations in mitochondrial DNA, particularly the m.8344A>G variant in MT-TK, and is characterized by epilepsy, myoclonus, ataxia, and other multisystemic features. With no curative therapy, recent attention has turned to the gut microbiome as a modifiable factor influencing neurologic symptoms in mitochondrial diseases. Dysbiosis-induced by antibiotics, diet, or preservatives-has been linked to altered microbial metabolites such as short-chain fatty acids and indoxyl sulfate, which may exacerbate neurological dysfunction. Preliminary clinical trials and preclinical studies suggest that probiotics and dietary interventions can modestly improve disease burden and symptoms such as constipation. However, significant challenges remain, including lack of standardization in analytical protocols, heterogeneous host-microbiota responses, and inadequate patient stratification. To fully realize the therapeutic potential of microbiome-based approaches in MERRF, coordinated multicenter trials, clear regulatory guidelines, and machine learning-enhanced stratification will be essential.

Keywords:  MERRF syndrome; gut microbiome; mitochondrial disease; neurologic symptoms

DOI:  https://doi.org/10.1097/MS9.0000000000003777
Curr Biol. 2025 Nov 03. pii: S0960-9822(25)01254-0. [Epub ahead of print]35(21): R1053-R1055

Size control: Tune the mitochondrial volume to time your cell division!

Mikael Björklund.

A new study links mitochondrial volume control with growth and cell division, suggesting that cells not only sense their mitochondrial content but also use this information to decide when to divide.

DOI: https://doi.org/10.1016/j.cub.2025.09.054
Geroscience. 2025 Nov 04.

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.

Juri Kim, Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.

  Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores the function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, a decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt promote longevity. These and other studies have started to question whether UPRmt is directly correlated with longevity. Here, we attempt to address this controversy by unraveling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce mitochondrial stress by performing RNA sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPRmt and longevity. Altogether, this study will provide mechanistic insights on mitohormesis and how it correlates with the lifespan of C. elegans.

Keywords:  Aging; Caenorhabditis elegans; Mitohormesis; UPRmt

DOI:  https://doi.org/10.1007/s11357-025-01912-2
Front Physiol. 2025 ;16 1695681

Mitochondrial quality control in neurodegenerative diseases: from molecular mechanisms to natural product therapies.

Boxun Chen, Qing Wang, Yannan Wang, Qingzhi Liu, Weiyue Chen, Hong Mao, Jiamin Li, Qi Liu, Xue Zhou.

   Background: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, etc., are a group of complex and heterogeneous disorders characterized by progressive synaptic loss and pathological protein alterations. Mitochondria are the main source of energy produced by neurons and support the high energy consumption of the nervous system. Mitochondrial quality control, involving processes like mitophagy and mitochondrial biogenesis, is crucial for mitochondrial homeostasis, and mitochondrial dysfunction is closely related to neurodegenerative diseases pathogenesis, making targeting mitochondrial quality control a potential therapeutic strategy. Natural products offer benefits such as cost-effectiveness, fewer side effects, and other positive qualities, making them suitable choices as supplements or alternatives to traditional drugs for treating neurodegenerative diseases.
Methods: A thorough search was conducted on many databases including Web of Science, PubMed, EMBASE, and MEDLINE to investigate the role of mitochondria in neurodegenerative diseases and the therapeutic effects of natural products.
Results: By searching the relevant studies on neurodegenerative diseases and mitochondria in recent years, we observed a rise in the number of studies examining the functional characteristics and biological events of mitochondrial quality control systems in neurodegenerative diseases pathogenesis and the potential for natural products regulating mitochondrial quality control to improve neurodegenerative diseases.
Conclusion: This review summarizes the functional characteristics and biological events of mitochondrial quality control systems in neurodegenerative diseases pathogenesis, and comprehensively analyzes the pharmacological mechanisms by which natural products regulate mitochondrial quality control to improve neurodegenerative diseases, aiming to provide a scientific basis for further research and new clinical drug development.

Keywords:  mitochondrial quality control; molecular mechanisms; natural products; neurodegenerative diseases; toxicology and adverse effects

DOI:  https://doi.org/10.3389/fphys.2025.1695681
Circ Genom Precis Med. 2025 Nov 05. e005503

Calmodulinopathies: The Need for a Registry.

Peter J Schwartz, Lia Crotti.

  Calmodulinopathies are very rare genetic disorders associated with a high risk for sudden cardiac death. Disease-causing variants in 1 of the 3 identical CALM genes cause severe forms of long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, or idiopathic ventricular fibrillation, and there are many open questions concerning management and underlying mechanisms. What is currently known depends largely on the initial publications from the International Calmodulinopathy Registry. However, progress is delayed because the accrual of patients in the International Calmodulinopathy Registry is slow. As we did long ago for long QT syndrome, this is a call for action, requesting doctors all over the world to enroll even their isolated cases in the registry. This is the only way to obtain, for an adequate number of patients, the data necessary to define the spectrum of clinical manifestations and the genotype-phenotype correlation essential for an improved risk stratification and best therapeutic management. If you are willing to contribute, please contact us.

Keywords:  arrhythmias, cardiac; calmodulin; ion channels; long QT syndrome; rare diseases; sudden cardiac death; sympathetic denervation

DOI:  https://doi.org/10.1161/CIRCGEN.125.005503
Syst Biol Reprod Med. 2025 Dec;71(1): 549-573

Mitochondrial quality control disorder: a potential mechanism of male infertility.

Shanshan Qin, Ziming Zhu, Shenmin Lv, Zhipeng Guo, Linhui Xia, Xiaoyu Gong, Xiangyu Wang, Jinxiang Yuan, Kai Meng, Jianping Zhu.

  In recent years, the incidence of male infertility has increased to approximately 10%, with a continued upward trend. Therefore, understanding the mechanisms underlying male infertility and developing effective treatment strategies have become essential areas of focus. Mitochondria are regulated by a complex quality control system including mitochondrial dynamics, mitophagy and biogenesis, which not only maintains mitochondrial structural and functional integrity, but also supports the stability of testicular tissue and the intracellular environment necessary for male fertility. Several studies have demonstrated that dysfunction in mitochondrial dynamics and mitophagy is closely associated with a decline in male fertility. Disruptions caused by excessive external stimuli or gene mutations can impair these processes, resulting in oxidative damage, apoptosis, inflammation, and ferroptosis. These pathological changes ultimately damage testicular cells and tissues. Consequently, this review will focus on the two key mechanisms: mitochondrial dynamics and mitophagy. Furthermore, mitochondrial biogenesis-responsible for producing new mitochondria and regulating the number of mitochondria-also plays an important role in maintaining male fertility. Related studies have shown that mitochondrial biogenesis dysfunction can trigger a cascade of pathological events that lead to testicular tissue damage. In summary, this review systematically examines the roles of mitochondrial dynamics and mitophagy in regulating male fertility. It provides an in-depth analysis of the pathological mechanisms by which dysfunction in these processes leads to male infertility. Additionally, this review summarizes current therapeutic agents targeting mitochondrial dynamics and mitophagy, aiming to identify potential strategies for the clinical treatment of male infertility.

Keywords:  infertility treatments; male fertility; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1080/19396368.2025.2574003
J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]

Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.

Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.

  Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.

Keywords:  Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone

DOI:  https://doi.org/10.1093/jb/mvaf062
Bioorg Med Chem. 2025 Nov 02. pii: S0968-0896(25)00419-5. [Epub ahead of print]132 118478

Natural products that suppress 2-deoxy-d-glucose-induced cell death as potential drug seeds for mitochondrial diseases.

Koyo Honda, Yuki Hitora, Yusaku Sadahiro, Masahiro Wato, Yuriko Nagano, Sachiko Tsukamoto.

  Mitochondrial dysfunction is not only a known cause of mitochondrial disease but has also been implicated in diabetes and neurodegenerative diseases. Therefore, modulating mitochondrial function may provide new insights into the treatment of these diseases. In this study, we used a cancer cell-based energy metabolism restriction model with a glycolytic inhibitor and screened a natural product library and a fungal extract library to identify natural products that improve mitochondrial function. Seven compounds, including quillaic acid (1) and 20-deoxyingenol (2), were identified as mitochondrial function modulators from the Selleck natural product library. Furthermore, an extract of a fungus, Trichoderma sp., from an in-house fungal extract library suppressed 2-deoxy-d-glucose-induced cell death. Bioassay-guided fractionation of the extract afforded seven known sorbicillinoids. Among them, bisvertinol (8) did not directly affect cellular energy metabolism but appeared to protect mitochondria from oxidative stress through its antioxidant properties.

Keywords:  2-Deoxy-d-glucose; Energy metabolism; Fungus; Mitochondrial modulator; Natural product; Trichoderma sp.

DOI:  https://doi.org/10.1016/j.bmc.2025.118478
Front Cell Neurosci. 2025 ;19 1681891

CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.

Anas Shamsi, Mohammed Alrouji, Othman AlOmeir, Syed Tasqeruddin, Khzuin Dinislam, Azna Zuberi.

  Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.

Keywords:  Alzheimer’s disease; CRISPR-Cas9; Huntington’s disease; Parkinson’s disease; aging; amyotrophic lateral sclerosis (ALS); gene editing; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fncel.2025.1681891
Front Cell Infect Microbiol. 2025 ;15 1686785

Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.

Tracy Okine, Eleanor Hill, Kate Sheran, Talia H Swartz.

  Antiretroviral therapy (ART) has transformed HIV into a chronic, manageable condition, yet people living with HIV (PLWH) continue to experience persistent immune activation and systemic inflammation that drive long-term comorbidities, including neurocognitive impairment and cardiovascular disease. This residual inflammation requires new mechanistic explanations and targeted therapeutic approaches. Increasing evidence highlights mitochondria as central hubs in the regulation of cellular metabolism and immune responses. In PLWH, both HIV and ART disrupt mitochondrial function, leading to the release of proinflammatory mediators such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These signals activate the NLRP3 inflammasome, resulting in secretion of IL-1β and other cytokines. In parallel, excess mitochondrial ATP engages purinergic receptors such as P2X1 and P2X7, propagating inflammatory signaling to surrounding immune cells. This review examines the mito-immune axis in HIV, focusing on OxPhos dysregulation, inflammasome activation, and purinergic receptor signaling, and explores potential interventions-including purinergic antagonists-that aim not only to suppress viral replication but also to restore immunometabolic balance. By recognizing mitochondria as dynamic regulators of immune function, we outline a paradigm shift in HIV treatment that addresses the underlying drivers of chronic inflammation.

Keywords:  ATP; HIV; OxPhos; inflammasome; inflammation; mitochondria

DOI:  https://doi.org/10.3389/fcimb.2025.1686785
Cell Mol Bioeng. 2025 Oct;18(5): 403-417

Surface-Engineered Mitochondria with Targeting Potential for Endothelial Repair.

Brandon Applewhite, Natalia Matiuto, Aurea Del Carmen, Bin Jiang.

   Purpose: Mitochondrial dysfunction contributes to endothelial injury in vascular diseases and interventions. While mitochondrial transplantation offers a promising therapeutic strategy, current approaches lack target specificity, efficient uptake, and long-term retention. This study presents a surface-engineering approach to enhance mitochondria delivery to the vascular endothelium as a step toward novel endothelial repair strategies.
Methods: Mitochondria were isolated from healthy induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) and surface functionalized with a phospholipid-based coating platform (DSPE-PEG) to enable peptide functionalization. DSPE-PEG was conjugated to either VCAM-1-binding peptide and collagen-binding peptide to enable targeting to dysfunctional and injured endothelium. Mitochondria particle characteristics were measured using flow cytometry, dynamic light scattering and Seahorse. Mitochondrial uptake, retention, and function were assessed in human diabetic aortic endothelial cells (DAECs) using confocal microscopy, flow cytometry, JC-1 staining, and Seahorse metabolic analysis.
Results: iPSC-MSCs provided bioenergetically competent mitochondria suitable for therapeutic delivery. DSPE-PEG surface functionalization significantly enhanced mitochondrial uptake in DAECs, compared to uncoated mitochondria. Confocal imaging and quantitative analysis revealed increased cytoplasmic retention and greater colocalization with the endogenous mitochondrial network after 24 h. Functional assays demonstrated improved mitochondrial membrane potential and sustained oxygen consumption in recipient cells, indicating enhanced host mitochondrial function following treatment with surface-engineered mitochondria.
Conclusions: This study establishes a proof-of-concept for mitochondria surface engineering to enhance mitochondria transplantation to damaged endothelium, demonstrating improved cellular uptake and bioenergetic restoration. These findings provide a foundation for developing adaptable, cell-free therapeutics for vascular disease.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-025-00862-1.

Keywords:  Bioenergetic restoration; Endothelial dysfunction; Lipid-polymer coatings; Mitochondrial transplantation; Surface engineering; Vascular regeneration

DOI:  https://doi.org/10.1007/s12195-025-00862-1
Curr Eye Res. 2025 Nov 05. 1-15

Cell Free Regenerative Extracellular Vesicle Therapy for Ocular Diseases.

Alexander Mike Tseng, Sangeetha Kandoi, Martin Heur, Sun Young Lee.

   PURPOSE: To assess the therapeutic potential of extracellular vesicles (EVs) derived from stem cells and ocular tissues as a cell-free alternative to traditional stem cell therapies for a broad spectrum of ocular diseases.
METHODS: A comprehensive literature review was performed, focusing on preclinical studies involving EVs derived from mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), neural progenitor cells, immune cells, and ocular-resident cells. Data were extracted on EV cellular origin, isolation methods, routes of administration, preclinical disease models, therapeutic outcomes, and proposed mechanisms of action. Registered clinical trials were also evaluated.
RESULTS: EVs exhibited regenerative and immunomodulatory effects across a range of ocular conditions, including dry eye, uveitis, glaucoma, retinal degenerations, and optic neuropathies. Various cell sources have been explored for EV production, including MSCs, iPSCs, hESCs, retinal organoids, and other ocular tissue-resident cells. In addition, bioengineered EVs have been developed to modify surface properties or enhance therapeutic cargo. Reported mechanisms of action include miRNA-mediated gene regulation, immune modulation, and oxidative stress reduction. Several early-phase clinical trials are currently underway to translate these findings into human therapies.
CONCLUSION: Stem cell-derived EVs represent a promising next-generation, cell-free regenerative therapy for ocular diseases. While preclinical data are promising, successful clinical translation will require optimal EV source selection, scalable and GMP-compliant production, identification of disease-relevant mechanisms of action, rigorous cargo characterization, and alignment with regulatory standards.

Keywords:  Extracellular vesicles; ocular therapy; regenerative medicine

DOI:  https://doi.org/10.1080/02713683.2025.2570810
Hepatobiliary Pancreat Dis Int. 2025 Oct 14. pii: S1499-3872(25)00172-9. [Epub ahead of print]

From preservation to repair: Mitochondrial transplantation as a paradigm shift in organ transplantation.

Emma Peveri, Timothy Sganga, Emilio Peveri, Adam Jones, Thomas Ritchey, Sandrine Lablanche, Kelsey Fisherwellman, Amish Asthana, Giuseppe Orlando, Quentin Perrier.

  Organ transplantation faces a persistent mismatch between the number of available donor organs and the growing demand for transplants. Conventional preservation techniques primarily focus on delaying deterioration rather than actively restoring organ function, especially at the mitochondrial level, a key site of injury during ischemia-reperfusion. Mitochondrial transplantation, a novel regenerative strategy, offers a compelling solution by delivering viable mitochondria to damaged tissues ex vivo, particularly during machine perfusion. This approach not only improves bioenergetic recovery and reduces oxidative stress but also reconditions marginal organs to meet transplantation standards. Preclinical studies across heart, lung, and kidney models demonstrate the potential of mitochondrial transplantation to bridge preservation and repair, expanding the transplantable organ pool. This review highlights mitochondrial transplantation as a transformative intervention poised to reshape the future of organ preservation and transplant viability.

Keywords:  Ex vivo; Ischemia-reperfusion injury; Mitochondria; Organ transplantation

DOI:  https://doi.org/10.1016/j.hbpd.2025.10.003
Phytomedicine. 2025 Oct 20. pii: S0944-7113(25)01057-8. [Epub ahead of print]148 157420

Network pharmacology of natural alkaloids: Rewiring the vicious cycle of mitochondrial dysfunction.

Li He, Yumei Zhuo, Linlin Yang, Ying Zhou, Siyan Liu, Xinyu Tang, Hui Huang, Xuan Wang.

   BACKGROUND: Mitochondrial dysfunction constitutes a self-reinforcing vicious-cycle network (VCN)-involving bioenergetic failure, oxidative stress, calcium dysregulation, and defective quality control-that drives chronic diseases. Conventional single-target therapies often fail to disrupt this interconnected pathology.
PURPOSE: This review synthesizes the network-level mechanisms by which structurally diverse natural alkaloids modulate the mitochondrial VCN. We analyze their multi-target engagement, the resulting "double-edged sword" effects, pharmacokinetic challenges, and strategies for clinical translation.
METHODS: We conducted a comprehensive review using Web of Science, PubMed databases, focusing on alkaloids' role in mitochondrial function and their therapeutic effects, including "alkaloids", "mitochondria" and "mitochondrial function", primarily analyzing literature published between 2011 and 2025.
RESULTS: Alkaloids, facilitated by mitochondrial accumulation, simultaneously engage multiple VCN nodes. Compounds like berberine and matrine recalibrate energy metabolism and biogenesis (via AMPK/SIRT1/PGC-1α), restore redox balance (Nrf2), and enhance quality control (PINK1/Parkin). This network modulation underpins their context-dependent effects, which can be cytoprotective in degenerative models or cytotoxic in cancer (e.g., via PI3K/AKT/mTOR inhibition). However, translation is hindered by a PK/PD paradox linked to poor bioavailability and narrow therapeutic windows. Nanodelivery and structural optimization show promise in overcoming these limitations and mitigating mitochondria-centric toxicities.
CONCLUSION: Alkaloids offer potent multi-target strategies for rewiring mitochondrial dysfunction networks. Realizing their therapeutic potential requires prioritized efforts in bioavailability enhancement, advanced predictive toxicology (including AI-driven models), and rigorous clinical validation.

Keywords:  Alkaloids; Mitochondrial dysfunction; Nanodelivery; Natural product; Oxidative stress; Pharmacological therapy

DOI:  https://doi.org/10.1016/j.phymed.2025.157420
FASEB Bioadv. 2025 Nov;7(11): e70065

Advances in Induced Pluripotent Stem Cell Reprogramming and Its Application in Amyotrophic Lateral Sclerosis: A Review.

Yingliu Luo, Zhenru Xu, Zunxiong Li.

  Since Yamanaka's landmark achievement in reprogramming somatic cells into induced pluripotent stem cells (iPSCs) using the four key transcription factors-OCT4, SOX2, KLF4, and c-Myc (OSKM)-iPSC technology has made significant strides. Notable advancements include refining reprogramming factors, delivery systems, somatic cell selection, and optimization of reprogramming conditions, along with developing chemical reprogramming methods. With their unparalleled proliferative capacity and near-pluripotent differentiation potential, iPSCs have become invaluable tools for investigating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Neuronal models derived from ALS patient-specific iPSCs, particularly iPSC-derived motor neurons (iPSC-MNs), offer a robust platform to recapitulate disease-specific pathology and investigate the molecular mechanisms underpinning ALS, thereby accelerating the discovery of novel therapeutic strategies. This review highlights the evolution of iPSC technology and its transformative applications in ALS modeling, drug discovery, and therapeutic development.

Keywords:  amyotrophic lateral sclerosis; induced pluripotent stem cell; motor neuron

DOI:  https://doi.org/10.1096/fba.2025-00126
Commun Biol. 2025 Nov 05. 8(1): 1526

Integrating allostasis and emerging technologies to study complex diseases.

InWha Park, Hyokyeong Gwon, Yeonjeong Jung, Boyoung Kim, Gaeun Ju, Eugene Sin, Hye In An, Hye Jung Bang, Taegwan Yun, Seung Hwan Lee, Wonsik Lee, Choon-Gon Jang, Hyo-Jong Lee, Chung Sub Kim, Jeongmi Lee, Soah Lee.

The study of complex diseases has traditionally relied on reductionist methods, which, although informative, tend to overlook the dynamic interactions and systemic interconnectivity inherent in biological systems. Allostasis, a framework that focuses on physiological adaptations to stress and the maintenance of stability through change, provides a valuable perspective for understanding these diseases. This review summarizes how the allostasis framework defines the cumulative physiological burden-known as allostatic load-imposed by chronic stressors such as persistent psychosocial pressure, drug abuse, and chronic infections. It also explores how adaptive physiological shifts, or changes in allostatic state, contribute to disorders, particularly drug addiction, immune diseases, and cancer. We then review recent studies that uncover stress adaptation mechanisms using cutting-edge technologies, such as multi-omics approaches, induced pluripotent stem cells (iPSCs), and organoid technology. This integrative approach, combining advanced technologies with the allostasis framework, can deepen our understanding of complex disease pathogenesis and inform the development of more effective diagnostic and therapeutic strategies.

DOI: https://doi.org/10.1038/s42003-025-08939-3
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]

Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.

Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.

  Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.

Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity

DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
STAR Protoc. 2025 Oct 30. pii: S2666-1667(25)00580-5. [Epub ahead of print]6(4): 104174

Protocol for mitochondria lipid encapsulation using a dual-tube system for mitochondria transfer therapy.

Gen Hamanaka, Dong Bin Back, Ester Licastro, Shin Ishikane, Takafumi Nakano, Kazuhide Hayakawa.

  Mitochondria transplantation therapy is emerging as a novel therapeutic approach to promote neuroprotection in central nervous system (CNS) disorders. Here, we present a protocol for mitochondrial surface modification that enhances the restoration of intracellular adenosine triphosphate (ATP) levels under conditions of oxidative stress. We describe steps for isolating mitochondria, preparing the dual-tube system, and encapsulation with lipid coat. We then detail procedures for performing assays and analyses. For complete details on the use and execution of this protocol, please refer to Nakano et al.1.

Keywords:  Metabolism; Neuroscience; cell Biology; tissue Engineering

DOI:  https://doi.org/10.1016/j.xpro.2025.104174
Biochim Biophys Acta Rev Cancer. 2025 Oct 31. pii: S0304-419X(25)00233-1. [Epub ahead of print]1880(6): 189491

The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.

Woo Hyun Park.

  Mitochondria, far from being mere cellular powerhouses, act as central command hubs dictating cell fate by integrating metabolic cues with life-or-death decisions. In cancer, these organelles undergo profound functional and structural reprogramming to support relentless proliferation, survival, and adaptation to stress. This metabolic plasticity, however, creates unique vulnerabilities exploitable for therapeutic gain. This comprehensive review synthesizes recent insights into the multifaceted roles of mitochondria in cancer, focusing on how inhibiting their core functions can trigger diverse cell death pathways and modulate the tumor microenvironment. This paper delves into the central role of mitochondria in orchestrating various forms of regulated cell death (RCD), including apoptosis, ferroptosis, necroptosis, and the newly defined cuproptosis. A primary focus is placed on the dual nature of mitochondrial reactive oxygen species (ROS), which can promote tumorigenesis but can also be pharmacologically elevated to catastrophic levels, triggering oxidative stress-induced demise. This review systematically categorizes and discusses a burgeoning pharmacopeia of mitochondrial inhibitors-targeting the electron transport chain (ETC), metabolic enzymes like glutaminase, protein homeostasis, and ion channels-and analyzes their mechanisms of action, preclinical evidence, and clinical translation status. Furthermore, this paper examines how these agents can overcome chemoresistance and synergize with existing treatments, including the exciting interface with immunotherapy, where mitochondrial fitness is paramount for robust anti-tumor T-cell responses and the induction of immunogenic cell death (ICD). By dissecting the complex interplay between mitochondrial inhibition, metabolic disruption, oxidative stress, and cell death, this review highlights the immense promise of mitochondria-targeted therapies and charts the course for future innovations in oncology.

Keywords:  Cancer metabolism; Immunotherapy; Mitochondria; Oxidative stress; Regulated cell death; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189491
Cell Death Differ. 2025 Nov 01.

Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.

Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.

The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.

DOI: https://doi.org/10.1038/s41418-025-01603-7
Neuroradiology. 2025 Nov 05.

Imaging patterns of paediatric CNS mitochondrial disorders.

Pritika Gaur, Cesar Alves, Harun Yildiz, Kshitij Mankad, Sniya Sudhakar, Shamima Rahman, Asthik Biswas.

  This review seeks to provide neuroradiologists and clinicians with an imaging-based pattern recognition framework for primary mitochondrial disorders affecting the central nervous system (CNS). By utilising a comprehensive imaging phenotype approach to CNS mitochondrial disorders, it highlights the wide spectrum of neuroimaging patterns and the complexities they present in clinical settings. Using illustrative case examples, the review demonstrates how imaging acts as a vital bridge between clinical phenotypes and genotypes.

Keywords:  Brain; Mitochondrial disorders; Paediatric; Spine

DOI:  https://doi.org/10.1007/s00234-025-03805-9
J Cell Mol Med. 2025 Nov;29(21): e70896

Inter-Organ Crosstalk and Regulatory Mechanisms of Skeletal Muscle-Derived Extracellular Vesicles in Systemic Metabolic Homeostasis.

Zhuoying Wu, Yuanyuan Gao, Qi Chen, Li Yuan.

  Extracellular vesicles (EVs), including exosomes, play a pivotal role in intercellular communication by facilitating the transfer of bioactive molecules between cells. These vesicles, which encompass a variety of subtypes such as exosomes, microvesicles and apoptotic bodies, carry functional proteins, mRNAs, miRNAs and other molecular cargo that influence various physiological processes. In particular, skeletal muscle-derived EVs have recently emerged as a novel category of myokines, contributing to muscle homeostasis through paracrine signalling and exerting systemic endocrine effects on metabolic tissues, including the pancreas, adipose tissue and liver. This review systematically examines the regulatory mechanisms of skeletal muscle-derived EVs, with particular focus on exosomes, in mediating inter-organ crosstalk. Additionally, it examines the factors that influence the release of skeletal muscle-derived EVs, particularly exosomes and their subsequent effects on metabolism.

Keywords:  adipose tissue; extracellular vesicles; liver; pancreas; skeletal muscle

DOI:  https://doi.org/10.1111/jcmm.70896
Acta Myol. 2025 Sep;44(3): 93-95

National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey.

Michelangelo Mancuso, Costanza Lamperti, Olimpia Musumeci.

   Objective: Thymidine kinase 2 (TK2) deficiency is a rare mitochondrial disease with variable phenotypes and emerging treatments. Prompt diagnosis is essential to optimize patient outcomes and management. To assess the current awareness, diagnostic approaches, and readiness to include TK2 screening in Italian neuromuscular clinical practice.
Methods: A nationwide survey was distributed to AIM-affiliated clinicians. The questionnaire assessed TK2 awareness, diagnostic pathways, gene panel content, and attitudes towards screening in unresolved cases.
Results: while awareness of TK2 deficiency was almost universal, inclusion of TK2 in genetic panels varied: 85% in metabolic myopathy panels, 56% in LGMD panels. Screening for TK2 in genetically unsolved SMA, FSHD, and OPMD phenotypes was inconsistent.
Conclusions: Although awareness of TK2 deficiency is widespread, diagnostic strategies are inconsistent. Standardizing TK2 inclusion in NGS panels and promoting differential screening are key steps toward earlier diagnosis in the view of future treatment options.

Keywords:  TK2; awareness; mitochondrial disease

DOI:  https://doi.org/10.36185/2532-1900-1424
Stem Cell Res Ther. 2025 Nov 05. 16(1): 613

Cellular senescence and cell therapy in cardiovascular diseases.

Dehua Chang, Jiaqi Wang, Shuoji Zhu, Yunchao Shentu, Yuanli Wang, Ping Zhu, Minoru Ono.

  The issue of population aging presents a significant challenge for many countries, and the related physical health implications have been receiving increasing attention. Senescence impacts several aspects of the cardiovascular system, contributing to diseases such as atherosclerosis, myocardial infarction (MI), pulmonary hypertension, and heart failure (HF). In recent decades, scientists have significantly advanced in understanding the molecular and cellular processes involved in cardiovascular aging, including telomere shortening and damage, oxidative stress, mitochondrial dysfunction, and DNA damage. Molecules such as p53, p21, and p16Ink4a, along with enhanced signals for SA-β-gal, are commonly used to detect senescent cells. Researchers have identified pathways and factors that could be potential targets for treating or alleviating cardiovascular aging. Furthermore, the rapid advancement of regenerative medicine, including mesenchymal stem cell (MSC) and induced pluripotent stem cell (iPSC) transplantation, has positioned heart regeneration as a promising strategy for addressing age-related cardiovascular diseases. This review summarizes the current understanding of senescent cells, such as cardiomyocytes, endothelial cells, fibroblasts/myofibroblasts, and vascular smooth muscle cells, and their roles in associated cardiovascular diseases. We will also discuss recent factors contributing to cardiovascular aging, including but not limited to Akt and AMPK, and emphasize the potential of heart regeneration research and insights into future regenerative therapies for cardiovascular aging.

Keywords:  Cardiac aging; Cardiovascular diseases; Cellular senescence; MSC; iPSC

DOI:  https://doi.org/10.1186/s13287-025-04731-6
J Inherit Metab Dis. 2025 Nov;48(6): e70107

Removal of Toxic Metabolites-Chelation: Manganese Disorders.

Hendrik Vogt, George E Kostakis, Rupert Purchase, John Spencer, Karin Tuschl.

  Manganese (Mn) overload is a characteristic of multiple disease entities, from acquired manganism upon environmental or occupational overexposure, to end-stage liver disease and certain genetic disorders. The latter include hypermanganesaemia with dystonia 1 and 2 caused by pathogenic variants in the genes encoding the Mn transporters SLC30A10 and SLC39A14. Excess Mn accumulates in the brain, particularly in the globus pallidus, leading to progressive dystonia-parkinsonism. Furthermore, Mn dyshomeostasis is a characteristic feature of common neurodegenerative disorders such as Parkinson's disease, whether as a cause or consequence needs to be determined, suggesting that Mn as an environmental toxicant may play a role in its aetiology. Therefore, there is a need for therapeutics that effectively chelate Mn and remove excess Mn from the brain. This review discusses the Mn chelators currently used in clinical practice, their advantages and disadvantages as well as their adverse effects. Na2CaEDTA is the primary chelating agent used to re-establish Mn homeostasis; however, its burdensome treatment regimen, need for intravenous administration, and lack of metal specificity make it a poor drug for clinical application. The development of novel, Mn-specific chelating agents is therefore a clinical priority. An ideal chelator would be orally bioavailable, soluble in both lipids and water to reach the sites of metal storage, chemically inert, and non-toxic whilst retaining chelating abilities at physiological pH. We discuss current progress in identifying novel Mn ligands that have been primarily developed as magnetic resonance imaging contrast agents.

Keywords:  SLC30A10; SLC39A14; chelation; coordination chemistry; manganese; manganism

DOI:  https://doi.org/10.1002/jimd.70107
Epileptic Disord. 2025 Nov 07.

Stem cell-based interventions for epilepsy: Current progress and future promise.

Dinesh Kumar, Mehboob's Ashraf, Vrinda Gupta, Rajni Tanwar, Thamir M Alshammari, Md Faiyazuddin.

  Epilepsy affects millions globally, with a significant proportion of patients remaining refractory to conventional pharmacological and surgical treatments. Stem cell therapy represents a promising regenerative treatment. It can repair damaged neural networks, restore inhibitory balance, and modulate the inflammatory microenvironment characteristic of epileptic brains. Preclinical studies using diverse models, such as pilocarpine, kainic acid, and kindling have demonstrated seizure reduction, cognitive improvements, and histological repair following stem cell transplantation. Various cell types associated with stem cells, such as embryonic growth stem cells, neural growth stem cells, induced pluripotent stem cells, and mesenchymal stem cells, have been explored, each offering unique therapeutic advantages and challenges. Early clinical trials have demonstrated preliminary safety and feasibility, with encouraging trends toward seizure control and improvement in quality of life. Innovative strategies, including gene editing, preconditioning, scaffold integration, and exosome-based therapies, are being actively developed to overcome existing translational hurdles. Personalized regenerative approaches, regulatory harmonization, and sustainable economic models are crucial for advancing stem cell therapies from experimental settings to mainstream clinical applications. With continued multidisciplinary collaboration and scientific innovation, stem cell treatment holds the caliber for redefining the assessment of the landscape of refractory epilepsy.

Keywords:  epilepsy; gene editing; induced pluripotent stem cells; mesenchymal stem cells; neural regeneration; neural stem cells; preclinical studies; stem cell therapy

DOI:  https://doi.org/10.1002/epd2.70120
Curr Drug Targets. 2025 Nov 04.

Recent Advances in Organelle-Targeted Drug Delivery: Precision Medicine at the Subcellular Level.

Omar Awad Alsaidan.

  Organelle-targeted drug delivery (OTDD) is an advanced strategy in the field of precision medicine, which delivers therapeutic agents to subcellular organelles. The OTDD provides a more targeted and efficient approach for neurodegenerative, cancer, and metabolic disorders, by addressing the root cause of diseases that are associated with organelle dysfunction. The recent advances in nanotechnology have enabled intelligent drug carriers, which have the potential to target organelles. This study aimed to explore the recent advancements in OTDD, emphasizing the role of nanocarriers, targeting approaches, and stimulus-responsive systems to enhance therapeutic accuracy and overcome major challenges in clinical translation. This review discusses advanced progress in OTDD, focusing on various nanocarriers. It discusses the function of targeting moieties, including peptides and ligands, as well as stimuli-responsive drug delivery systems that are activated by intracellular stimuli, like pH or reactive oxygen species, capable of targeting the delivery of the drug using organelles. Moreover, challenges in clinical translation, regulatory issues, and patient-specific factors are analyzed. OTDD advancements have shown promising preclinical and clinical outcomes in enhancing drug targeting and therapeutic efficiency. However, its clinical use involves barriers in standardization, regulatory approvals, and disease-specific variation, which primarily hinder its clinical application. Personalized strategies need to be employed to enhance the outcome of therapy. The OTDD has the potential to revolutionize subcellular precision medicine by providing specific drugs for different diseases. Interdisciplinary collaboration is required to address the existing challenges and facilitate clinical translation, thereby improving patient- specific therapeutic approaches.

Keywords:  Nanoparticles; nanocarriers.; organelle targeted drug delivery; subcellular organelles

DOI:  https://doi.org/10.2174/0113894501385872251015095644
Sci China Life Sci. 2025 Oct 29.

Efficient mitochondrial DNA editing in rabbits with engineered sTALED base editors.

Di Wang, Yuqiang Qian, Wenchao Niu, Heng Gong, Ding Zhao, Xun Gao, Deqiang Kong, Jiale Zhou, Yang Han, Liangxue Lai, Zhanjun Li.

DOI: https://doi.org/10.1007/s11427-025-3125-8
Epigenomics. 2025 Nov 05. 1-11

Advancing epigenetic signatures as functional biomarkers in rare diseases.

Andrea Ciolfi, Marco Ferilli, Camilla Cappelletti, Marco Tartaglia.

  Alterations of the DNA methylation (DNAm) status of the genome underlie an increasing number of rare diseases. Recently, DNAm has also emerged as a highly informative biomarker for diagnosing rare disorders, which can be associated with distinctive genome-wide DNAm patterns (i.e., episignatures). Indeed, episignature testing has proven to represent an effective orthogonal omics technology, providing independent functional evidence to support or prioritize specific diagnostic hypotheses for hundreds of rare diseases, and reclassify variants of uncertain significance (VUS) emerging from genomic sequencing. Furthermore, the stability and plasticity inherent in DNAm make it a promising tool for personalized medicine, including patient stratification and therapeutic monitoring. This review outlines current technologies and analytical methodologies for genome-wide DNAm profiling and explores potential avenues of research, emphasizing artificial intelligence and multiomics integration to effectively manage patients with rare and complex phenotypes. We critically assess the current limitations and future directions of genome-wide DNAm profiling to expand the implementation of DNAm signatures as functional biomarkers, highlighting their importance as supplementary tools to genomic sequencing in clinical and research settings.

Keywords:  DNA methylation; DNAm signature; animal models; biomarker; diagnosis; epigenomics; episignature; patient stratification; rare diseases; therapy

DOI:  https://doi.org/10.1080/17501911.2025.2583891
Small. 2025 Nov 06. e07981

Ultra-High-Throughput Viscoelastic Squeezing for Mechanoporation and Efficient Intercellular Delivery.

Rashin Mohammadi, Irma Sakic, Ankit Jain, Prerit Mathur, Tobias Weiss, Andrew J deMello, Stavros Stavrakis, Mohammad Asghari.

  Cell-based therapies have transformed the treatment landscape for a range of diseases, leveraging both genome modification and cell reprogramming to create targeted treatments. Such therapies rely on the efficient internalization of biomolecules into living cells. Unfortunately, existing cargo delivery methods, such as those based on viral vectors and electroporation, are often compromised by cytotoxicity, poor delivery efficiencies, and low throughput. To overcome these limitations, a viscoelastic squeezing methodology is presented that uses viscoelastic microfluidics to perform mechanoporation in a rapid and contact-free manner. Through the control of the flow rates of a sample stream containing cells and cargo and a surrounding viscoelastic sheath flow, the width of a "virtual channel" formed between the two streams can be regulated. Elastic forces generated within this virtual channel are then used to deform contained cells and internalize user-defined payloads. The effectiveness and utility of the platform are assessed through the delivery of mRNA, plasmid DNA, and clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) ribonucleoprotein complexes into a variety of cell lines. Data confirms that viscoelastic squeezing provides for enhanced delivery efficiencies when compared to conventional poration techniques, whilst maintaining high cell viabilities and throughputs of 20 million cells per minute, and thus represents a powerful tool for cellular engineering.

Keywords:  cell squeezing; cell transfection; intracellular delivery; mechanoporation; microfluidics

DOI:  https://doi.org/10.1002/smll.202507981
Mol Neurobiol. 2025 Nov 08. 63(1): 14

Insights into the Versatile Role of Extracellular Vesicles in the Treatment of CNS Disorders.

Koushik Jana, Somnath Ghosh, Pijus Parua, Biplab Debnath, Jitu Halder, Rakesh Kumar Sahoo, Vineet Kumar Rai, Deepak Pradhan, Priyanka Dash, Chandan Das, Biswakanth Kar, Goutam Ghosh, Goutam Rath.

  E xtracellular vesicles (EVs) are lipid bilayer-enclosed nanocarriers composed primarily of phospholipids and membrane proteins. They are released by cells into the surrounding extracellular environment and vary in size, composition, and biogenesis pathways. Beyond their natural role in intercellular communication, mediating the transfer of proteins, lipids, and nucleic acids (like mRNA and miRNA) between cells, EVs have emerged as a highly versatile and promising therapeutic platform for a range of challenging disorders, particularly those affecting the central nervous system (CNS) and various cancers. The CNS presents unique therapeutic challenges, notably the formidable blood-brain barrier (BBB), which restricts the entry of most conventional drugs. EVs, however, possess an inherent capacity to traverse this barrier, either naturally or through engineered modifications. This characteristic positions them as ideal nanocarriers for delivering therapeutic payloads such as neurotrophic factors, gene therapy constructs, or anti-inflammatory agents directly to target neural cells for conditions like Alzheimer's disease, Parkinson's disease, stroke recovery, multiple sclerosis, and even glioblastoma. Their biocompatibility and low immunogenicity further reduce systemic side effects, making them a safer alternative to synthetic delivery systems. This review outlines recent progress in extraction techniques using EVs for treating neurological disorders. It covers clinical applications in neurodegenerative, infectious diseases, inflammatory, genetic, and oncological diseases and highlights current limitations and considerations for advancing future research in this evolving field.

Keywords:  Blood–brain barrier (BBB); Central nervous system (CNS); Extracellular vehicles (EVs); Nanocarriers; Neurodegeneration

DOI:  https://doi.org/10.1007/s12035-025-05283-9
Epilepsia Open. 2025 Nov 05.

Self-completed patient-reported outcome measures in adults with epilepsy: A review.

Alison L Conquest, Terence J O'Brien, Patrick Kwan, Jacqueline A French, Charles B Malpas, Emma C Foster.

  Epilepsy affects 65 million people worldwide, and is a World Health Organization priority disease as highlighted in their 2022-2031 Intersectoral Global Action Plan (IGAP) on Epilepsy and other Neurological Disorders. IGAP's objectives include improving epilepsy treatment and care. Patient-reported outcomes measures (PROMs) may assist with this. PROMs are self-report instruments that assess the lived experience of disease, for example, quality of life, mood, and treatment adverse effects. Regulatory agencies recommend including PROMs in clinical trials, and incorporating PROMs into routine clinical practice may improve patient outcomes. We conducted a narrative review of PubMed and health regulatory agencies' guidelines to identify PROMs used in clinical epilepsy research and practice. We identified 390 unique PROMs used in epilepsy settings. We summarize the practical considerations for PROMs selection, including the various psychometric properties that can be used to measure how "good" a PROM is; the role for generic, neurology-specific, and epilepsy-specific PROMs; and ways to optimize the collection of PROMs in clinical settings. This review discusses the strengths and limitations of 22 PROMs, covering four domains (health-related quality of life, disability and seizure severity, mood, and antiseizure medication adverse effects), that are commonly used in clinical epilepsy research and practice. This article may serve as a useful reference for researchers and clinicians when selecting PROMs for use in clinical epilepsy trials and routine clinical practice, and complements the recently published report from the International Consortium for Health Outcomes Measurement that recommends five specific PROMs assessing quality of life, depression, anxiety, cognition, and sleep. The judicious selection and application of PROMs may lead to better understanding of patient experiences, inform clinical decision-making, and ultimately improve outcomes. PLAIN LANGUAGE SUMMARY: Patient-reported outcome measures (PROMs) are questionnaires completed by patients, assisting with communication of their lived experience of disease with clinicians. PROMs cover topics such as quality of life, disability, mood, and treatment side effects. PROMs may improve patient satisfaction and communication with healthcare providers, detect hitherto undisclosed issues, and can be used to monitor treatment response. This current review summarizes the strengths and limitations of 22 PROMs that are commonly used in clinical epilepsy research and practice.

Keywords:  epilepsy; mood disorders; patient reported outcome; quality of life; seizure

DOI:  https://doi.org/10.1002/epi4.70170
Am J Med Genet C Semin Med Genet. 2025 Nov 03.

Navigating Drug Discovery for Myhre Syndrome: The Complexity of a Multisystemic Rare Disease.

Armelle Pindon, Nicola Brunetti-Pierri, Kathy H Young, Mary K Young, Maria J Macias, Xiulei Mo.

  Myhre syndrome is a rare, multisystemic disorder caused by gain-of-function mutations in the SMAD4 gene, a key component of the TGF-β signaling pathway. These mutations lead to manifestations affecting neurodevelopment, bone and joint development, fibrosis and stenosis, immune responses, reproductive health, and cardiac function. The Myhre Syndrome Foundation (MSF) is a patient-centered organization focused on accelerating drug discovery while supporting patients, prioritizing research targeting fibrosis/stenosis and autism/intellectual and developmental disabilities, the most significant burdens reported by patients. Their short-term strategy involves: (1) Creating and running a preclinical platform to screen potential treatments using patient-derived and animal models. (2) Clinical readiness, addressing challenges associated with low disease incidence and heterogeneity in clinical trial design, by developing multi-domain endpoints, responder index, and biobanks/biomarkers. (3) Target identification investigating SMAD4 pathogenic variants rewiring protein-protein interactions in key signaling pathways. (4) Fostering partnerships with regulatory authorities, industries, and other patient research organizations. The MSF portfolio includes targeting fibrosis with immunotherapy using FAP-CAR-T cells, and a precision medicine approach aimed at restoring normal SMAD4 function through gene editing and small molecules. MSF aims to develop therapies that address both acute and chronic manifestations of this complex disease, improving the quality of life for affected individuals.

Keywords:  Myhre syndrome; SMAD4; TGF‐β; drug discovery; multisystemic; neo‐PPI; patient‐organization

DOI:  https://doi.org/10.1002/ajmg.c.32156
Future Microbiol. 2025 Nov 04. 1-10

Regulation of mitochondria functions by Mycobacterium tuberculosis infection.

Jing Wang, Caixing Cao, Jiale Hua, Yahui Zhang, Changxin Wu, Li Xing.

  Tuberculosis, a leading killer among infectious diseases worldwide, is caused by Mycobacterium tuberculosis (Mtb). Mtb has strong ability to manipulate the intracellular environment of macrophages for successful surviving. Mitochondrion is a key organelle involved in diverse physiological processes, including Ca2+ fluxes, ATP synthesis, bioenergetic metabolism, and cell death, which are pivotal to cellular and organismal homeostasis. Mitochondrion is also targeted by Mtb to control various physiological responses of the host. Mtb has evolved a series of strategies to manipulate mitochondrial functions in favor of their survival, replication, and dissemination. In mitochondrion, Mtb regulates cell energy metabolism and cell death pathway. Herein, we reviewed the latest advances in the interactions between Mtb and mitochondria and discussed multiple aspects of the influence of Mtb on mitochondrial metabolism to shed light on the Mtb-induced pathogenesis.

Keywords:  Mycobacterium tuberculosis; Tuberculosis; cell death pathway; energy metabolism; mitochondria

DOI:  https://doi.org/10.1080/17460913.2025.2582374