bims-polgdi Biomed News
on POLG disease
Issue of 2025–10–26
39 papers selected by
Luca Bolliger, lxBio
  1. Macular OCT inner retinal changes reflect CNS involvement in m.3243A>G disease.
  2. Molecular consequences of mitochondrial replacement may be masked from organismal traits in Tigriopus californicus.
  3. Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency.
  4. Correlation of Body Mass Index and Exercise on Telomere Length and Mitochondrial DNA Copy Number in Saliva Samples.
  5. Stem-cell-derived extracellular vesicles in neurodegeneration and neuroaging: therapeutic potential and challenges.
  6. Calcium dynamics unplugged: NCLX in disease and therapeutic frontiers.
  7. Mitochondrial genotypes affect thermal plasticity of longevity in Drosophila melanogaster.
  8. Stem cell-free therapy for healthy brain aging: Mechanisms, challenges, and prospects.
  9. The IQ-compete assay for measuring mitochondrial protein import efficiencies in living yeast cells.
  10. The development and emerging trends in Parkinson's disease from the perspective of mitochondrial dysfunction: a bibliometric analysis using CiteSpace.
  11. Mitochondrial orchestration of PANoptosis: mechanisms, disease pathogenesis, and emerging therapeutic frontiers.
  12. Subcellular two-pronged targeting therapeutics: disrupting mitochondria-endoplasmic reticulum communication in inflammatory disorders.
  13. Development of Two In Vitro ND1-LHON Models for Evaluating Gene Therapy Efficacy.
  14. Association of Epigenetic Age Acceleration and Mitochondrial DNA-Based Aging Metrics Provides Insights Into Mechanisms of Aging-Related Diseases.
  15. Implications of the mitochondrial CB1 receptor in the brain: from mitochondrial dysfunction to neuroprotection.
  16. Dravet syndrome diagnosed in adults.
  17. Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
  18. Molecular reflection of the mind: Exosomes in major depressive disorder.
  19. Short-Chain Fatty Acids as a Therapeutic Strategy in Parkinson's Disease: Implications for Neurodegeneration.
  20. Mitochondrial dysfunction in age-related sarcopenia: mechanistic insights, diagnostic advances, and therapeutic prospects.
  21. The hidden driver of osteoporosis: mitochondria-dominated inflammation.
  22. Mitochondrial dysfunction, a new marker warning of neuropsychiatric disorder risk: evidence from genetics and epidemiology.
  23. Neuromuscular disorders with evidence of both neuropathic and myopathic phenotype.
  24. Novel single-domain antibodies targeting a unique transferrin receptor 1 epitope for cross-species delivery of drugs in the central nervous system.
  25. Newborn screening for fatty acid oxidation disorders: epidemiological and genetic findings in Southeastern China.
  26. A brain-body perspective on thermoregulatory adaptation.
  27. Can Gene Therapy Transform the Treatment Landscape of Posterior Segment Eye Diseases? A Comprehensive Review of Recent Advancements.
  28. Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.
  29. Challenges and opportunities in nanotherapeutics targeted for central nervous system disorders.
  30. Dimethyl fumarate reprograms cervical cancer cells to enhance antitumor immunity by activating mtDNA-cGAS-STING pathway.
  31. Effects of acute psychological stress on blood cell-free mitochondrial DNA (cf-mtDNA): A crossover experimental study.
  32. Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT.
  33. [Ferroptosis: from molecules to diseases].
  34. Bringing Genetics to Mental Health: Integrating Genetic Counseling into a Mental Health Program at Monash Health, Australia.
  35. A PLAN to address the Parkinson pandemic.
  36. TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.
  37. SIRT1-Mediated Mitochondrial Homeostasis in Cardiac Aging: Molecular Mechanisms and Therapeutic Implications.
  38. Dravet syndrome therapeutics: where are we, what works, and what's next?
  39. Revitalizing equine metabolism: how SHBG improves mitochondrial function and reduces inflammation.
  1. BMJ Neurol Open. 2025 ;7(2): e001232
    Macular OCT inner retinal changes reflect CNS involvement in m.3243A>G disease.
    Hatem Jouda, Andrew C Browning, Akhunzada M Aftab, Ikhlas Mahmoud, Saima Bibi, Robert McFarland, Sarah J Pickett, Helen Devine.
       Background: The m.3243A>G mitochondrial DNA variant is the most common cause of adult mitochondrial disease and is associated with a heterogeneous clinical phenotype. The retina and optic nerve are among the most metabolically active tissues, making them vulnerable to mitochondrial dysfunction. Optical coherence tomography (OCT) studies have demonstrated retinal nerve fibre layer (RNFL) thinning in mitochondrial and other neurodegenerative diseases. We investigated whether temporal RNFL thinning is associated with central nervous system (CNS) involvement in individuals with the m.3243A>G variant.
    Methods: High-resolution OCT was used to assess peripapillary RNFL thickness and perform macular segmentation. Participants were categorised into normal RNFL (n=14) or temporal RNFL thinning (n=15) groups. Demographic data, mean-corrected m.3243A>G heteroplasmy, Newcastle Mitochondrial Disease Adult Scale (NMDAS) scaled scores and NMDAS neurological traits were compared.
    Results: Temporal RNFL thinning was significantly associated with neurological features (Fisher's exact test, p=0.027). In multivariable analysis, RNFL thinning and age were independent predictors of neurological involvement. Macular OCT revealed concomitant thinning of the ganglion cell-inner plexiform (GC-IPL) complex in the RNFL thinning group, with preservation of outer retinal layers, supporting primary retinal ganglion cell vulnerability. No significant associations were found between RNFL thinning and m.3243A>G heteroplasmy or NMDAS scaled scores.
    Conclusion: Temporal RNFL thinning, accompanied by GC-IPL loss, is associated with neurological involvement in m.3243A>G-related mitochondrial disease, supporting its potential as a non-invasive biomarker of CNS dysfunction. Longitudinal studies are needed to determine whether these retinal changes are progressive and predictive of neurological decline.
    Keywords:  CLINICAL NEUROLOGY; MITOCHONDRIAL DISORDERS; NEUROMUSCULAR; NEUROOPHTHALMOLOGY
    DOI:  https://doi.org/10.1136/bmjno-2025-001232
  2. PLoS One. 2025 ;20(10): e0335181
    Molecular consequences of mitochondrial replacement may be masked from organismal traits in Tigriopus californicus.
    Jacob R Denova, Ben A Flanagan, Murad Jah, Scott L Applebaum, Suzanne Edmands.
      Mitochondrial replacement therapy (MRT) presents a promising preventative measure to combat mitochondrial diseases. However, the long-term consequences of disrupting mitonuclear coevolution at both the molecular and organismal levels remain understudied. Data on sex-specific effects are also lacking despite predictions that males may be especially vulnerable to mitochondrial replacement. To address this, we used backcrossed lines of the copepod Tigriopus californicus to produce offspring with nuclear genotype contributions from two populations and a mitochondrial genotype from a third, separate, population. When compared to hybrid controls with mitochondrial genotypes that matched the maternal nuclear genotype but not the paternal, these "three-parent offspring" did not significantly differ in lifespan or routine metabolic rate. While these organismal-level traits showed no effect, molecular metrics of mitochondrial health revealed consequences of mitochondrial replacement. Oxidative DNA damage, measured by 8-hydroxy-2'-deoxyguanosine content, was higher in three-parent offspring, and mitochondrial DNA content was lower than in hybrid controls. While differences between sexes were present in some traits, sex did not interact with mitochondrial replacement for any of these metrics. Although these results could be due either to donor mitochondrial DNA matching neither of the nuclear parents, or to deficits in the donor mitochondrial DNA itself, they highlight the importance of considering molecular level consequences of mitochondrial replacement that may be masked at the organismal level when evaluating the health impacts of this treatment.
    DOI:  https://doi.org/10.1371/journal.pone.0335181
  3. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2505237122
    Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency.
    John Soukar, Kanwar Abhay Singh, Ari Aviles, Sarah Hargett, Harman Kaur, Samantha Foster, Shounak Roy, Feng Zhao, Vishal M Gohil, Irtisha Singh, Akhilesh K Gaharwar.
      Intercellular mitochondrial transfer, the spontaneous exchange of mitochondria between cells, is a recently described phenomenon crucial for cellular repair, regeneration, and disease management. Enhancing this natural process holds promise for developing novel therapies targeting diseases associated with mitochondrial dysfunction. Here, we introduce a nanomaterial-based approach employing molybdenum disulfide (MoS2) nanoflowers with atomic-scale vacancies to stimulate mitochondrial biogenesis in cells to make them mitochondrial biofactories. Upon cellular uptake, these nanoflowers result in a two-fold increase in mitochondrial mass and enhancing mitochondrial transfer to recipient cells by several-fold. This enhanced efficiency of transfer significantly improves mitochondrial respiratory capacity and adenosine triphosphate production in recipient cells under physiological conditions. In cellular models of mitochondrial and cellular damage, MoS2 enhanced mitochondrial transfer achieved remarkable restoration of cell function. This proof-of-concept study demonstrates that nanomaterial-boosted intercellular mitochondrial transfer can enhance cell survivability and function under diseased conditions, offering a promising strategy for treating mitochondrial dysfunction-related diseases.
    Keywords:  biomaterials; cellular medicine; mitochondria; nanomaterials; regenerative medicine
    DOI:  https://doi.org/10.1073/pnas.2505237122
  4. FASEB J. 2025 Oct 31. 39(20): e71159
    Correlation of Body Mass Index and Exercise on Telomere Length and Mitochondrial DNA Copy Number in Saliva Samples.
    Fatemeh Masoudi, Sareh Arjmand, Rana Fayazmilani, Samira Pourmirzaei.
      Mitochondrial DNA (mtDNA) copy number and telomere length are widely recognized as biomarkers of cellular aging and metabolic health. This study aimed to investigate the relationships between BMI, exercise modality, mtDNA copy number, and telomere length using saliva samples from Iranian adults. Participants (n = 96) were categorized into four groups: endurance athletes, strength athletes, overweight/obese individuals (BMI > 25), and healthy controls (BMI 18-25). Saliva samples were collected for DNA extraction, and mtDNA copy number and telomere length were quantified using real-time PCR. Statistical analyses included Kruskal-Wallis and Dunnett's post hoc tests, as well as linear regression to assess correlations among variables. The results indicated that endurance athletes exhibited a significantly higher mtDNA copy number compared to controls and strength athletes, reflecting enhanced mitochondrial biogenesis from aerobic training. No significant differences in telomere length were observed among groups. While BMI showed no significant correlation with telomere length or mtDNA copy number overall, a significant negative correlation between mtDNA copy number and BMI was found exclusively in endurance athletes. Additionally, a strong positive correlation between mtDNA copy number and telomere length was observed in all groups except strength athletes. No significant differences were found between saliva and blood samples for either biomarker, and women demonstrated longer telomeres than men. This study highlights the positive impact of endurance exercise on mitochondrial biogenesis while revealing complex relationships between BMI, exercise modality, and cellular aging biomarkers. These findings offer insights into exercise-specific effects on cellular aging.
    Keywords:  body mass index; endurance athletes; mitochondrial DNA copy number; strength athletes; telomere length
    DOI:  https://doi.org/10.1096/fj.202501961R
  5. Extracell Vesicles Circ Nucl Acids. 2025 ;6(3): 594-608
    Stem-cell-derived extracellular vesicles in neurodegeneration and neuroaging: therapeutic potential and challenges.
    Mohit Kumar, Sudipta Ray, Susmita Sil.
      Neuroaging is a complex biological process in which the brain undergoes progressive functional decline marked by synaptic loss, neuroinflammation, and cognitive decline. At the molecular and cellular level, aging is driven by multiple interconnected hallmarks, including genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Among these, cellular senescence, a state of irreversible cell cycle arrest, has emerged as a critical contributor to brain aging. Senescent cells accumulate with age, driven by the p53-p21 and p16-pRb pathways, and secrete pro-inflammatory factors via senescence-associated secretory phenotype (SASP), thereby exacerbating neurodegeneration, vascular dysfunction, and cognitive decline. Extracellular vesicles (EVs) are natural nanocarriers of proteins, lipids, and nucleic acids, and have emerged as key mediators of intercellular communication and therapeutics for aging and age-related conditions. EVs derived from various cell types, such as mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), can modulate senescence-related pathways, reduce inflammation, and promote tissue repair. Preclinical studies demonstrate that stem-cell-derived EVs can improve cognitive performance, enhance neurogenesis, reduce senescence phenotype, improve neuronal survival through neuroprotective miRNAs (miR-181a-2-3p), suppress neuroinflammation via inhibition of NLRP3 inflammasome, and support synaptic plasticity. Stem cell EVs possess natural biocompatibility, the ability to cross the blood-brain barrier (BBB), and targeted delivery mechanisms, making them promising candidates for anti-aging interventions. This review elaborates on the multifaceted role of stem cell EVs in mitigating brain aging, senescence, and age-associated chronic disease phenotype.
    Keywords:  Brain aging; extracellular vesicles; neurodegeneration; stem cell therapy
    DOI:  https://doi.org/10.20517/evcna.2025.65
  6. Mol Biol Rep. 2025 Oct 25. 53(1): 12
    Calcium dynamics unplugged: NCLX in disease and therapeutic frontiers.
    Dhriti Majumder.
      Mitochondrial ion channels and transporters are pivotal for cellular bioenergetics, signalling, and homeostasis, with the sodium-calcium-lithium exchanger (NCLX) emerging as a critical regulator of mitochondrial calcium dynamics. By extruding calcium in exchange for sodium or lithium ions, NCLX prevents calcium overload, a key contributor to mitochondrial dysfunction and cell death. While previous reviews have explored NCLX in the context of specific diseases or immune cell function, this article provides a comprehensive analysis of its role across multiple disease states, including cardiovascular, neurological, metabolic, and pregnancy-related conditions. Moreover, it highlights the potential of ethnobotanical compounds such as resveratrol and curcumin as therapeutic candidates targeting NCLX. By integrating insights from structural biology, disease mechanisms, and emerging therapeutic strategies, this review aims to advance our understanding of NCLX's role in pathophysiology and explore novel avenues for its targeted modulation in diseases characterized by disrupted mitochondrial calcium homeostasis.
    Keywords:  Calcium exchange; Cardiovascular diseases; Mitochondria; NCLX; NCLX targeting therapeutics; Neurodegeneration
    DOI:  https://doi.org/10.1007/s11033-025-11188-6
  7. J Evol Biol. 2025 Oct 20. pii: voaf127. [Epub ahead of print]
    Mitochondrial genotypes affect thermal plasticity of longevity in Drosophila melanogaster.
    Ekta Kochar, Venkatesh Nagarajan-Radha, Rebecca E Koch, Damian K Dowling.
      Sequence variation in mitochondrial DNA was once considered neutral, but growing evidence indicates it can influence metabolic, physiological and life-history traits. Two hypotheses offer explanations for this non-neutral mtDNA variation: the mitochondrial climatic adaptation hypothesis, which posits that natural selection shapes mtDNA variation to match local environments, and the mother's curse hypothesis, which predicts the accumulation of male-harming variants due to maternal inheritance. We explored these hypotheses using genetic strains of Drosophila melanogaster bearing eight mtDNA haplotypes-nested within two distinct haplogroups (A1 and B1) that segregate along an Australian latitudinal cline. We measured the longevity of flies under cool (18 °C) and warm (28 °C) conditions, predicting that the A1 haplogroup-which has been reported to predominate at subtropical latitudes-would confer higher longevity in warm but reduced longevity in cool temperatures relative to the B1 counterpart. We also tested whether effects of mtDNA haplotype on longevity were larger in males, as predicted under the mother's curse hypothesis. We found mtDNA haplogroup and haplotype is associated with longevity, with the magnitude of effects varying with temperature, but not in a pattern consistent with either hypothesis. Haplogroup-by-environment interactions did not align with reported spatial distributions of the haplogroups, and haplotype effects on longevity were similar across sexes. Our findings add to the growing evidence that mtDNA variation contributes to thermal plasticity in longevity, but do not provide clear insight into whether this variation is adaptive or maladaptive.
    Keywords:  climatic adaptation; gene-by-environment; lifespan; mitochondrial haplotype; mitochondrial plasticity; mother’s curse; mtDNA; phenotypic plasticity; thermal stress
    DOI:  https://doi.org/10.1093/jeb/voaf127
  8. Biomed Pharmacother. 2025 Oct 22. pii: S0753-3322(25)00870-4. [Epub ahead of print]192 118676
    Stem cell-free therapy for healthy brain aging: Mechanisms, challenges, and prospects.
    Jahnavy Madhukar Joshi, Shweta Verma, Raviraja Neelavar Seetharam, Abhishek Kumar Singh.
      The stem cell secretome, which includes bioactive molecules and extracellular vesicles (EVs), has been reported to have neuroprotective effects in various neurological conditions. Current research indicates that secretome constituents, particularly EVs, can regulate pathways related to aging hallmarks and are therapeutic targets for brain aging. EVs can traverse the blood-brain barrier (BBB) and transfer neuroprotective cargoes such as proteins, peptides, miRNAs, and lipids to aged neural tissue. By acting on inflammation, apoptosis, mitochondrial damage, and cellular senescence, the secretome can restore neural homeostasis and induce neurogenesis and angiogenesis. While stem cell therapy is hindered by the risk of tumorigenicity and immune rejection, secretome and EV-based acellular therapies are safer and possibly more targeted choices. The content and delivery optimization of such vesicles to influence significant regulatory pathways of aging is currently of interest. This review highlights the dual importance of mechanistic insights and translational perspectives and discusses our current understanding of how the secretome, along with EVs, regulates hallmarks of brain aging with practical aspects of clinical application. The present review provides a novel and comprehensive analysis of current knowledge on stem cell-derived secretome and EVs as targeted modulators for healthy brain aging, with a critical evaluation of translational hurdles and clinical implementation.
    Keywords:  Age-related disorders; Aging; Extracellular vesicles; Stem cell secretome
    DOI:  https://doi.org/10.1016/j.biopha.2025.118676
  9. FEBS Lett. 2025 Oct 25.
    The IQ-compete assay for measuring mitochondrial protein import efficiencies in living yeast cells.
    Yasmin Hoffman, Annika Egeler, Saskia Rödl, Johannes M Herrmann.
      Most mitochondrial proteins are synthesized in the cytosol and imported into the organelle. Here, we describe a novel Import and de-Quenching Competition (IQ-compete) assay which monitors the import efficiency of model proteins by fluorescence in living cells. For this method, the sequence of the tobacco etch virus (TEV) protease is fused to a mitochondrial precursor and coexpressed with a cytosolic reporter which becomes fluorescent upon TEV cleavage. Thus, inefficient import of the fusion protein leads to a fluorescent signal. With the IQ-compete assay, the import efficiency of proteins can be reliably analyzed in fluorescence readers, by flow cytometry, by microscopy, and by western blotting. We are convinced that the IQ-compete assay will be a powerful strategy for many different applications. Impact statement This article describes a novel method to monitor the mitochondrial import efficiency for a given protein in living yeast cells. With this IQ-compete assay, protein import efficiencies can be quantified by fluorescent microscopy, flow cytometry, fluorescence spectrometry or western blotting.
    Keywords:  fluorescence quenching; genetically encoded sensors; mitochondria; presequences; protein targeting
    DOI:  https://doi.org/10.1002/1873-3468.70206
  10. J Neurol. 2025 Oct 22. 272(11): 721
    The development and emerging trends in Parkinson's disease from the perspective of mitochondrial dysfunction: a bibliometric analysis using CiteSpace.
    Yanzhi Lu, Xuannan Chen, Yu Lai.
       BACKGROUND: Parkinson's disease (PD) is an increasingly prevalent neurodegenerative disease. Although diagnosis and management have improved, the global burden remains a significant concern. Currently, it is challenging to achieve effective treatment due to the gap in understanding the pathological cascade mechanism of PD. Converging clinical, genetic, and experimental evidence suggests that mitochondrial dysfunction plays a central role in the pathogenesis of PD. Therefore, research progress and the systematic exploration of the remaining unknowns regarding mitochondrial dysfunction in PD are clarifying pathogenesis and guiding therapeutic strategies.
    METHODS: Using CiteSpace, we collected 5,040 publications on PD and mitochondrial dysfunction from Web of Science Core Collection. Visualization analysis based on betweenness centrality, count, and burst values aims to identify current research hotspots and predict emerging trends.
    RESULTS: Recent years have seen a significant increase in publications on PD and mitochondrial dysfunction. Current research hotspots focus on "oxidative stress," "alpha-synuclein," "rotenone," "PINK1/Parkin pathway," "complex I," and various neurodegenerative diseases. Analysis predicts "NLRP3 inflammasome," "cognitive impairment," "gut microbiota," and "insulin resistance" as potential future research frontiers. Multidimensional pathway exploration is crucial for comprehensively understanding PD pathogenesis, with mitochondrial dysfunction serving as a central hub that represents a key future therapeutic target.
    CONCLUSION: The multipathology of PD creates synergistic therapeutic opportunities, particularly through mitochondria-focused approaches that modulate core disease mechanisms. On this basis, enhancing mitochondrial biogenesis is a fundamental path forward, moving beyond protection to actively restore mitochondrial networks and promote neuronal recovery. These findings help comprehend PD's complex pathogenesis and guide precision therapeutic strategies.
    Keywords:  Bibliometric analysis; CiteSpace; Mitochondrial dysfunction; Neurodegenerative disease; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s00415-025-13472-8
  11. Cell Death Discov. 2025 Oct 21. 11(1): 476
    Mitochondrial orchestration of PANoptosis: mechanisms, disease pathogenesis, and emerging therapeutic frontiers.
    Jiale Zhang, Xiaoya Fu, Feifan Jia, Yahao Jing, Jiameng Zhang, Aoxue Bai, Mengyuan Cui, Lei Zhang, Kunhou Yao.
      Mitochondria, traditionally known as cellular powerhouses, are now recognized as central regulators of programmed cell death (PCD) and key players in disease pathogenesis. This review synthesizes current knowledge on mitochondrial mechanisms in PANoptosis-a convergent pathway integrating apoptosis, necroptosis, and pyroptosis-and their implications in diverse pathologies. Mitochondria govern intrinsic apoptosis via Bcl-2 family proteins and mitochondrial outer membrane permeabilization (MOMP), amplify necroptosis through RIPK1/RIPK3-driven ROS signaling, and indirectly regulate pyroptosis via inflammasome-mitochondria crosstalk. Dysfunctional mitochondria contribute to neurodegenerative diseases, cardiovascular disorders, cancer, and autoimmune/metabolic syndromes. Emerging therapies targeting mitochondrial pathways, such as Bcl-2 inhibitors, mPTP modulators, and ROS-inducing agents, demonstrate clinical promise in restoring cell death sensitivity and mitigating inflammation. By bridging molecular mechanisms with therapeutic innovations, this work underscores mitochondria as dynamic hubs of cellular fate and disease intervention.
    DOI:  https://doi.org/10.1038/s41420-025-02750-z
  12. Acta Biomater. 2025 Oct 17. pii: S1742-7061(25)00775-5. [Epub ahead of print]
    Subcellular two-pronged targeting therapeutics: disrupting mitochondria-endoplasmic reticulum communication in inflammatory disorders.
    Jianheng Ren, Yuanyi Hua, Zhumei Liao, Xin Wen, Qin Wang.
      Researchers have made significant efforts to develop mitochondria or endoplasmic reticulum (ER)-targeting strategies to regulate cellular signaling cascades in inflammatory diseases. Although ER and mitochondria function relatively independently, these organelles can form extensive physical interactions, known as mitochondria-associated ER membranes (MAMs). Emerging evidence suggests that the development of inflammatory diseases depends largely on the pathological crosstalk between mitochondria and ER through MAMs, whereby ER stress and mitochondrial dysfunction collectively activate inflammatory signaling. Due to the presence of MAMs, single-organelle (ER or mitochondria)-specific therapies may not adequately suppress inflammatory signaling activation, highlighting the need for two-pronged strategies to thoroughly interfere with the pathological crosstalk between ER and mitochondria. This review highlights how the interaction between mitochondria and ER contributes to the progression of inflammatory diseases, and systematically summarizes the current advances in delivery strategies for ER and mitochondria targeting. Furthermore, we emphasize the therapeutic potential of simultaneously regulating mitochondrial and ER function to achieve precise control of inflammatory disorders. Our review aims to establish a framework for two-pronged targeting strategies that can restore ER and mitochondrial homeostasis, thereby facilitating the treatment of inflammatory diseases. STATEMENT OF SIGNIFICANCE: Due to the extensively formed mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) under inflammatory conditions, previous studies focusing on modulating the dysfunction of either mitochondria or ER have demonstrated limited efficacy in inflammatory disorders. MAM-mediated pathological inter-organelles crosstalk can drive the vicious cycle between mitochondria dysfunction and ER stress in inflammatory diseases, underscoring the need for two-pronged approaches that precisely disrupting mitochondria-ER communication. This review highlighted the key role of MAMs in inflammation and summarized recent advances in ER/mitochondria targeted delivery strategies. Furthermore, we underscored the potential therapeutic targets within MAMs for inflammatory intervention, and discussed therapeutic potential of two-pronged approaches in restoring organelle homeostasis and mitigating inflammatory diseases.
    Keywords:  Drug delivery systems; Inflammatory diseases; Mitochondrial-associated endoplasmic reticulum membranes (MAMs); Organelle targeting
    DOI:  https://doi.org/10.1016/j.actbio.2025.10.029
  13. Invest Ophthalmol Vis Sci. 2025 Oct 01. 66(13): 34
    Development of Two In Vitro ND1-LHON Models for Evaluating Gene Therapy Efficacy.
    Xin Li, Jun Yuan, Zhang Chen, Yue Zhang, Yuefeng Liu, Yong Zhang.
       Purpose: The purpose of this study was to address the lack of effective treatments for NADH-ubiquinone oxidoreductase chain 1 (ND1)-related Leber hereditary optic neuropathy (LHON), this study aimed to (1) establish in vitro models mimicking mitochondrial dysfunction in LHON and (2) evaluate the therapeutic potential of recombinant adeno-associated virus (AAV)-mediated ND1 gene therapy (rAAV-ND1).
    Methods: Two in vitro models were developed: (1) transmitochondrial cybrid cells carrying the m.3460G>A mutation in the ND1 gene; and (2) patient-derived induced pluripotent stem cells (iPSC)-differentiated retinal ganglion cells (RGCs). Mitochondrial function was assessed via measurements of oxygen consumption and adenosine triphosphate (ATP) production. The efficacy of rAAV-ND1 was tested by infecting both models to rescue mitochondrial deficiency.
    Results: Our two LHON models - ND1-mutant cybrid cells and patient-derived iPSC-RGCs - successfully recapitulated characteristic mitochondrial dysfunction, demonstrating impaired oxidative phosphorylation and reduced ATP production. Through qPCR and subcellular fractionation analyses, we confirmed dose-dependent ND1 transgene expression and proper mitochondrial localization. Notably, rAAV2-ND1 treatment effectively restored mitochondrial function in both models: in ND1-cybrids, it recovered spare respiratory capacity to 85% of the control levels, enhanced complex I activity from 65.5% to 90.5%, and increased ATP production from 47.6% to 69.5%; whereas in ND1-RGCs, it also ameliorated bioenergetic deficits, partially reversing SRC reduction, and improving ATP-linked respiration.
    Conclusions: The study demonstrates the utility of transmitochondrial cybrids and iPSC-derived RGCs as reliable in vitro models for studying ND1-related LHON. The rAAV-ND1 gene therapy effectively restored mitochondrial function, highlighting its potential as a treatment for LHON caused by ND1 mutations. These findings underscore the value of in vitro systems for evaluating therapies when robust animal models are unavailable.
    DOI:  https://doi.org/10.1167/iovs.66.13.34
  14. Aging Cell. 2025 Oct 24. e70279
    Association of Epigenetic Age Acceleration and Mitochondrial DNA-Based Aging Metrics Provides Insights Into Mechanisms of Aging-Related Diseases.
    Mengyao Wang, Yinan Zheng, Meng Lai, Emmanuel Saake, Xue Liu, Xiuqing Guo, Kent D Taylor, Tianxiao Huan, Roby Joehanes, Drew R Nannini, Kai Zhang, Nicole J Lake, Christina A Castellani, Stephen S Rich, Jerome I Rotter, Yongmei Liu, Laura M Raffield, April P Carson, Myriam Fornage, Jiantao Ma, Dan E Arking, Lifang Hou, Daniel Levy, Chunyu Liu.
      Investigating the interplay between mitochondrial DNA (mtDNA) variations and epigenetic aging metrics may elucidate biological mechanisms associated with age-related diseases. We estimated epigenetic age acceleration (EAA) metrics from DNA methylation data and derived mtDNA metrics, including heteroplasmic variants and mtDNA copy number (mtDNA CN) from whole genome sequencing. Linear regressions and meta-analyses were conducted to assess associations between EAA and mtDNA metrics, adjusting for chronological age, self-identified sex, and other covariates in 6,316 participants (58% female, 41% non-White Americans). Mediation analysis was conducted to examine whether EAA mediated the relationship between mtDNA CN and metabolic traits. A higher burden of rare heteroplasmic variants was associated with accelerations of first-generation EAA metrics, while a lower level mtDNA CN was associated with accelerations of second- and third-generation EAA metrics. For example, one standard deviation (SD) higher MSS, a score based on the predicted functions of rare heteroplasmic variants, was associated with a 0.22-year higher EAA by the Hannum method (p = 1.3E-6) among all participants, while one SD lower mtDNA CN was associated with higher DunedinPACE (β = -0.005, p = 6.0E-4). No significant association was observed between the heteroplasmy burden of common variants and EAAs. Furthermore, we observed DunedinPACE mediated 11.1% and 10.8% of the associations of mtDNA CN with obesity and T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants.
    Keywords:  DNA methylation; epigenetic aging; heteroplasmy; mitochondrial DNA
    DOI:  https://doi.org/10.1111/acel.70279
  15. Rev Neurosci. 2025 Oct 22.
    Implications of the mitochondrial CB1 receptor in the brain: from mitochondrial dysfunction to neuroprotection.
    Ari Misael Martínez-Torres, Keyla Tamara Cerdán-Centeno, Crisalde Ramirez-Celis, Suly Peniche-Zamudio, Teresa de Jesús Durán-González, Camila Roa-Gutierrez, Cynthia Navarro-Mabarak, Julio Morán.
      Mitochondrial activity is essential for brain function, as ATP produced by mitochondria is crucial for neuronal activity, growth, and regeneration. Bioenergetic failure is a hallmark in neurodegenerative and acquired brain diseases and converts the mitochondria into a molecular target to prevent neuronal death. Mitochondrial regulation can play a crucial role in energetic balance, calcium homeostasis, and neuronal signaling. Different molecules have been implicated in the regulation of this organelle, and recently, the endocannabinoid system (ECS) became a relevant mitochondrial regulator through the mitochondrial CB1 receptor (mtCB1R). The recent discovery of this receptor and its participation in mitochondrial homeostasis opens new insights about its role in neuronal plasticity and neurodegeneration. This review briefly describes the endocannabinoid system, with a major focus on mtCB1R and its role in mitochondrial homeostasis, learning, memory, and neuronal death. Relevant aspects of the role of mtCB1R in the brain in health and diseases remain unclear; however, exploring this topic holds promising implications in the comprehension of mitochondrial degeneration and future therapeutic advantages.
    Keywords:  cannabinoids; endocannabinoid system; mitochondrial dysfunction; mtCB1; neurodegeneration
    DOI:  https://doi.org/10.1515/revneuro-2025-0086
  16. Pract Neurol. 2025 Oct 24. pii: pn-2025-004743. [Epub ahead of print]
    Dravet syndrome diagnosed in adults.
    Alex M Dudley, Javier Peña-Ceballos, Hany El-Naggar, Patrick B Moloney, Norman Delanty.
      Dravet syndrome is a rare and severe developmental and epileptic encephalopathy, caused by pathogenic variants of SCN1A in 80%-90% of patients. It is a clinical diagnosis typically made in childhood, but many adults who may never have had appropriate genetic testing remain undiagnosed. We present four patients with longstanding drug-resistant epilepsy and intellectual disability where genetic testing led to a diagnosis of Dravet syndrome or another SCN1A-related epilepsy syndrome. These descriptions highlight important and atypical clinical features. There are also challenges including interpreting variants of uncertain significance, and considering the function of the SCN1A variant. It is important to recognise Dravet syndrome in adults, since inappropriate antiseizure medications increase the risk of seizures. As precision medicine and gene therapies advance, it is increasingly important to make an accurate clinical and molecular diagnosis. Neurologists should consider Dravet syndrome in adults with early-onset epilepsy and intellectual disability.
    Keywords:  EEG; EPILEPSY; GENETICS; NEUROPHARMACOLOGY
    DOI:  https://doi.org/10.1136/pn-2025-004743
  17. Mol Cell. 2025 Oct 20. pii: S1097-2765(25)00815-9. [Epub ahead of print]
    Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
    Nils Bertram, Toshiaki Izawa, Felix Thoma, Serena Schwenkert, Stéphane Duvezin-Caubet, Sae-Hun Park, Nikola Wagener, Anne Devin, Christof Osman, Walter Neupert, Dejana Mokranjac.
      Ribosome-associated protein quality control (RQC) protects cells against the toxic effects of faulty polypeptides produced by stalled ribosomes. However, mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins that are generated in this process, and faulty nuclear-encoded mitochondrial proteins are handled by the recently discovered mitoRQC. Here, we performed a genome-wide screen in yeast to identify additional proteins involved in mitoRQC. We found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without majorly affecting the CAT-tailing process itself. Peptidyl-tRNA hydrolase activity is essential during this process, yet the activity of Pth2 can be substituted by another peptidyl-tRNA hydrolase upon proper localization. Our data suggest that Pth2 acts by modulating protein translocation and that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones. Other hits obtained in the screen show that, in general, delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
    Keywords:  RQC; TOM complex; cellular homeostasis; mitoRQC; mitochondria; peptidyl-RNA hydrolase; protein translocation
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.030
  18. Brain Res Bull. 2025 Oct 16. pii: S0361-9230(25)00401-0. [Epub ahead of print]232 111589
    Molecular reflection of the mind: Exosomes in major depressive disorder.
    Shayan Boozarjomehri Amnieh, Mohammad Yazdi, Melika Abrishami, Nazanin Zahra Keshvari, Kiarash Saleki, Nima Rezaei.
      Exosomes, nanoscale extracellular vesicles (EVs) released by neural and peripheral cells, have become essential mediators in major depressive disorder (MDD). Their diverse cargo, including MicroRNAs (miRNAs), proteins, lipids, and metabolites, impacts key biological processes involved in depression, such as neuroinflammation, synaptic plasticity, hypothalamic-pituitary-adrenal (HPA) axis activity, and mitochondrial function. Therapeutically, both natural and engineered exosomes are being researched for their ability to deliver neuroprotective and anti-inflammatory molecules across the blood-brain barrier (BBB). In this review, we carefully analyze current findings, highlighting advantages and drawbacks across different cohorts, and identify common limitations that hinder reproducibility. We also suggest a framework connecting mechanistic insights with biomarker discovery and therapeutic development. Overall, these advances underscore exosomes as versatile tools for precision psychiatry.
    Keywords:  Biomarkers; Exosomes; Extracellular Vesicles; MDD; Major Depressive Disorder; Mesenchymal Stem Cells; MicroRNAs; Precision Psychiatry
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111589
  19. Cell Mol Neurobiol. 2025 Oct 22. 45(1): 90
    Short-Chain Fatty Acids as a Therapeutic Strategy in Parkinson's Disease: Implications for Neurodegeneration.
    Abinash Ravi, Suganiya Umapathy, Ieshita Pan.
      Neurodegeneration involves the progressive deterioration of neuronal structure and function, leading to deficits in cognition, motor skills, and other neurological processes. Parkinson's disease (PD) is notably prevalent among neurodegenerative disorders, characterized by dopaminergic neurodegeneration, protein misfolding, and an inflammatory brain environment. Despite advancements in understanding its pathophysiology, PD and other neurodegenerative conditions still lack effective disease-modifying therapies. This shortfall highlights the need for novel, multifactorial approaches to treatment. Recent research has spotlighted the gut-brain axis as a significant player in neurological health, particularly through the activity of gut-derived short-chain fatty acids (SCFAs). These microbial metabolites, primarily acetate, propionate, and butyrate, are produced via the fermentation of dietary fibers and are vital for maintaining intestinal and neural homeostasis. SCFAs exert anti-inflammatory effects, preserve blood-brain barrier integrity, and modulate neurotransmitter systems. Among them, butyrate shows notable neuroprotective capabilities, including histone deacetylase inhibition and mitochondrial enhancement. Disruption in SCFA production has been associated with PD progression, further underscoring their relevance. This review explores the mechanistic roles of SCFAs in modulating neurodegeneration, with an emphasis on PD. SCFA-based strategies offer a promising adjunctive route to restoring microbial balance, mitigating neuroinflammation, and safeguarding neurological function in neurodegenerative disorders.
    Keywords:  Gut dysbiosis; Gut–brain axis; Neurodegenerative diseases; Neuroinflammation; Short-chain fatty acids
    DOI:  https://doi.org/10.1007/s10571-025-01609-2
  20. Front Cell Dev Biol. 2025 ;13 1590524
    Mitochondrial dysfunction in age-related sarcopenia: mechanistic insights, diagnostic advances, and therapeutic prospects.
    Yingtao Huang, Chenchen Wang, Haijian Cui, Guangjiang Sun, Xiaonan Qi, Xiaosheng Yao.
      Sarcopenia is a progressive age-related decline in skeletal muscle mass, strength, and function, representing a significant health burden in older adults. Diagnostic criteria have been established that integrate measures of muscle mass, strength, and physical performance [e.g., European Working Group on Sarcopenia in Older People 2010 (EWGSOP1) and 2019 (EWGSOP2) criteria]. Mechanistically, sarcopenia is driven by hormonal changes, chronic inflammation, cellular senescence, and, importantly, mitochondrial dysfunction. Age-related declines in sex hormones and activation of myostatin impair muscle regeneration and metabolism, while chronic low-grade inflammation disrupts protein synthesis and accelerates proteolysis via the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP). The accumulation of senescent cells and their secretory phenotype further exacerbates muscle degeneration and functional decline. Mitochondrial dysfunction plays a central role, characterized by impaired biogenesis, excessive reactive oxygen species (ROS) production, compromised autophagy/mitophagy, and accumulation of mitochondrial DNA (mtDNA) mutations. These defects collectively disrupt muscle energy homeostasis, promoting atrophy. The AMPK/SIRT1/PGC-1α and mTORC1 signaling pathways, along with PINK1/Parkin-mediated and receptor-dependent mitophagy, are essential for regulating mitochondrial biogenesis, protein synthesis, and mitochondrial quality control. Current and emerging therapeutic approaches include resistance and endurance exercise, nutritional and pharmacological agents targeting mitochondrial health, and hormonal modulation. Innovative treatments such as senolytics, exerkines, and gene therapies show promise but require further validation. Future advances in mechanistic understanding, diagnostics, and therapeutic strategies offer hope for mitigating sarcopenia and improving the quality of life in aging populations.
    Keywords:  aging; chronic inflammation; mitochondrial dysfunction; muscle atrophy; sarcopenia; therapeutic strategies
    DOI:  https://doi.org/10.3389/fcell.2025.1590524
  21. Cell Commun Signal. 2025 Oct 22. 23(1): 450
    The hidden driver of osteoporosis: mitochondria-dominated inflammation.
    Binghan Yan, Wenhan Ju, Haipeng Xue, Zhanwang Xu, Daodi Qiu, Guoqing Tan.
      Mitochondria are powerful multifunctional intracellular organelles involved in a wide array of cellular processes. Emerging evidence has highlighted mitochondria as pivotal activators of innate immunity and key participants in inflammatory responses, including in sterile inflammatory diseases, beyond their well-established role as the "powerhouse" of cells. Osteoporosis (OP) is a metabolic disorder characterized by chronic low-grade inflammation, suggesting potential therapeutic value for OP treatment by targeting mitochondria-driven inflammatory pathways. Current research on mitochondrial involvement in OP primarily focuses on its functions in energy metabolism, calcium signaling transduction, oxidative stress, and cell death. However, it remains elusive regarding the precise relationship between mitochondria-mediated inflammatory mechanisms and OP pathogenesis. Accordingly, this review aims to synthesize recent advancement in understanding mitochondria-mediated inflammatory mechanisms and their implications in OP development, to offer insights that may inform future mechanistic investigations and therapeutic strategy development.
    Keywords:  Inflammation; Mitochondria; Osteoporosis; mtDAMPs; mtDNA
    DOI:  https://doi.org/10.1186/s12964-025-02453-z
  22. Ann Gen Psychiatry. 2025 Oct 22. 24(1): 64
    Mitochondrial dysfunction, a new marker warning of neuropsychiatric disorder risk: evidence from genetics and epidemiology.
    Qingan Fu, Jizhen Li, Huangxin Zhu, Qingyun Yu, Tianzhou Shen, Zhekang Liu, Yue Liu, Wei Zhou.
       BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of neuropsychiatric disorders, but its causal role remains unclear. Mitochondrial DNA copy number (mtDNA-CN) and methylmalonic acid (MMA) are well-recognized biomarkers of mitochondrial function, but their association with psychiatric disorders has not yet been fully assessed.
    METHODS: We performed two-step two-sample Mendelian randomization (MR) analyses using genome-wide association study (GWAS) data to assess causal associations between mtDNA-CN and 13 major neuropsychiatric disorders. In addition, we conducted a cross-sectional analysis using National Health and Nutrition Examination Survey (NHANES) data 2011-2014 to examine the association between serum MMA levels and cognitive impairment and depressive symptoms to further validate the correctness and robustness of the results of the MR analysis.
    RESULTS: MR analysis showed a significant negative causal effect of mtDNA-CN on bipolar disorder, Alzheimer's disease, dementia, depressive symptoms, and autism spectrum disorders (OR ranged from 0.15 to 0.84, all p < 0.05). Reverse MR analysis showed that only depressive symptoms had a significant causal effect on reducing mtDNA-CN. NHANES analysis further showed that higher MMA levels were significantly associated with an increased risk of cognitive impairment (OR = 1.56, p = 0.036) and depression (OR = 1.53, p = 0.020), suggesting that mitochondrial dysfunction and neuropsychiatric disorders have a close association.
    CONCLUSION: The mitochondrial function biomarkers mtDNA-CN and MMA are expected to be potential therapeutic targets for depression and cognitive dysfunction, emphasizing the need for mitochondrial function monitoring and interventions in future therapies targeting neuropsychiatric disorders.
    Keywords:  Mendelian randomization; Methylmalonic acid; Mitochondrial dysfunction; MtDNA copy number; Neuropsychiatric disorders
    DOI:  https://doi.org/10.1186/s12991-025-00604-7
  23. Brain. 2025 Oct 23. pii: awaf399. [Epub ahead of print]
    Neuromuscular disorders with evidence of both neuropathic and myopathic phenotype.
    Christian Laurini, Luca Bosco, Alberto Andrea Zambon, Benedetta Sorrenti, Yuri Matteo Falzone, Stefano Carlo Previtali.
      The landscape of genetic research in neuromuscular diseases is revealing an increasing number of genes capable of manifesting both neuropathic and myopathic phenotypes, sometimes in the same patient. While including these genes in broader next-generation sequencing panels addresses the clinical and neurophysiological challenges posed by overlapping or atypical features, it also introduces complexities in the interpretation of their results. In this review, we examine genes that can present with a mixed phenotype, classifying them into categories of clinical utility, and propose a clinical-neurophysiological grid algorithm to guide clinicians toward diagnosis. To better understand the molecular and functional connections of the described genes, we conducted a Gene Set Enrichment Analysis, which highlighted proteostasis, autophagy, and mitochondrial function as key biological processes shared between neuropathy and myopathy. Our aim is to provide a structured framework for interpreting these dual presentations, highlighting the convergence of pathogenic pathways, and emphasizing the importance of a comprehensive, multifaceted approach in managing such cases.
    Keywords:  hereditary; mixed; muscle; nerve; pathophysiology; phenotype
    DOI:  https://doi.org/10.1093/brain/awaf399
  24. J Control Release. 2025 Oct 17. pii: S0168-3659(25)00958-7. [Epub ahead of print] 114344
    Novel single-domain antibodies targeting a unique transferrin receptor 1 epitope for cross-species delivery of drugs in the central nervous system.
    Marion David, Romy Cohen, Diane Beuzelin, Géraldine Ferracci, Marina Cresci, Aude Faucon, Karima Abouzid, Gersande Godefroy, Maxime Masse, Yasmine Mechioukhi, Stéphane D Girard, Ingrid Julien-Gau, Cléa Boursery, Christophe Fraisier, Karine Varini, Morgane Thomas, Guillaume Jacquot, Pascaline Lecorche, Bastien Serrano, Andréa Romette, Gauthier Dangla Pélissier, Magali Godard, Vincent Saillant, Tiphanie Pruvost, Raphael Sierocki, Patrick Chames, Brigitte Kerfelec, Jamal Temsamani, Michel Khrestchastisky.
      The blood-brain barrier (BBB) is a major obstacle for delivering therapeutic agents to the central nervous system (CNS), posing significant challenges for treating neurological disorders. Among current strategies to improve brain drug exposure, hijacking physiological pathways involved in receptor-mediated transcytosis has emerged as a promising strategy. While targeting transferrin receptor 1 (TfR1) is widely explored, many TfR1- antibodies lack cross-species reactivity, limiting translational development. In the present study, we identified and characterized camelid-derived single-domain antibodies (VHHs) with robust cross-reactivity to rodent, rhesus monkey, and human TfR1. Epitope mapping of the VHH revealed a novel binding site at the interface of the TfR1 dimer. When fused to a human IgG1 Fc domain, these VHHs, as monomers or homodimers, were efficiently internalized by engineered CHO cells and brain endothelial cells expressing TfR1 from different species. Systemic administration of VHH-Fc constructs in mice demonstrated significantly improved brain uptake compared to irrelevant controls. Functional delivery was confirmed using neurotensin-induced hypothermia, and we established correlations between in vivo effects and binding properties determined by surface plasmon resonance. Notably, efficient BBB transcytosis was associated with intermediate affinity and rapid dissociation rates. Engineered variants maintained favorable cross-species binding, including similar affinities to human and non-human primate TfR1, facilitating translational studies. The cross-reactive anti-TfR1 VHHs we developed offer a versatile and modular platform for CNS drug delivery and hold promise as molecular shuttles for transporting therapeutic agents across the BBB. Our work establishes a robust foundation for developing next-generation brain-targeted biotherapeutics, including peptides, enzyme replacement therapies, antibody-based treatments for neurodegenerative diseases, and oligonucleotide delivery for CNS disorders, enabling seamless translation from preclinical to clinical applications.
    Keywords:  Blood-brain barrier (BBB); Brain shuttles; Fc fusion; Neurotensin-induced hypothermia; Receptor-mediated transcytosis (RMT); Single domain antibody
    DOI:  https://doi.org/10.1016/j.jconrel.2025.114344
  25. BMC Pediatr. 2025 Oct 24. 25(1): 863
    Newborn screening for fatty acid oxidation disorders: epidemiological and genetic findings in Southeastern China.
    Suping Zhang, Xintong Li, Sheng Ye, Weiting Song, Hong Chen.
      Fatty acid oxidation disorders (FAODs) are a group of rare diseases caused by deficiencies in the function of enzymes or proteins involved in the mitochondrial oxidation of fatty acids. This study aimed to analyze the incidence, disease spectrum, gene profile, and clinical phenotypes of FAODs in the southeastern coastal region of China. Between January 2016 and June 2024, acylcarnitine, genetic mutation, and clinical manifestation data were collected from patients diagnosed with FAOD through newborn screening. A total of 210,913 newborns were screened, identifying 36 cases of FAODs, with an overall incidence of 1 in 5,859. Primary carnitine deficiency (PCD) was the most prevalent FAOD, with an incidence of 1 in 9,587, followed by multiple acyl-CoA dehydrogenase deficiency (MADD). Moreover, we identified 32 mutations, including 5 novel variants. Patients with PCD who carried homozygous variants (R254*) of the SLC22A5 gene demonstrated significantly lower average free acylcarnitine levels than those with compound heterozygous variants (2.45 ± 1.27 µmol/L versus 4.42 ± 1.13 µmol/L, p < 0.05). In patients with MADD, rescreening revealed lower levels of characteristic acylcarnitines (C6, C8, C10, C12, and C14) compared with initial screening values, with 42.3% returning to normal levels. During long-term follow-up (approximately 6 years), all patients remained under clinical surveillance initiated based on their NBS diagnosis. One patient with PCD developed severe retinal detachment at age 5. Three patients with long-chain FAOD (two VLCADD, one CPT-IID) died following infections that triggered metabolic crises (ages 5 and 8 months, respectively). These fatal outcomes occurred despite early diagnosis and initiation of standard management protocols prompted by the NBS results. No other severe complications were observed in the surviving cohort. Our findings highlight the importance of developing screening protocols and clinical management strategies to improve outcomes for affected newborns.
    Keywords:  Fatty acid oxidation disorders; Genetic variation; Multiple acyl-CoA dehydrogenase deficiency; Newborn screening; Primary carnitine deficiency; Tandem mass spectrometry
    DOI:  https://doi.org/10.1186/s12887-025-06250-y
  26. Curr Biol. 2025 Oct 20. pii: S0960-9822(25)01193-5. [Epub ahead of print]35(20): R1016-R1028
    A brain-body perspective on thermoregulatory adaptation.
    Sydney Aten, Nicole Lynch, Clifford B Saper, Natalia L S Machado.
      Homeothermic animals, including humans, regulate their body temperature within a narrow range to maintain physiological functions and survival. However, this refined thermoregulatory control is often challenged by external, physiological, and psychogenic stressors. Changes in external temperatures drive both behavioral and physiological responses required to maintain normothermia, while immune insults or negative energy balance can lead to regulated shifts in thermoregulatory set-points that support physiological adaptation to these adverse conditions. In this review, we dissect brain-body interactions required for thermoregulatory control and examine how coordination between the peripheral and central systems produces adaptive changes in the thermoregulatory system that enable survival.
    DOI:  https://doi.org/10.1016/j.cub.2025.09.023
  27. Drugs. 2025 Oct 25.
    Can Gene Therapy Transform the Treatment Landscape of Posterior Segment Eye Diseases? A Comprehensive Review of Recent Advancements.
    Kai-Yang Chen, Hoi-Chun Chan, Chi-Ming Chan.
      Posterior segment eye diseases (PSEDs) encompass a diverse group of conditions affecting the retina, choroid, optic nerve, and vitreous humor, often leading to progressive and irreversible vision loss. Age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and inherited retinal diseases (IRDs) are among the most clinically significant PSEDs with a substantial global burden and economic impact. Conventional treatments for PSEDs have limitations that necessitate the development of novel therapies that address the underlying molecular drivers of the disease. Gene therapy has emerged as a promising approach, offering the potential for durable and curative outcomes through precise genetic manipulation. Advancements in gene therapy strategies, including gene augmentation, gene editing, RNA-based therapies, and optogenetics, have led to significant progress in preclinical studies and clinical trials across various PSED subtypes. US Food and Drug Administration (FDA) approval of voretigene neparvovec (Luxturna®) for RPE65-associated IRDs validated the clinical viability of ocular gene therapy, while ongoing trials for AMD, DR, and other IRDs continue to expand the therapeutic landscape. Innovations in viral and non-viral delivery systems, such as dual AAV vectors, lipid nanoparticles, and novel biomaterials, have enhanced the efficiency and specificity of gene delivery to the retina. However, challenges persist, including immune responses to viral vectors, limited transduction efficiency in certain cell types, and anatomical barriers posed by the blood-retinal barrier. Future directions in ocular gene therapy include the development of precision genome editing techniques, such as prime editing, miRNA-based regulation, and combinatorial approaches integrating gene therapy with stem cell transplantation or neuroprotective agents. As the field continues to evolve, addressing these challenges and optimizing gene therapy strategies will be crucial in translating the transformative potential of ocular gene therapy into clinical reality for patients with PSEDs.
    DOI:  https://doi.org/10.1007/s40265-025-02237-2
  28. Cent Nerv Syst Agents Med Chem. 2025 ;25(3): 245-260
    Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.
    Aysha Javed, Purba Mandal, Imran Khan, Aditya Singh, Juber Akhtar, Shubhrat Maheshwari, Bhupendra G Prajapati.
      Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.
    Keywords:  Alzheimer's disease; Liposomal drug delivery; Parkinson's disease; bioavailability; blood-brain barrier (BBB); multiple sclerosis.; stroke
    DOI:  https://doi.org/10.2174/0118715249319942240903134353
  29. Nanoscale. 2025 Oct 22.
    Challenges and opportunities in nanotherapeutics targeted for central nervous system disorders.
    Joel Yong, Karen Hakobyan, Sk Al Zaheri Mahmud, Daniel James Johnson, Jacob Lee, Ashish D Diwan, Sophia Gu, Gila Moalem-Taylor, Guangzhao Mao.
      Central nervous system (CNS) disorders represent some of the most challenging problems for modern medicine. The complexity of the CNS structure, incomplete understanding of disease, chronic neuroinflammation, and physiological barriers limiting drug delivery all contribute to the difficulty of treating neurological diseases. This review covers the neuroanatomical barriers of the CNS and discusses current treatments, shortcomings of these treatments, recent clinical trials, and opportunities for nanotherapeutic approaches in common CNS disorders. Focus is placed on selected CNS disorders stemming from trauma, neurodegenerative diseases and infectious diseases. The review concludes with a summary and perspectives on the nanotherapeutics development highlighting key challenges and future directions for the field.
    DOI:  https://doi.org/10.1039/d5nr02463c
  30. J Biomed Sci. 2025 Oct 20. 32(1): 92
    Dimethyl fumarate reprograms cervical cancer cells to enhance antitumor immunity by activating mtDNA-cGAS-STING pathway.
    Han Jiang, Liting Liu, Shan He, Shen Qu, Yifan Yang, Guijie Kang, Min Wu, Hangyu Liu, Yuwei Zhang, Zixuan Wang, Wenjing Tian, Ying Chen, Liming Wang, Qiangqiang Wang, Ting Ye, Junyan Han, Hui Wang, Yafei Huang.
       BACKGROUND: Cervical cancer (CC) remains a significant global health challenge for women, especially in advanced stages where effective treatments are limited. Current immunotherapies, including PD-1/PD-L1 blockades and adoptive T cell therapies, show limited response rates and durability. Dimethyl fumarate (DMF), an FDA-approved drug for autoimmune diseases, has demonstrated direct antitumor activity in several cancers. However, its influence on anti-tumor immunity and its function in CC remain poorly understood. This study aims to investigate the therapeutic potential of DMF in CC models and elucidate its underlying mechanisms of action.
    METHODS: CC cell lines and mouse models were treated with DMF. Transcriptomics profiling of cervical cancer cells following DMF treatment were analyzed by RNA-seq and bioinformatic methods. Mitochondrial DNA (mtDNA) release, and cGAS-STING activation were assessed via qPCR, immunofluorescence, immunoblotting and ELISA. CD8+ T cell recruitment was analyzed by flow cytometry. Combinatorial therapies (DMF + anti-PD-1/TILs) were tested in syngeneic or patient-derived xenografts (PDX) models.
    RESULTS: DMF treatment induces mitochondrial dysfunction in tumor cells, resulting in the release of mtDNA into the cytosol. The cytosolic mtDNA in turn activates the cGAS-STING-TBK1 pathway and type I interferon response, leading to the secretion of CCL5 and CXCL10, thereby enhancing CD8⁺ T cell infiltration. Additionally, DMF exhibits synergistic effect with PD-1 blockade in murine CC model, and can enhance the therapeutic efficacy of adoptively transferred T cells toward CC in patient-derived xenografts model.
    CONCLUSION: This work elucidated that DMF reprograms CC cells to activate the mtDNA-cGAS-STING pathway, fostering a chemokine-rich microenvironment that recruits CD8+ T cells. The synergistic effect of DMF and PD-1 blockade or TIL therapy underscores its potential as an immunostimulatory adjuvant. These findings suggest that DMF holds promise as a novel immunotherapeutic strategy for improving clinical outcomes in CC.
    Keywords:  CCL5; CD8+ T; CXCL10; Cervical cancer; Dimethyl fumarate; Immunotherapy
    DOI:  https://doi.org/10.1186/s12929-025-01187-x
  31. Psychoneuroendocrinology. 2025 Oct 12. pii: S0306-4530(25)00367-1. [Epub ahead of print]182 107644
    Effects of acute psychological stress on blood cell-free mitochondrial DNA (cf-mtDNA): A crossover experimental study.
    Caroline Trumpff, David Shire, Seonjoo Lee, Katie Stanko, Aidan Park, Annette Wilson, Mark R Scudder, Peter J Gianaros, Brett A Kaufman, Martin Picard, Anna L Marsland.
      In response to acute stress, prior studies have found an increase in circulating cell-free mitochondrial DNA (cf-mtDNA) and pro-inflammatory cytokines, highlighting two potential inter-related mechanisms by which stressors can get under the skin. However, prior studies lacked a resting control condition to isolate the effect of psychological stress from other aspects related to laboratory procedures. Here, we conducted a crossover experimental trial examining responses to a socio-evaluative stressor under laboratory conditions. 72 volunteers (aged 20-50, 48 % women) were tested on two occasions, counterbalanced, separated by at least a month. On one occasion, they were exposed to a 5-min socio-evaluative stressor (speech task), and on the other occasion, rested for the same period. Blood samples were obtained at 10 timepoints from pre- to 2 h post-exposure to assess neuroendocrine (cortisol, catecholamines), pro-inflammatory cytokine (IL-6, IL-10, TNF-ɑ), and both plasma and serum cf-mtDNA responses. Compared to the control visit, the stressor significantly increased anxiety, heart rate, blood pressure, cortisol, and norepinephrine (p's < 0.05-0.0001), confirming the psychobiological impact of the stressor. Unexpectedly, IL-6 and plasma cf-mtDNA increased (time effect p < 0.0001) in both the stress and control conditions. While no significant effect of time was found for serum cf-mtDNA, plasma cf-mtDNA showed a bi-phasic response with an initial 22-24 % increase at 5-10 min (g=0.07, stress-control visits), followed by a decrease and another 70-81 % increase from 45 to 75 min (g=0.59 (stress visit), g= 0.41 (control visit)). There were no significant associations between the pro-inflammatory and cf-mtDNA responses, pointing to their independent regulation. While mood, cardiovascular, and neuroendocrine reactivity were selectively induced by socio-evaluative stress, IL-6 and blood cf-mtDNA increased across both the stress and control conditions, suggesting that these biomarkers may reflect non-specific responses to the laboratory protocols (e.g., blood draw) rather than to socio-evaluative stress itself.
    Keywords:  Acute psychological stress; Cell-free mitochondrial DNA (cf-mtDNA); Control condition; IL6; Mitochondrion; Pro-inflammatory cytokines
    DOI:  https://doi.org/10.1016/j.psyneuen.2025.107644
  32. Circ Res. 2025 Oct 23.
    Increased Intermembrane Space [Ca2+] Drives Mitochondrial Structural Damage in CPVT.
    Shanna Hamilton, Radmila Terentyeva, Roland Veress, Fruzsina Perger, Zuzana Nichtova, Mark Bannister, Jinxi Wang, Sage Quiggle, Rachel Battershell, Matthew W Gorr, Sandor Györke, Bum-Rak Choi, Christopher H George, Andriy E Belevych, György Csordás, Dmitry Terentyev.
       BACKGROUND: Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca2+] in the mitochondrial intermembrane space (IMS) and activates the Ca2+-sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1).
    METHODS: We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(±). We created a new biosensor to measure IMS-[Ca2+] in adult cardiomyocytes with intact Ca2+ cycling. We used ex vivo whole heart optical mapping, confocal and electron microscopy, as well as in vivo/in vitro gene editing techniques to test the effects of calpain in the IMS.
    RESULTS: We found altered mitochondrial cristae structure, increased IMS-[Ca2+], reduced OPA1 expression, and augmented mito-reactive oxygen species emission in catecholaminergic polymorphic ventricular tachycardia myocytes. We show that calpain-mediated OPA1 cleavage led to disrupted cristae organization and, thereby, decreased electron transport chain supercomplex assembly, resulting in accelerated reactive oxygen species production. Genetic inhibition of calpain activity in IMS reversed mitochondria structural defects in catecholaminergic polymorphic ventricular tachycardia myocytes and reduced arrhythmic burden in ex vivo optically mapped hearts.
    CONCLUSIONS: Our data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca2+], sufficient to activate IMS-residing calpain. Calpain activation leads to proteolysis of OPA1 and cristae widening, thereby decreasing assembly of electron transport chain components into supercomplexes. Consequently, excessive mito-reactive oxygen species release critically contributes to RyR2 hyperactivation and ventricular tachyarrhythmia. Our new findings suggest that targeting IMS calpain may be beneficial in patients at risk for sudden cardiac death.
    Keywords:  calcium; cardiovascular diseases; heart failure; mitochondrial proteins; sarcoplasmic reticulum
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326841
  33. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Oct;41(10): 937-953
    [Ferroptosis: from molecules to diseases].
    Xuesong Wang, Di Kang, Yingying Wang, Ye Shao, Hongbo Li.
      Ferroptosis is a regulated form of cell death, with its core mechanism being intracellular iron overload-induced lipid peroxidation, leading to cellular dysfunction and mitochondrial structural abnormalities. Ferroptosis is closely related to various diseases including neurodegenerative disorders, tumors, and ischemia-reperfusion organ damage, and has become a potential therapeutic target. Iron is essential for life but can also cause cell death. Despite continuous progress in iron-related biomedical research, many questions remain unanswered. Advances in high-throughput technologies, genomics and proteomics are expected to reveal the cellular iron regulatory mechanism and open up new therapeutic approaches for ferroptosis-related diseases. This article reviews the research progress on iron in terms of its biology, metabolism, regulation, and related diseases, aiming to provide clues and references for developing new ferroptosis-targeted therapeutic strategies and facilitating more in-depth molecular studies from multiple perspectives.
  34. J Genet Couns. 2025 Oct;34(5): e70123
    Bringing Genetics to Mental Health: Integrating Genetic Counseling into a Mental Health Program at Monash Health, Australia.
    Joanne Isbister, Anita Gorrie, Lia Laios, Joshua Schultz, Megan Galbally.
      Psychiatric disorders such as anxiety, bipolar disorder, depression, substance use disorder, and schizophrenia are highly heritable, yet access to genetic counseling for psychiatric disorders remains limited. Despite evidence supporting its benefits, systemic barriers in Australia limit access to this service. To address this gap, a genetic counselor was embedded within the Monash Mental Health Program -marking the first initiative of its kind in Australia. This initiative represents a novel, collaborative model that improves access to genetic services and fosters interdisciplinary partnerships between genetic counselors and mental health professionals. By embedding the service within a public health context, it also addresses critical equity issues in access to genomic healthcare. This paper outlines the structure, implementation, and function of the service, demonstrating its adaptability across a range of clinical areas. Initially focused on women of reproductive age with psychiatric histories, the service rapidly expanded to include dual disability, inpatient adult psychiatry, and child and adolescent mental health. It proved particularly valuable in high-risk perinatal cases, where psychiatric conditions intersected with fetal anomalies. Genetic counseling facilitated timely interventions, guided genetic testing where appropriate, and supported complex case management. By identifying key enablers and challenges, this paper offers practical insights for developing similar interdisciplinary services. It contributes unique evidence from the Australian context and provides a foundation for future research, policy, and service planning in psychiatric genetic counseling. This innovative, scalable model demonstrates how genetic counseling can be effectively integrated into mental health care, improving outcomes for individuals with psychiatric disorders and their families.
    Keywords:  genetic counseling; health service innovation; mental health services; perinatal psychiatry; psychiatric disorders; psychiatric genetic counseling
    DOI:  https://doi.org/10.1002/jgc4.70123
  35. J Parkinsons Dis. 2025 Oct 21. 1877718X251378115
    A PLAN to address the Parkinson pandemic.
    E Ray Dorsey, Michael S Okun, Bastiaan R Bloem.
      The Parkinson pandemic continues to spread. Almost 12 million individuals now have the disease, nearly double the estimate from just six years ago. Its human-made nature is also increasingly clear as more studies tie environmental toxicants to the disease. Chief among these are certain pesticides, the dry-cleaning chemicals trichloroethylene and perchloroethylene, and air pollution. An etiological role for these toxicants-inhaled or ingested-is also consistent with the emerging brain- and body-first models of Parkinson's disease.To address the pandemic will require a "PLAN" that (1) Prevents the disease; (2) Learns why it starts; (3) Amplifies the voices of persons with the disease and their caregivers; and (4) Navigates the frontier of new treatments. Reducing or eliminating toxicants will help slow its rise. Learning why the disease begins will require investigating exposures, interactions of the environment with genes, and modifiers. Amplifying the voices of those affected can raise awareness, improve care, and change the disease's course. Vastly expanding the scale and scope of research funding will accelerate efforts to prevent the disease and find more effective therapies. If successfully implemented, such a plan will translate to bold "0-10-100" goals by 2035. The goals include a 0% rise in the global incidence of Parkinson's, a 10-fold increase in research funding and in the proportion devoted toward prevention, and 100% of individuals having access to levodopa and receiving appropriate care. The results will lay the foundation for even greater ambitions, including the fall of Parkinson's disease.
    Keywords:  Parkinson disease; air pollution; delivery of health care; environment; epidemiology; patient advocacy; pesticides; solvents; therapeutics; trichloroethylene
    DOI:  https://doi.org/10.1177/1877718X251378115
  36. BMC Biol. 2025 Oct 21. 23(1): 316
    TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.
    Serena Ghisletti, Marta Russo.
      Mitochondrial enzymes are increasingly recognized for their ability to translocate to the nucleus, where they generate metabolites essential for epigenetic regulation and gene expression. Yet, whether this phenomenon broadly involves metabolic enzymes or is restricted to specific subunits remains unclear. In this review, we assess current evidence, highlight knowledge gaps, and suggest future directions on the nuclear localization and functions of metabolic enzymes, with a focus on acyl-CoA producers. Emerging studies reveal multiple mechanisms guiding these enzymes to chromatin for localized metabolite synthesis. Key questions concern nuclear import machinery, chromatin interactions, and the regulatory impact of their activity.
    Keywords:  Histone modifications; Metabolism; Mitochondrial enzymes; Transcriptional regulation
    DOI:  https://doi.org/10.1186/s12915-025-02423-4
  37. Aging Dis. 2025 Oct 22.
    SIRT1-Mediated Mitochondrial Homeostasis in Cardiac Aging: Molecular Mechanisms and Therapeutic Implications.
    Sitong Chen, Hanying Xu, Xiaonan Li, Xiaolei Tang, Lan Yang, Jing Lu, Jun Li.
      Cardiovascular disease (CVD) remains the leading cause of global mortality and disability. As an inevitable risk factor, cardiac aging significantly exacerbates the incidence and progression of age-related cardiovascular pathologies, including coronary artery disease, cardiomyopathies, and heart failure in the elderly population. Mitochondria function as central organelles in cardiac energy metabolism. Dysregulation of functional homeostasis, characterized by impaired quality control mechanisms, such as diminished energy production efficiency and exacerbated oxidative stress, is a primary driver of the cardiac aging process. Accumulating evidence in recent years indicates that sirtuin 1 (SIRT1) plays a crucial role in regulating cardiac aging. A range of therapeutic agents, including natural compounds and synthetic molecules, ameliorate cardiac aging and related pathologies by activating SIRT1 to modulate mitochondrial function. This review systematically summarizes the emerging roles of SIRT1 in cardiac aging, with a focus on the molecular mechanisms through which SIRT1 governs mitochondrial homeostasis. We also highlight recent advances in SIRT1-targeted therapeutic strategies, thereby providing a theoretical basis and translational perspectives for preventing and treating cardiac aging-related diseases.
    DOI:  https://doi.org/10.14336/AD.2025.1128
  38. Expert Opin Pharmacother. 2025 Oct 20.
    Dravet syndrome therapeutics: where are we, what works, and what's next?
    Vikram A Bagchi, Julie Ziobro, Lori L Isom.
       INTRODUCTION: Dravet Syndrome (DS) is a devastating developmental and epileptic encephalopathy marked by early refractory seizures and pervasive symptoms impacting cognition, behavior, motor function, sleep, and autonomic control. This review appraises established and emerging therapeutics, tracing the field's shift from broad antiseizure medications to gene-modifying strategies. Sustained progress hinges on targeting defined nodes in DS pathophysiology to improve the whole patient, not just seizure control.
    AREAS COVERED: We searched PubMed and ClinicalTrials.gov for 'Dravet syndrome' OR 'DS' AND 'pharmacotherapy' AND 'treatments' OR "therapeutics. We prioritized DS-specific randomized controlled trials, open-label extensions, structured reviews, network meta-analyses, and natural-history cohorts to assess clinical use, efficacy, and safety, and integrated preclinical in vitro/in vivo models to map mechanisms of action.
    EXPERT OPINION: DS therapeutics are converging on disease modification: gene-regulatory approaches lead, and targeted small molecules extend, mechanism-based care. We outline a practical precision ecosystem with four pillars: (i) early genetic screening with genotype-informed prediction, (ii) pharmacogenomic-guided prescribing, (iii) patient-specific variant modeling to clarify mechanism and optimize drug selection, and (iv) targeted restorative gene-modifying therapies that address causation. Together, these elements shift DS care toward individualized, mechanism-matched treatment providing seizure control as well as measurable gains in communication, learning, mobility, sleep, and autonomic stability.
    Keywords:  Dravet syndrome; SCN1A; anti-seizure drug; developmental and epileptic encephalopathy; gene-modifying therapy
    DOI:  https://doi.org/10.1080/14656566.2025.2576608
  39. BMC Vet Res. 2025 Oct 21. 21(1): 620
    Revitalizing equine metabolism: how SHBG improves mitochondrial function and reduces inflammation.
    Nabila Bourebaba, Justyna Domagała, Lynda Bourebaba.
      
    Keywords:  ASC; EMS; Inflammation; Mitochondria; OXPHOS; SHBG
    DOI:  https://doi.org/10.1186/s12917-025-05033-y
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