bims-polgdi Biomed News
on POLG disease
Issue of 2025–10–12
forty-four papers selected by
Luca Bolliger, lxBio
  1. First approved drug for mitochondrial disease raises hopes for more.
  2. Mesenchymal stromal cell-mediated mitochondrial transfer unveils new frontiers in disease therapy.
  3. Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
  4. Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
  5. Morpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseases.
  6. A bioinformatics pipeline for identifying homoplasmic and heteroplasmic mitochondrial DNA SNVs in single-cell RNA-Seq datasets.
  7. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  8. Public funding for mitochondrial donation: An Australian public deliberation.
  9. Advances in mitochondria-nucleus crosstalk in septic cardiomyopathy.
  10. Melatonin alleviates oxidative stress induced damage in human iPSCs harboring mtDNA 3243A>G mutation via MAPK pathway.
  11. Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.
  12. Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
  13. Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
  14. Advancements in Understanding the Role and Mechanisms of Mitochondria in Diabetes: A Comprehensive Review.
  15. Multifaceted mitochondria in innate immunity.
  16. Lipid and polymeric nanocarrier for siRNA delivery to the brain.
  17. Imperial strategy of cancer cells through mitochondrial transfer.
  18. Healthy mitochondria attenuate metabolic dysfunction-associated steatohepatitis by restoring cell metabolism.
  19. Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.
  20. Mesenchymal stromal cell extracellular vesicles as immune modulators and drug carriers in neurodegenerative disorders.
  21. Therapeutic extracellular vesicles as a cornerstone of medicine in the next decade with gerontological focus.
  22. Developing Treatments for Rare Diseases on a Shoestring.
  23. Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
  24. Proteasome regulation of petite-negativity in fission yeast.
  25. Clinical translation of human iPSC technologies: advances, safety concerns, and future directions.
  26. Role of telomere length and telomerase activity in accelerated cellular aging and major depressive disorder: a systematic review.
  27. Approaches to Humanization of Mitochondrial Proteins in Saccharomyces cerevisiae on the Example of Replacing the Yeast Mitochondrial Translation Termination Factor MRF1 with Its Human Homologues.
  28. Red Blood Cells in Health and Disease.
  29. Salivary mitochondrial DNA is associated with biomarkers of Alzheimer's disease in cognitively normal older adults.
  30. Stem Cells to Organoids: Pioneering the Future of Regenerative Therapies.
  31. Mitochondrial damage-associated molecular patterns (mito-DAMPs): Determinants of hepatopathy progression and therapeutic implications.
  32. Mitochondrial dysfunction in PTSD: A mechanism to understand trauma susceptibility?
  33. The dual role of extracellular vesicles derived from animal and human immune cells: A systematic review.
  34. A machine learning approach using semen parameters and sperm mitochondrial DNA copy number to predict couples' fecundity.
  35. Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.
  36. Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
  37. Inhibition of S100A9 Improves Aortic Dissection in Association With Mitochondrial Function Enhancement.
  38. Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.
  39. The biophysical mechanism of mitochondrial pearling.
  40. Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids.
  41. Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
  42. PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.
  43. Exploring CRISPR-Cas: The transformative impact of gene editing in molecular biology.
  44. STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  1. Science. 2025 Oct 09. 390(6769): 114-115
    First approved drug for mitochondrial disease raises hopes for more.
    Mitch Leslie.
      Researchers are testing multiple treatments for the rare genetic conditions.
    DOI:  https://doi.org/10.1126/science.aec9018
  2. Stem Cell Res Ther. 2025 Oct 08. 16(1): 546
    Mesenchymal stromal cell-mediated mitochondrial transfer unveils new frontiers in disease therapy.
    Huan Chen, Xu Chen, Zi-Hao Zhou, Jia-Rong Zheng, Ye Lu, Pei Lin, Yun-Fan Lin, Yu-Cheng Zheng, Bin Xiong, Rong-Wei Xu, Li Cui, Xin-Yuan Zhao.
      Mitochondrial dysfunction is a pivotal factor in the progression of various diseases, making it a critical therapeutic target. Mesenchymal stromal cells (MSCs) have shown promise in mitigating this dysfunction through the transfer of healthy mitochondria to damaged cells. This review comprehensively analyzes the mechanisms of MSC-derived mitochondrial transfer, including tunneling nanotubes (TNTs) and extracellular vesicles, and highlights their therapeutic potential across a spectrum of diseases, such as neurodegenerative disorders, ocular diseases, and inflammatory conditions. Additionally, strategies to enhance mitochondrial transfer efficiency-such as genetic modifications and optimization of MSC sources-are thoroughly explored. Despite these promising findings, challenges remain, including the need for a deeper understanding of transfer mechanisms, ensuring the quality and functionality of transferred mitochondria, and addressing potential immune responses. While MSC-derived mitochondrial transfer holds significant therapeutic potential, careful consideration of its dual nature, especially in specific pathological contexts such as cancer, is essential. With further research and technological advancements, this approach could become a cornerstone in the treatment of diseases characterized by mitochondrial dysfunction.
    Keywords:  Mesenchymal stromal cell; Mitochondrial transfer; Therapeutic efficacy
    DOI:  https://doi.org/10.1186/s13287-025-04675-x
  3. Clin Genet. 2025 Oct 11.
    Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
    Jun Wang, Minhan Song, Zhimei Liu, Chaolong Xu, Ying Zou, Xin Duan, Yang Liu, Weihua Zhang, Jiuwei Li, Fang Fang.
      This study investigated clinical and genetic characteristics of Chinese pediatric patients with single large-scale mitochondrial DNA deletions (SLSMD). We analyzed 28 patients (July 2004-March 2025) using long-range PCR and next-generation sequencing. Spearman correlation and ANOVA assessed genotype-phenotype relationships. Patients (mean age 5.52 ± 3.96 years) exhibited multi-organ involvement (5.43 ± 1.87 organs). Common initial presentations included ocular (29%), neurologic, and endocrine dysfunction. Only 14.3% had the classic 4977 bp deletion, and 23 novel deletions were identified in 25 patients. Larger deletions correlated with more deleted MRC complexes (r = 0.516, p = 0.0123) and more deleted tRNAs (r = 0.534, p = 0.0103). Kearns-Sayre syndrome (KSS) patients had later onset (p = 0.0337), larger deletions (p = 0.0263), and greater tRNA/MRC complex (p = 0.0263, p = 0.0319) involvement than non-KSS patients. SLSMD in Chinese children primarily causes KSS, Pearson syndrome (PS), and progressive ophthalmoplegia with multi-organ involvement. Genotype-phenotype correlations exist, particularly between deletion size, onset age, and disease severity. KSS patients show distinct genetic and clinical profiles, suggesting slower progression. This study expands the known SLSMD spectrum and underscores mitochondrial testing in pediatric multi-organ disorders.
    Keywords:  KSS; mitochondrial diseases; mtDNA; single large deletions
    DOI:  https://doi.org/10.1111/cge.70089
  4. Placenta. 2025 Oct 01. pii: S0143-4004(25)00704-0. [Epub ahead of print]171 140-149
    Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes.
    Leena Kadam, Kaylee Chan, Ethan Tawater, Leslie Myatt.
       INTRODUCTION: The placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in male and female placentas of pregnancies complicated by obesity and GDM. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria.
    METHODS: We collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner.
    RESULTS: Only placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1α and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), but GDM placentas failed to mount this response.
    DISCUSSION: Obesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.
    Keywords:  Diabetes; Mitochondria; Obesity; Placenta; Pregnancy
    DOI:  https://doi.org/10.1016/j.placenta.2025.09.019
  5. Neuromolecular Med. 2025 Oct 11. 27(1): 69
    Morpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseases.
    Mateus Laranjeira, Jorge M A Oliveira, Filippo M Santorelli, Maria Marchese, Célia Nogueira.
      Mitochondrial diseases (MDs) are heterogeneous multisystemic disorders often caused by genetic defects in either nuclear or mitochondrial DNA. Although next-generation sequencing technologies have dramatically expanded the number of variants associated with these diseases, many remain variants of unknown significance (VUS). This review explores the utility of zebrafish (Danio rerio) as a vertebrate model system for studying mitochondrial dysfunction, with a focused analysis on the application of morpholino oligonucleotides (MOs) to functionally characterize and interpret VUS. MO-induced knockdown produces a transient suppression of target genes during zebrafish early development, recapitulating key MD phenotypes. Furthermore, rescue experiments involving co-injection of MO and either wild-type or mutant mRNA have proven useful to functionally assess the pathogenicity of specific variants. Specifically, while wild-type mRNA rescues the morphant phenotype, failure of mutant mRNA to do so confirms the variant's pathogenic effect. This approach has successfully linked previously uncharacterized genes to MD and helped reclassify ambiguous variants. The use of MO-based strategies in zebrafish remains a valuable tool for variant interpretation and functional validation, bridging the gap between genomic data and clinical action, and ultimately reducing the diagnostic odyssey. Overall, this review places MO knockdown and rescue assays in zebrafish as a robust and versatile platform to address functional genomics in MD research.
    Keywords:  Mitochondrial diseases; Morpholino oligonucleotides; Rescue experiments; Variants of unknown significance; Zebrafish
    DOI:  https://doi.org/10.1007/s12017-025-08890-w
  6. Genomics. 2025 Oct 06. pii: S0888-7543(25)00138-7. [Epub ahead of print] 111122
    A bioinformatics pipeline for identifying homoplasmic and heteroplasmic mitochondrial DNA SNVs in single-cell RNA-Seq datasets.
    Zhiling Guan, Patrick Lindsey, Rick Kamps, Hubert J M Smeets.
      Mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) are associated with various pathologies, predominantly in energy-demanding tissues like muscles and brain. Characterizing these SNVs at the single-cell level is crucial for understanding their mechanism and clinical manifestation. Publicly available single-cell RNA sequencing (scRNA-seq) data could be an invaluable resource, but existing pipelines fall short in reliable detection of mtDNA SNVs from scRNA-seq data. Therefore, we developed a novel bioinformatics pipeline, that includes quality control, alignment to the mitochondrial genome, SNV calling, and annotation, and that filters-out sequencing errors. Coverage-dependent thresholds are customizable for detecting heteroplasmic SNVs. Duplicate reads can be retained as the majority were valid biological duplicates. Strand bias errors, exceeding a 1:3 ratio, RNA modification-induced errors, identified by the presence of multiple alternative alleles at the same position, and overrepresented SNVs were removed. Our data demonstrated that this pipeline effectively detects homoplasmic and heteroplasmic mtDNA SNVs in scRNA-Seq data.
    Keywords:  Mitochondrial DNA; SNVs calling; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.ygeno.2025.111122
  7. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  8. BMC Med Ethics. 2025 Oct 08. 26(1): 131
    Public funding for mitochondrial donation: An Australian public deliberation.
    Ainsley J Newson, Jane Williams, Giuliana Fuscaldo, Ashleigh Hill, Ezra Kneebone, Karinne Ludlow, Catherine Mills, Megan Munsie, Sarah Norris, Paul Scuffham, Liz Sutton, David R Thorburn, Chris Degeling.
       BACKGROUND: Mitochondrial donation (MD) is a reproductive technique that aims to allow individuals at-risk of having a child with mitochondrial DNA disease avoid this outcome. Research to inform possible clinical use of MD is underway in Australia and births following the use of this technique have been announced in the United Kingdom. However, how the availability of MD will be funded in the mid- to long-term remains uncertain. One factor impacting funding decisions is public sentiment, yet there is scant evidence globally regarding attitudes toward MD funding. We sought to discern attitudes of informed members of the Australian public to how the provision of MD should be funded.
    METHODS: We held three community juries to gauge public views on how MD should be funded. A community jury involves providing a diverse group of citizens with expert testimony and facilitating deliberation to arrive at a position.
    RESULTS: Forty-two jurors participated across three juries. All juries voted by majority to support public funding for MD. Each jury made slightly different funding choices: one preferred full public funding, another preferred co-payment, while the third was divided among full public funding, co-payment, and no public funding. Reasons in favour of public funding comprised value for money, equity (i.e., the fair and just distribution of MD) and promoting innovation. Reasons against were opportunity cost, that MD wasn't necessary, and ethical objections to MD. Jurors also devised conditions for future funding: external review, capped services, better funding for alternative interventions and means testing.
    CONCLUSIONS: Should the current Australian MD research trial enable clinical provision, assuming that our participants' views are consistent with those of most Australians when informed of the trade-offs, benefits and costs, then it is likely that there will be strong public support for governments to fund access. However, some people may object to this expenditure.
    Keywords:  Bioethics; Citizens’ jury; Deliberative public engagement; Health expenditures; Mitochondrial Replacement Therapy; Public opinion
    DOI:  https://doi.org/10.1186/s12910-025-01284-4
  9. Cell Biol Toxicol. 2025 Oct 06. 41(1): 136
    Advances in mitochondria-nucleus crosstalk in septic cardiomyopathy.
    Wei Chen, Zeze Zhao, Zhengguang Geng, Han Zhang, Xiaoyun Fu.
      Sepsis-induced cardiomyopathy (SICM), a critical contributor to the high mortality rate associated with sepsis, involves complex pathophysiological mechanisms that remain incompletely elucidated. In recent years, dysregulation of bidirectional signaling communication between mitochondria and the nucleus has been recognized as a pivotal factor in the pathogenesis of SICM. The anterograde signaling pathways-including the PGC-1α/NRF1/NRF2 axis, SIRT3-mediated deacetylation, and TFAM-dependent mitochondrial DNA (mtDNA) maintenance-are suppressed by inflammation and metabolic disturbances. This suppression leads to impaired mitochondrial biogenesis and disrupted energy metabolism. Concurrently, within retrograde signaling pathways, molecular mediators such as reactive oxygen species (ROS), mtDNA, and calcium signaling activate pro-inflammatory and apoptotic pathways, notably NF-κB and cGAS-STING. This activation establishes a vicious cycle perpetuating inflammation and cellular damage. Although current targeted interventions aimed at modulating mitochondrial-nuclear crosstalk have demonstrated some efficacy in animal models, their clinical translation faces significant challenges. These include the dynamic nature of the disease, substantial interindividual variability, and difficulties in achieving targeted delivery. This review summarizes the mechanisms of mitochondrial-nuclear bidirectional signaling in SICM and explores potential therapeutic targets, aiming to provide novel insights for SICM treatment strategies.
    Keywords:  Anterograde signaling; Mitochondrial dysfunction; Mitochondria–nucleus crosstalk; Retrograde signaling; Sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.1007/s10565-025-10090-y
  10. Stem Cell Res Ther. 2025 Oct 10. 16(1): 554
    Melatonin alleviates oxidative stress induced damage in human iPSCs harboring mtDNA 3243A>G mutation via MAPK pathway.
    Zhixin Pu, Peiwen Wang, Mengyao Wang, Yaxin Chen, Yating Zhu, Yuan Jiao, Weiwei Zou, Biao Yu, Huiru Cheng, Yajing Liu, Yunxia Cao, Dongmei Ji, Dan Liang.
       BACKGROUND: Mitochondrial diseases are a group of serious inherited multisystem disorders caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA and still have faced a significant challenge to therapy due to their complicated genotype-phenotype relationships and diverse clinical manifestations. Human induced pluripotent stem cell (hiPSC) offered novel opportunities for cell-based modeling mitochondrial diseases in a patient-specific level. This study aims to explore possibility to potential strategy against mutation-associated oxidative damage through hiPSCs derived from mitochondrial diseases patients.
    METHODS: A human induced pluripotent stem cell line (mt-hiPSCs) from a patient harboring 70.70% heteroplasmic m.3243A>G mutation was established and exposed to hydrogen peroxide (H₂O₂). The cell viability, apoptosis level and mitochondrial function were measured through CCK-8, western blot, flow cytometry, RT-qPCR, fluorescence staining and compared to wild-type hiPSCs. Thereafter, the participation of mitogen-activated protein kinases (MAPK) pathway in the melatonin-mediated protection against H₂O₂-induced oxidative injury was also evaluated.
    RESULTS: Under prolonged low-dose hydrogen peroxide (H₂O₂) exposure, mt-hiPSCs showed significantly reduced viability, elevated apoptosis (52.13 vs. 25.62% in wild-type hiPSCs, P < 0.001), and exacerbated mitochondrial dysfunction, including superoxide accumulation and membrane potential depolarization. Melatonin pretreatment effectively mitigated H₂O₂-induced damage, restoring cell viability, reducing lactate dehydrogenase release, and suppressing apoptosis by normalizing BAX/BCL2 ratios and CASPASE-3 activation. Moreover, melatonin preserved mitochondrial fusion dynamics (MFN1) and respiratory chain integrity (COX IV), counteracting H₂O₂-induced abnormalities. Mechanistically, mt-hiPSCs displayed hyperactivation of MAPK signaling (p-p38, p-ERK, p-JNK) under oxidative stress, which was attenuated by melatonin. Consistently, administration of the MAPK inhibitor SB203580 further confirmed that melatonin's protective effects are closely associated with modulation of MAPK pathway activity in mt-hiPSCs exposed to oxidative stress.
    CONCLUSIONS: These findings highlight the vulnerability of m.3243A>G mutant cells to oxidative stress and demonstrate melatonin's therapeutic potential in alleviating mitochondrial dysfunction via MAPK pathway modulation. This study provides a patient-derived model for exploring mitochondrial disorders and identifies melatonin as a promising cytoprotective agent against mutation-associated oxidative damage.
    Keywords:  Apoptosis; Human induced pluripotent stem cells; MAPK signaling pathway; Melatonin; Mitochondrial dysfunction; mtDNA
    DOI:  https://doi.org/10.1186/s13287-025-04666-y
  11. Brain Commun. 2025 ;7(5): fcaf342
    Outcomes misaligned in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): implications for trial design.
    Renae J Stefanetti, Sarah J Charman, Jane Newman, Kate Hallsworth, Alasdair P Blain, Yi Shiau Ng, Gráinne S Gorman.
      The m.3243A>G variant in the MT-TL1 gene is the most prevalent pathogenic variant in mitochondrial DNA in adults, associated with a wide clinical spectrum from asymptomatic individuals to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Although pharmacological trials in mitochondrial disorders are increasing, the lack of validated endpoints remains a significant barrier to therapeutic development. This cross-sectional observational study aimed to evaluate patients with and without mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome to identify factors associated with disease burden. Seventeen individuals genetically confirmed to harbour the heteroplasmic m.3243A>G pathogenic variant were enrolled: six who met the consensus-based diagnostic criteria for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (median age: 30.0 (inter-quartile range: 29.3-45.0) years). Ten patients who did not have a previous history of stroke-like episodes were assigned as 'non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes' (age: 37.5 (32.8-48.3) years). Of these patients in the non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes group, seven exhibited variable features of mitochondrial disease, including hearing loss, diabetes mellitus, migraine and gastrointestinal involvement, while the remaining three were asymptomatic. One patient was excluded from analysis due to a confirmed ischaemic stroke unrelated to mitochondrial disease. Assessments included disease severity (Newcastle mitochondrial disease adult scale) and patient-reported outcomes of fatigue (fatigue impact scale), health-related quality of life (Newcastle Mitochondrial-QoL), mental well-being (Warwick-Edinburgh mental wellbeing scale), autonomic symptoms (the composite autonomic symptom) and physical activity (The International Physical Activity Questionnaire). Performance outcomes included timed-up and go, handgrip strength, cardiopulmonary exercise testing and accelerometry. Age- and sex-matched healthy controls were included for comparison of accelerometry data (age: 35.5 (28.8-50.5) years). Despite comparable age and mitochondrial DNA heteroplasmy, patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome had significantly higher disease burden, reduced exercise capacity and lower levels of objectively measured physical activity compared to non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and controls (P < 0.05-0.001). Patient-reported outcomes did not significantly differ between mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome/non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. While non-mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes patients showed expected alignment between perceived and objective measures, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome patients demonstrated weak, absent, or paradoxical associations. This mismatch may reflect altered symptom perception, cognitive impairment, or disease-related adaptation. These findings underscore the complexity of disease expression in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Regulatory agencies encourage the inclusion of patient-centred endpoints; however, this study highlights the potential limitations of relying solely on patient-reported outcomes. The divergence between subjective and objective assessments supports the need for multi-dimensional outcomes that integrate both patient perspectives and objective measures to enhance the reliability and interpretability of clinical trials in primary mitochondrial disease.
    Keywords:  MELAS syndrome; m.3243A>G; mitochondrial; outcome measures; stroke-like episodes
    DOI:  https://doi.org/10.1093/braincomms/fcaf342
  12. Cell Host Microbe. 2025 Oct 08. pii: S1931-3128(25)00363-4. [Epub ahead of print]33(10): 1645-1647
    Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
    Evie R Hodgson, Diana Stojanovski.
      In a recent Science paper, Medeiros et al. describe how infected cells use mitochondria as metabolic guardians, outcompeting Toxoplasma parasites for folate, an essential vitamin for DNA synthesis. This metabolic immunity strategy transforms the cell's powerhouse to an active defender, sequestering nutrients away from invaders in a metabolic tug-of-war.
    DOI:  https://doi.org/10.1016/j.chom.2025.09.002
  13. Nat Commun. 2025 Oct 10. 16(1): 9053
    Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
    Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.
      Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.
    DOI:  https://doi.org/10.1038/s41467-025-64147-x
  14. J Steroid Biochem Mol Biol. 2025 Oct 06. pii: S0960-0760(25)00203-1. [Epub ahead of print] 106875
    Advancements in Understanding the Role and Mechanisms of Mitochondria in Diabetes: A Comprehensive Review.
    Xia Ge, Min Ye, Aihua Fei, Qingping Zhang, Aihong Yuan.
      Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochondrial dysfunction in the onset and progression of diabetes. It outlines how defects in mitochondrial oxidative phosphorylation, increased free radical production, and mitochondrial DNA damage contribute to insulin resistance, β-cell apoptosis, and systemic metabolic dysfunctions. The review highlights the critical roles of mitochondria in energy metabolism, oxidative balance, and the interplay of genetic and environmental factors in diabetes. It also emphasizes the association of impaired mitochondrial function with various diabetes-related complications and organ-specific diseases, underscoring the urgent need for innovative therapeutic strategies. Potential interventions discussed include pharmacological agents promoting mitochondrial biogenesis and enhancing mitochondrial dynamics, alongside dietary and lifestyle modifications that support mitochondrial function and overall metabolic health. The review calls for intensified research into mitochondrial mechanisms and their therapeutic targets, advocating for comprehensive clinical trials and support from medical and governmental institutions to advance diabetes management strategies centered on mitochondrial health.
    Keywords:  Diabetes metabolism; Mechanism interventions; Mitochondria
    DOI:  https://doi.org/10.1016/j.jsbmb.2025.106875
  15. NPJ Metab Health Dis. 2024 May 27. 2(1): 6
    Multifaceted mitochondria in innate immunity.
    Eloïse Marques, Robbin Kramer, Dylan G Ryan.
      The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.
    DOI:  https://doi.org/10.1038/s44324-024-00008-3
  16. J Control Release. 2025 Oct 02. pii: S0168-3659(25)00899-5. [Epub ahead of print] 114286
    Lipid and polymeric nanocarrier for siRNA delivery to the brain.
    Sushil Koirala, Kun Cheng.
      Brain diseases refer to any pathological condition that impairs the normal functions of the brain. These mainly include neurodegenerative disorders, brain injuries, and malignant tumors. Researchers have explored various therapeutic approaches to treat these conditions, with gene modulation gaining significant attention in recent years due to its potential to apparently address the root cause of disease. One promising approach is the use of siRNAs as therapeutic agents for brain diseases. Most preclinical studies on siRNA delivery to the brain have employed invasive intracerebral methods to target specific brain regions, posing significant challenges for clinical translation. The challenges associated with the intracerebral route highlight the need for safer, more practical, and patient-compliant alternatives, such as systemic delivery. However, systemic siRNA delivery faces obstacles due to its inherent instability in circulation and the restrictive nature of the blood-brain barrier (BBB). Nanocarriers have emerged as a promising strategy to overcome these challenges. These nanocarriers can be made from various natural, synthetic, or biological materials, with polymers and lipids being the most commonly used due to their biocompatibility, ease of surface modification for targeting, controlled drug release, and improved stability. In this review, we discuss lipid- and polymer-based nanotechnology strategies aimed at overcoming the challenges of siRNA delivery and enhancing its therapeutic potential for treating a range of brain diseases.
    Keywords:  Blood-brain barrier; Brain diseases; Lipid-based nanocarriers; Nanotechnology; Polymeric nanocarriers; siRNA
    DOI:  https://doi.org/10.1016/j.jconrel.2025.114286
  17. Mol Oncol. 2025 Oct 05.
    Imperial strategy of cancer cells through mitochondrial transfer.
    Takamasa Ishino, Yosuke Togashi.
      Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of intercellular communication. Notably, an increasing number of studies have reported its occurrence in the tumor microenvironment (TME), where it contributes to tumor progression. While previous studies largely characterized cancer cells as recipients of mitochondria, Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts via tunneling nanotubes. The mitochondrial transfer to fibroblasts reprogrammed them into cancer-associated fibroblasts exhibiting combined myofibroblastic and inflammatory characteristics, with enhanced oxidative metabolism and pro-tumorigenic activity. Our group has identified mitochondrial 'hijack' from cancer cells to tumor-infiltrating lymphocytes, leading to an impaired antitumor immunity. These insights underscore the need to recognize cancer cells as mitochondrial donors in the TME capable of reshaping the TME to their own advantage, resembling a dynastic expansion strategy that exerts influence by strategically placing lineages.
    Keywords:  cancer‐associated fibroblast; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70142
  18. Mol Biomed. 2025 Oct 11. 6(1): 80
    Healthy mitochondria attenuate metabolic dysfunction-associated steatohepatitis by restoring cell metabolism.
    Peiyu Zhou, Jingli Li, Yafang Xie, Xiaorong Li, Zhihong Cui, Ailing Fu.
      Metabolic dysfunction-associated steatohepatitis (MASH) has become a major global health issue. Mitochondrial damage plays a crucial role in the development and progression of MASH. Therefore, it is speculated that mitochondrial transplantation therapy, which could replace dysfunctional mitochondria with normal ones, might potentially restore the liver cell metabolism of MASH. In palmitate-damaged AML-12 hepatocytes, exogenous mitochondria could eliminate lipid deposits and recover cell viability. However, in transforming growth factor β (TGF-β)-activated hepatic stellate cells (HSCs), the exogenous mitochondria showed the capability to inhibit the generation of α-smooth muscle actin (α-SMA) and collagen I. Moreover, the mechanism by which the exogenous mitochondria initiated the mitochondria-nucleus signaling pathway of liver cells was studied. The results showed the mitochondria could prevent metabolism disorders in the liver cells by regulating silent information regulator 1 (SIRT1) activity. Subsequently, a MASH animal model was established by the administration of a high-fat diet and the intraperitoneal injection of carbon tetrachloride to Kunming mice. The results indicated that the mitochondrial therapy significantly inhibited the livery injury and restored liver cell function in the experimental MASH mice (p < 0.01). The mitochondrial therapy would be a promising strategy to improve MASH pathological features, which could be developed as a new treatment option against MASH.
    Keywords:  Healthy mitochondria; Metabolic dysfunction-associated steatohepatitis (MASH); Oxidative stress; Silent information regulator 1 (SIRT1)
    DOI:  https://doi.org/10.1186/s43556-025-00328-w
  19. Research (Wash D C). 2025 ;8 0912
    Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.
    Jianliang Huang, Can Zhang, Cheng Huang, Kun Deng, Yun Xiao, Wei Gao, Minghua Wu, Mingsheng Lei.
      Neurodegenerative diseases represent a major health threat, with dysfunction in energy metabolism and imbalance in glucose-lipid homeostasis constituting key pathogenic factors. As the cell's energy hub, mitochondria are closely associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, the precise mechanism by which mitochondrial energy metabolism affects glucose-lipid homeostasis remains unclear. This review summarizes currents insights into the role of mitochondrial function in energy metabolism and glucose-lipid regulation in neurodegenerative diseases. We examined how mitochondrial dynamics, oxidative phosphorylation, calcium homeostasis, and key signaling pathways-AMP-activated protein kinase/mammalian target of rapamycin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and Sirtuin 1-contribute to neuronal energy balance and metabolic regulation. We further explored the impact of other organelles on mitochondria and how the dynamic switching of mitochondrial morphology and function disrupts the critical glucose-lipid homeostasis. By focusing on mitochondrial dysfunction, metabolic disorders, and their interactions, we introduce the mitochondria-centered multi-organelle-energy metabolic-glucose-lipid homeostasis (MMH) network as a unifying theoretical framework that positions the progressive loss of metabolic flexibility as the fundamental essence of neurodegenerative disorders. The MMH network furnishes a novel lens through which the shared mechanistic underpinnings of neurodegenerative diseases can be deciphered, and thereby enable earlier diagnosis and precision therapeutics.
    DOI:  https://doi.org/10.34133/research.0912
  20. Trends Neurosci. 2025 Oct 08. pii: S0166-2236(25)00194-8. [Epub ahead of print]
    Mesenchymal stromal cell extracellular vesicles as immune modulators and drug carriers in neurodegenerative disorders.
    Lien Van Hoecke, Cristiano Lucci, Roosmarijn E Vandenbroucke.
      Mesenchymal stromal cells (MSCs) hold significant therapeutic potential, but their clinical application is often hindered by limitations such as donor variability. MSC-derived extracellular vesicles (EVs) present a promising alternative, offering comparable or superior therapeutic effects while overcoming some of these challenges. MSC-EVs exhibit strong anti-inflammatory and immunomodulatory properties, which could be leveraged in neurodegenerative diseases given the central role of neuroinflammation in these conditions. Additionally, MSC-EVs can be engineered for targeted drug delivery, enhancing their clinical utility. In this review we highlight the dual role of MSC-EVs as immunomodulators and drug carriers in neurodegenerative disorders. We discuss the current challenges, and outline strategies for clinical translation. Future advances in understanding MSC-EVs and their mechanisms of action could support their development into effective therapies for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; brain targeting; drug delivery; immune modulation; neuroinflammation
    DOI:  https://doi.org/10.1016/j.tins.2025.09.008
  21. Biogerontology. 2025 Oct 10. 26(5): 190
    Therapeutic extracellular vesicles as a cornerstone of medicine in the next decade with gerontological focus.
    Alexander Yu Pulver, Roman E Tokmachev, Natalie A Pulver, Lyubov N Antakova, Mariia A Emelianova.
      Extracellular vesicles present a promising alternative to stem cells in regenerative medicine and gerontology. They offer significant advantages over cell transplantation, demonstrating potential for slowing aging and treating age-related diseases. Extracellular vesicles secreted by diverse cell types modulate inflammation, stimulate tissue regeneration, and exhibit anti-inflammatory and immunomodulatory properties. This work explores the therapeutic potential of extracellular vesicles as alternatives to cell therapy, examining their key advantages and current limitations. It specifically focuses on their roles within established aging mechanisms and their dual utility as biomarkers and therapeutic agents. Critical aspects of extracellular vesicle translation are addressed, including standardized methods for production, storage stability optimization, and engineering strategies for cargo loading and targeting. Extracellular vesicles possess unique biological properties-inherent biocompatibility, low immunogenicity, ability to cross biological barriers, and high biological activity at low doses. Preclinical studies across various age-related pathologies (neurodegeneration, cardiovascular disease, sarcopenia) consistently report efficacy in reducing inflammation, promoting tissue repair, and improving functional outcomes. These findings strongly support the capacity of extracellular vesicles to mimic many therapeutic effects of parental cells while mitigating risks like tumorigenicity or immunorejection associated with whole-cell therapies. Overcoming challenges in scalable manufacturing, quality control, regulatory standardization, and targeted delivery is essential for the clinical translation of extracellular vesicles. Despite these hurdles, their compelling preclinical evidence and inherent advantages position them as a major future direction. They are expected to play a key role in combating age-related decline and advancing regenerative medicine, becoming a cornerstone of next-generation biomedical interventions over the next decade.
    Keywords:  Extracellular vesicles; Gerontology; Heterochronic parabiosis; Plasmapheresis; Regenerative medicine; Rejuvenation
    DOI:  https://doi.org/10.1007/s10522-025-10332-w
  22. GEN Biotechnol. 2023 Oct;2(5): 353-359
    Developing Treatments for Rare Diseases on a Shoestring.
    Ana C Puhl, Sarah Negri, Maggie A Z Hupcey, Sean Ekins.
      There are thousands of rare genetic diseases lacking an approved treatment, many of which are life-limiting to children. Those caused by a missing protein may represent a target for protein replacement either by enzyme replacement therapy or gene therapy. One of the many challenges working on these types of genetic diseases is the availability of funding, as these diseases typically affect very small numbers of patients. Here we offer a novel case study of our approach to developing a treatment for one such rare disease, which has not required venture capital, angel investment or funding by foundations to date. We have instead pursued NIH small business grants to fund the early preclinical work performed by our academic collaborators and ourselves. Our approach to developing a treatment for a rare disease on a shoestring budget is unlike any of the alternative approaches to funding.
    Keywords:  Funding; Rare diseases; SBIR; Small business grants
    DOI:  https://doi.org/10.1089/genbio.2023.0033
  23. Neurosci Lett. 2025 Oct 06. pii: S0304-3940(25)00299-X. [Epub ahead of print]868 138410
    Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
    Pallab Bhattacharya, Shailendra Saraf, Anirban Barik, Bijoyani Ghosh, Aishika Datta, Davendra Singh Malik.
      The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.
    Keywords:  Calcineurin; Calcium signaling; Cardiolipin; Mitochondrial aging; Stroke
    DOI:  https://doi.org/10.1016/j.neulet.2025.138410
  24. BMC Biol. 2025 Oct 09. 23(1): 302
    Proteasome regulation of petite-negativity in fission yeast.
    Katie Lin Amberg, Lyrica Hao, Susanne Cranz-Mileva, Mikel Zaratiegui.
       BACKGROUND: Mitochondria carry out essential functions in eukaryotic cells. The mitochondrial genome encodes factors critical to support oxidative phosphorylation and mitochondrial protein import necessary for these functions. However, organisms like budding yeast can readily lose their mitochondrial genome, yielding respiration-deficient petite mutants. The fission yeast Schizosaccharomyces pombe is petite-negative, but some nuclear mutations enable the loss of its mitochondrial genome.
    RESULTS: Here, we characterize the classical petite-positive mutation ptp1-1 as a loss of function allele of the proteasome 19S regulatory subunit component mts4/rpn1, involved in the ubiquitin-dependent degradation pathway. By comparison with another petite-enabling mutation in the g-subunit of the F1-ATPase, we show that ptp1-1 does not rescue mitochondrial membrane potential. Instead, the mutation results in increased levels of mitochondrial and cytoplasmic chaperones and an altered oxidative stress response.
    CONCLUSIONS: ptp1-1 is a partial loss of function mutation of the proteasome that enables growth of cells devoid of mitochondrial DNA through a mechanism that is independent of mitochondrial membrane potential rescue and associated with proteasome-dependent regulation of mitochondrial protein import precursors and the oxidative stress response.
    Keywords:  Fission yeast; Mitochondria; MtDNA; Petite; Proteasome; Schizosaccharomyces pombe
    DOI:  https://doi.org/10.1186/s12915-025-02409-2
  25. Front Cell Dev Biol. 2025 ;13 1627149
    Clinical translation of human iPSC technologies: advances, safety concerns, and future directions.
    Sarah Dhaiban, Sanjana Chandran, Mohammed Noshi, Abdulrahim A Sajini.
      Human induced pluripotent stem cells (hiPSCs) have opened new possibilities in regenerative medicine, providing a versatile platform for modeling human disorders, testing pharmacological agents, and developing personalized regenerative treatments. By reprogramming adult cells into a pluripotent state, scientists can generate patient-specific cells capable of differentiating into nearly any tissue type. Using the patient's own cells allows for therapies that are both biologically matched and ethically acceptable, while also reducing the likelihood that the immune system will reject transplanted cells. Despite this promise, translating hiPSCs into routine clinical use has proven challenging, with several practical and biological barriers yet to be overcome. Key concerns include variability in differentiation outcomes, immune responses to allogeneic cells, genetic and epigenetic abnormalities, and the risk of tumor formation. Reliable scale-up under GMP conditions remains a major technical hurdle, and critical questions around long-term engraftment, tissue integration, and immune tolerance are still unresolved. Recent advances, including CRISPR/Cas9 gene editing and AI-guided differentiation, are enhancing iPSC quality and enabling treatments to be tailored to individual patients. Clinical trials are ongoing in areas such as retinal disorders, neurodegenerative diseases, cardiac conditions, and cancer immunotherapy, with early findings suggesting these therapies may be both feasible and safe. However, widespread adoption will require rigorous, long-term evaluation. This review examines the latest progress in hiPSC technology and evaluates its movement toward clinical translation. We highlight the major challenges that continue to limit broader application, particularly those related to safety, large-scale manufacturing, and regulatory oversight, and discuss emerging advances that may help bring iPSC-based therapies closer to routine clinical practice.
    Keywords:  HLA-matched iPSC banks; cell therapy; clinical trials; gene editing; induced pluripotent stem cells (iPSCs); personalized medicine; regenerative medicine
    DOI:  https://doi.org/10.3389/fcell.2025.1627149
  26. Mol Psychiatry. 2025 Oct 07.
    Role of telomere length and telomerase activity in accelerated cellular aging and major depressive disorder: a systematic review.
    Samantha Wai Sam Au Young, Chuin Hau Teo, Ishwar S Parhar, Tomoko Soga.
      Recent research has increasingly focused on understanding the relationship between cellular aging and mental health, particularly Major Depressive Disorder (MDD). Telomeres, protective structures at the end of chromosomes, and telomerase, an enzyme responsible for their maintenance, have emerged as potential markers of cellular aging and targets for therapeutic interventions in MDD. This review synthesizes findings from 30 studies conducted over the past 15 years, examining alterations in telomere length (TL) and telomerase activity (TA) in individuals with MDD compared to healthy controls. Most studies reported shorter TL in MDD patients, particularly in cases of chronic or severe depression, determined by the duration of illness or illness episode and by measurements of depression severity (e.g. HAM-D, BDI, etc.), suggesting an association between MDD and accelerated cellular aging. Elevated TA was also observed in MDD, with potential implications for treatment response. However, conflicting findings and methodological variations highlight the complexity of the relationship between TL, TA, and MDD, warranting further research. Additionally, studies investigating other biomarkers of cellular aging, such as mitochondrial DNA, provide further insights into the pathophysiology of MDD. Studies on brain cells reveal regional variations in telomere dynamics, suggesting a nuanced relationship between depression and cellular aging across different brain regions. While evidence suggests a potential reversibility of TL alterations in MDD, further research is needed to elucidate underlying mechanisms and develop targeted interventions. Overall, this review underscores the importance of understanding cellular aging processes in MDD and their potential implications for diagnosis, treatment, and the development of novel therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41380-025-03296-3
  27. Biochemistry (Mosc). 2025 Sep;90(9): 1240-1251
    Approaches to Humanization of Mitochondrial Proteins in Saccharomyces cerevisiae on the Example of Replacing the Yeast Mitochondrial Translation Termination Factor MRF1 with Its Human Homologues.
    Rinat A Khannanov, Ivan V Chicherin, Mariya V Baleva, Sergey A Levitskii, Ruslan A Vasilev, Ulyana E Piunova, Piotr Kamenski.
      Mitochondrial translation is a highly specialized process of synthesizing mitochondrially encoded proteins, mainly the components of the oxidative phosphorylation system. It involves four key stages: initiation, elongation, termination, and recycling of mitochondrial ribosomes. Each of these stages is regulated by a specific set of translation factors, most of which are encoded by the nuclear genome and imported into mitochondria. The termination of mitochondrial translation in yeast (Saccharomyces cerevisiae) is carried out by the MRF1 release factor. This nuclear-encoded factor is crucial for ensuring accurate protein synthesis within the organelle, as it recognizes stop codons and facilitates the release of completed polypeptide chains from the ribosome. In addition to this main function, MRF1 participates in maintaining mitochondrial genome stability. The aim of this study was to investigate the capacity of human homologues, hMTRF1, hMTRF1A, and mitoribosome rescue factors hMTRFR and hMRPL58, to compensate for the absence of the yeast mitochondrial translation termination factor MRF1 in S. cerevisiae cells. The results obtained suggest that human orthologues of MRF1, such as hMTRF1 and hMTRF1A, can contribute to maintaining the integrity of the yeast mitochondrial genome. However, they do not fully replace the function of MRF1, as they do not restore normal respiration of the mutant yeast strains.
    Keywords:  baker’s yeast; humanization; mitochondria; mitochondrial DNA; protein biosynthesis; termination; translation
    DOI:  https://doi.org/10.1134/S0006297925601418
  28. J Microsc Ultrastruct. 2025 Jul-Sep;13(3):13(3): 130-136
    Red Blood Cells in Health and Disease.
    Aradhya Giri, Sandhya Tamgadge.
      Red blood cells (RBCs) play a crucial role in the normal functioning of the human body, primarily through their ability to transport oxygen and carbon dioxide. Various diseases, including anemia and other hemolytic disorders, can arise when there is an abnormality in RBC structure or function. The pathophysiology of other conditions, such as cancer and cardiovascular disease can also involve changes in RBCs. Advances in RBC research have led to a better understanding of their structure, function, and pathophysiology. The COVID-19 pandemic has also highlighted the critical role of RBCs in disease pathology, with research suggesting that RBCs may be directly affected by the virus. This review provides a comprehensive overview of the current state of RBCs in health and disease, including recent advances in diagnosis, treatment, and the role of RBCs in disease pathology.
    Keywords:  Anemia; dentists; disease; diseases; health; red blood cells
    DOI:  https://doi.org/10.4103/jmau.jmau_70_23
  29. Transl Psychiatry. 2025 Oct 06. 15(1): 355
    Salivary mitochondrial DNA is associated with biomarkers of Alzheimer's disease in cognitively normal older adults.
    Jose L Cantero, Mercedes Atienza, Petar Podlesniy, Margalida Puigròs, Ramon Trullas.
      A significant body of evidence suggests that mitochondrial dysfunction plays a key role in the development and progression of Alzheimer's disease (AD). However, the absence of peripheral biomarkers for mitochondrial dysfunction limits its clinical applicability. Mitochondrial DNA (mtDNA) copy number, a proxy for mitochondrial function, has shown promise in detecting early stages of AD and predicting AD risk in cerebrospinal fluid (CSF) and blood, respectively. Surprisingly, recent studies have identified mtDNA molecules in human saliva, but their relationship with AD remains unexplored. Here, we investigated potential associations between salivary mtDNA copy number and cortical amyloid-β (Aβ) load measured with PET, and blood AD markers measured with ultrasensitive single molecule array (SIMOA) assays, in cognitively normal older adults. We found that salivary mtDNA copy number was positively correlated with cortical Aβ burden and plasma levels of tau phosphorylated at threonine 181 (pTau-181), and negatively correlated with general cognitive ability. It is worth noting that salivary mtDNA was not significantly associated with other blood-based AD biomarkers, including Aβ1-40, Aβ1-42, neurofilament-light chain (NfL), or glial fibrillary acidic protein (GFAP). Additionally, plasma pTau-181 levels moderated the association between salivary mtDNA and Aβ accumulation in the inferior temporal lobe, while Aβ load in the occipital cortex mediated the association between plasma pTau-181 and salivary mtDNA. Together, these findings represent the first evidence linking salivary mtDNA to well-established AD biomarkers in normal aging, suggesting that salivary mtDNA may serve as a potential non-invasive biomarker for identifying individuals at risk for developing AD in the general population.
    DOI:  https://doi.org/10.1038/s41398-025-03589-9
  30. Stem Cell Rev Rep. 2025 Oct 09.
    Stem Cells to Organoids: Pioneering the Future of Regenerative Therapies.
    Dinesh Kumar, Sonia Gupta, Vrinda Gupta, Rajni Tanwar, Pooja Rani, Vikas Bansal.
       BACKGROUND: Understanding normal development, disease modeling, and regenerative medicine forms the cornerstone of modern biomedical research. Insights into embryonic and postnatal development enable the study of cellular processes critical for tissue and organ formation.
    OBJECTIVES: This review aims to summarize recent advancements in developmental biology, disease modeling techniques, and regenerative medicine, emphasizing the integration of these fields to improve therapeutic strategies.
    METHODS: A comprehensive literature analysis was conducted focusing on stem cell biology, tissue engineering, organoid technology, and bioengineering approaches relevant to normal development, disease modeling, and regenerative therapies.
    RESULTS: Advances in stem cell technologies, including embryonic and induced pluripotent stem cells, have facilitated transplantation therapies and tissue regeneration. The emergence of 3D multicellular culture systems, such as organoids, enhances disease modeling by more accurately replicating tissue architecture. Bioengineered organ germs represent a promising strategy for functional organ regeneration. However, challenges remain in mimicking the complex in vivo environment and addressing ethical and technical limitations.
    CONCLUSIONS: Multicellular and three-dimensional in vitro models represent critical tools for bridging gaps in our understanding of development, disease, and regeneration. Continued interdisciplinary efforts are essential to translate these findings into effective regenerative therapies and precise disease models.
    Keywords:  3D culture; Developmental biology.; Disease modeling; Normal development; Organ regeneration; Organoids; Regenerative medicine; Stem cells; Tissue engineering
    DOI:  https://doi.org/10.1007/s12015-025-10985-7
  31. Pharmacol Res. 2025 Oct 04. pii: S1043-6618(25)00405-0. [Epub ahead of print]221 107980
    Mitochondrial damage-associated molecular patterns (mito-DAMPs): Determinants of hepatopathy progression and therapeutic implications.
    Ranyi Luo, Yun Yang, Yinhao Zhang, Xiaoyong Xue, Mengyu Guo, Xiaojiaoyang Li.
      Liver diseases, as the primary representative disorders of the digestive tract, encompass metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis, and malignant liver or gallbladder cancers and pose a significant health challenge to millions of individuals worldwide. Meanwhile, to make matters worse, the incidence of MASLD, which can progress to end-stage liver disease, has gradually increased in recent years due to shifts in dietary practices and lifestyle choices. In the context of various liver diseases, endogenous danger signals released from damaged or dying cells, known as damage-associated molecular patterns (DAMPs), can be recognized by the innate immune system through pattern recognition receptors. This recognition subsequently leads to the recruitment of immune cells and the activation of an inflammatory cascade. Recently, mitochondria have garnered significant attention as a novel source of DAMPs, namely mito-DAMPs. Under stress conditions, various pro-inflammatory mediators, previously thought to play a crucial role in the pathogenesis of liver disease, are released from mitochondria, including mitochondrial DNA, reactive oxygen species, cytochrome c, adenosine triphosphate, cardiolipin and carbamoyl phosphate synthetase 1. Here, we emphasize the significance of these novel mito-DAMPs in the initiation and progression of various liver diseases and discuss the interplay among these molecules under different pathological environment. Our aim is to explore potential therapeutic targets and strategies in drug development that can be employed to combat liver diseases.
    Keywords:  Mito-DAMPs; liver diseases; mitochondria; mtDNA
    DOI:  https://doi.org/10.1016/j.phrs.2025.107980
  32. Psychopharmacology (Berl). 2025 Oct 10.
    Mitochondrial dysfunction in PTSD: A mechanism to understand trauma susceptibility?
    Felippe E Amorim, Charlotte S Rye, Amy L Milton.
       RATIONALE AND OBJECTIVES: Post-Traumatic Stress Disorder (PTSD) is a complex mental health condition that arises following exposure to traumatic events. Converging evidence suggests mitochondrial dysfunction and brain energy metabolism impairment in its pathophysiology. Thus, examining mitochondrial data from both preclinical and experimental medicine studies may help us to have a deeper understanding of the pathophysiological mechanisms underlying PTSD.
    METHODS: Using PubMed, Scopus and Web of Science online databases, we conducted a search for peer-reviewed manuscripts targeting both mitochondrial-related activity and PTSD. Our search yielded 43 studies in total, including 29 in rodent models and 15 clinical studies.
    RESULTS: Preclinical studies reported a decrease in energy metabolism with a reduction in adenosine triphosphate (ATP) level, upregulation of genes associated with ATP synthesis, impairment of the glycolytic pathway, citric acid cycle and oxidative phosphorylation pathways and increased oxidative stress and neuronal apoptosis in the brain, or systemically. In the clinical setting, studies identified 1108 participants with PTSD and 312 with partial PTSD, with these individuals showing alterations in energy production, mitochondrial DNA copy number (mtDNAcn) and elevated oxidative stress. Risperidone and AC-5216-a selective ligand for TSPO-emerged as potential treatments.
    CONCLUSION: Our synthesis of the published findings indicates a notable overlap between results from both animal models and humans which could show a potential usage of mitochondrial-related targets as biomarkers or for drug discovery. Additionally, these results highlight the need for future research in describing whether mitochondrial dysfunction is a cause or a symptom of PTSD.
    Keywords:  Inflammation; Metabolism; Mitochondria; Oxidative Stress; PTSD
    DOI:  https://doi.org/10.1007/s00213-025-06900-0
  33. J Adv Vet Anim Res. 2025 Jun;12(2): 497-515
    The dual role of extracellular vesicles derived from animal and human immune cells: A systematic review.
    Joseph Bagi Suleiman, Norhayati Liaqat Ali Khan, Maryam Azlan.
      This review aims to examine the functions of extracellular vesicles (EVs) originating from animal and human immune cells, with a focus on their roles in immunomodulation and therapeutic potential. It highlights their dual effects in infection and autoimmunity, cancer treatment, inflammatory conditions, and regenerative medicine while also addressing the challenges in standardizing EV production, isolation, and characterization for clinical applications. This review highlights the need for robust protocols to advance EV-based therapies. It also synthesizes current literature on immune cell-derived EVs, with a focus on their mechanisms of action in intercellular communication, immune modulation, and therapeutic delivery. Additionally, it examines studies that explore the regenerative potential of immune cell-derived EVs and discusses the technical and methodological challenges involved in EV research and clinical translation. EVs from immune cells can either boost or reduce immune responses in tumor therapy, which greatly affects how cancer develops and how well treatments work. These EVs also show promise in managing inflammatory diseases through immune modulation and targeted therapeutic delivery. Furthermore, immune cell-derived EVs possess regenerative properties, contributing to tissue repair and the maintenance of homeostasis. Despite these promising roles, challenges related to the standardization of EV production, isolation, and characterization continue to impede clinical translation, for improved protocols to ensure reproducibility and scalability. Immune cell-derived EVs possess substantial therapeutic potential in cancer treatment, inflammatory diseases, and regenerative medicine. These tiny membrane-bound particles, naturally released by immune cells, carry bioactive molecules that can modulate immune responses, suppress tumor growth, or promote tissue repair. However, before these therapies can be widely used in clinics, key challenges must be addressed, particularly in standardizing their production, characterization, and quality control.
    Keywords:  B cell; T cell; extracellular vesicles; immune cells; monocyte; neutrophil
    DOI:  https://doi.org/10.5455/javar.2025.l915
  34. F S Rep. 2025 Sep;6(3): 270-279
    A machine learning approach using semen parameters and sperm mitochondrial DNA copy number to predict couples' fecundity.
    Savni Sawant, Amanda L Paskavitz, Karolina Nowak, Allyson J Rosati, Ted Westling, Ricardo P Bertolla, Brian W Whitcomb, J Richard Pilsner.
       Objective: To examine the utility of semen parameters and sperm mitochondrial DNA copy number (mtDNAcn) to predict couples' time to pregnancy (TTP).
    Design: This study assessed the predictive power of sperm mtDNAcn and 34 semen parameters. Two composite semen quality indices (SQIs) were developed; an unweighted ranked-sperm quality index (ranked-SQI) derived from only semen parameters and a weighted sperm quality index generated using machine learning via elastic net (ElNet-SQI). Discrete-time proportional hazard models, logistic regression, and receiver operating characteristic (ROC) analyses were used to evaluate the predictive ability of achieving pregnancy at 3, 6, and 12 months, and the overall TTP.
    Subjects: The participants included 281 men from the Longitudinal Investigation of Fertility and the Environment study, a large preconception general population cohort designed to explore factors affecting conception.
    Exposure: Sperm mtDNAcn, 34 semen parameters, unweighted ranked-SQI, and a machine learning-based weighted SQI were evaluated for the ability to predict pregnancy.
    Main Outcomes Measures: The main outcome measures were the overall time taken to achieve pregnancy and the likelihood of achieving pregnancy within 3, 6, or 12 months of trying to conceive.
    Results: For individual semen measures, sperm mtDNAcn was most predictive of pregnancy at 12 menstrual cycles in ROC analyses (area under the curve [AUC], 0.68; 95% confidence interval [CI], 0.58-0.78). Among multiparameter biomarkers, ElNet-SQI (comprised of 8 semen parameters and mtDNAcn), demonstrated the highest AUC, 0.73; 95% CI, 0.61-0.84) for pregnancy status at 12 cycles. Furthermore, ElNet-SQI was the most strongly associated with TTP than any other individual or combinations of semen parameters (fecundability odds ratio [FOR], 1.30; 95% CI, 1.14-1.45; P=6.0∗10-5).
    Conclusion: Sperm mtDNAcn is associated with multiple conventional and detailed semen parameters. Moreover, a composite machine learning ElNet-SQI that included mtDNAcn and several semen parameters had the highest predictive ability of pregnancy. These results indicate that sperm mtDNAcn can serve as a biomarker of overall sperm fitness and likelihood of reproductive success.
    Keywords:  Fertility; machine learning; mitochondrial DNA copy number; semen parameters; semen quality; sperm
    DOI:  https://doi.org/10.1016/j.xfre.2025.05.002
  35. Front Biosci (Landmark Ed). 2025 Sep 26. 30(9): 44648
    Modulation of Mitochondrial Dynamics in Primary Hippocampal Cultures of 5xFAD Mice by Mdivi-1, MFP, and Exogenous Zinc.
    Alina Chaplygina, Daria Zhdanova.
       BACKGROUND: Mitochondrial dynamics-the balance between fission, fusion, and mitophagy-are essential for maintaining cellular homeostasis and are increasingly implicated in the pathogenesis of Alzheimer's disease (AD).
    METHODS: Here, we investigated the effects of targeted modulation of mitochondrial fission and fusion on mitochondrial morphology and metabolic status in primary hippocampal cultures derived from 5xFAD transgenic mice. Mitochondrial dynamics were modulated using the fission inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), the fusion promoter mitochondrial fusion promoter M1 (MFP M1), and exogenous zinc as a fission activator. We evaluated mitochondrial morphology, lipofuscin accumulation, beta-amyloid (Aβ42) levels, and reactive oxygen species (ROS). The general condition of the cultures was assessed morphologically using neuronal and astrocytic markers.
    RESULTS: Modulating mitochondrial dynamics altered mitochondrial morphology, decreased Aβ42, lipofuscin, and ROS levels, and improved cellular organization. Treatments with MFP and Mdivi-1 promoted mitochondrial hyperfusion without complete network integration and were associated with reduced astrogliosis and increased neuronal density. In contrast, zinc induced dose-dependent mitochondrial fragmentation and astrocytic clasmatodendrosis, with lower concentrations enhancing Aβ clearance and higher concentrations inducing toxicity.
    CONCLUSIONS: Mitochondrial fusion and fission significantly influence lipofuscin and amyloid accumulation in 5xFAD cultures, underscoring their potential as therapeutic targets in neurodegenerative diseases. We propose that mitochondrial morphology acts as a key regulator of both cellular homeostasis and disease pathology.
    Keywords:  Alzheimer’s disease; lipofuscin; mitochondria; mitochondrial dynamic; mitochondrial fission; mitochondrial fusion; primary cell culture
    DOI:  https://doi.org/10.31083/FBL44648
  36. iScience. 2025 Sep 19. 28(9): 113449
    Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice.
    Marica Meroni, Erika Paolini, Miriam Longo, Michele Battistin, Daniele Dondossola, Michela Ripolone, Laura Napoli, Ettore Mosca, Stefania Corti, Paola Dongiovanni.
      Hepatic mitochondrial maladaptation features the transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to Steatohepatitis (MASH) up to fibrosis/cirrhosis. However, it is still unexplored whether mitochondrial alterations also affect adipose tissue, muscle and heart during disease progression. C57Bl/6 mice were fed an AMLN diet to recapitulate the human MASLD spectrum. In the liver, TEM depicted a progressive morphologic dysfunction of mitochondria, which appeared swollen in MASH, with disorganized cristae/matrix loss in MASH-fibrosis. The mitophagy pathway was reduced in MASH-fibrosis, thus explaining the accumulation of damaged mitochondria, whereas mitochondrial complexes activities alongside OXPHOS protein levels and ATP production were dampened across the disease in liver, adipose, muscle, and cardiac tissues. Finally, the release of cell-free circulating mitochondrial DNA into the bloodstream reflected tissue mitochondrial impairment. In sum, we demonstrated that alterations in mitochondrial morphology, life cycle, and activity feature all disease stages in the liver but also in other tissues engaged in MASLD evolution.
    Keywords:  Biochemistry; Systems biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113449
  37. Front Biosci (Landmark Ed). 2025 Sep 29. 30(9): 44666
    Inhibition of S100A9 Improves Aortic Dissection in Association With Mitochondrial Function Enhancement.
    Keyu Zhang, Linman Li, Yiying Zhang, Kai Guo, Zhao Zhang, Mengning Wan, Yongzheng Guo, Yu Zhao, Xiaowen Wang.
       BACKGROUND: Aortic dissection (AD) is a high-mortality cardiovascular emergency with unclear pathophysiological mechanisms. This study investigated S100 calcium-binding protein A9 (S100A9) as a therapeutic target for AD and explored its underlying mechanisms.
    METHODS: Proteomic analysis compared aortic tissues from patients with acute type A and matched non-dissected vascular tissues from the same patients. An AD model was induced in wild-type and S100A9 knockout mice via β-aminopropionitrile (BAPN). Survival, aortic diameter, and S100A9 expression were quantified. Furthermore, single-cell RNA sequencing was used to analyze cell populations and mitochondrial pathways in AD mice treated with an S100A9 inhibitor. Finally, the effect of S100A9 on mitochondrial function was investigated in Tohoku Hospital Pediatrics-1 (THP-1) cells.
    RESULTS: Proteomics identified that S100A9 is significantly upregulated in AD tissue. Furthermore, S100a9 knockout (S100a9 KO) mice conferred protection against AD-induced mortality and aortic dilation. Single-cell RNA analysis revealed that S100A9 is predominantly expressed within the granulocyte population. S100A9 inhibition activated mitochondrial oxidative phosphorylation pathways and upregulated mtDNA-encoded gene expression. Human tissue mRNA levels confirmed decreased mtDNA in AD. Moreover, recombinant human S100A9 and angiotensin-II treatment in THP-1 cells reduced mitochondrial membrane potential and increased oxidative stress.
    CONCLUSIONS: S100A9 is a potential contributor to AD pathogenesis. Inhibition of S100A9 might be a promising therapeutic target for AD.
    Keywords:  S100A9; aortic dissection; mitochondrial function; proteomic analysis; single-cell RNA sequencing
    DOI:  https://doi.org/10.31083/FBL44666
  38. Front Neuroendocrinol. 2025 Oct 03. pii: S0091-3022(25)00043-3. [Epub ahead of print] 101217
    Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.
    George B Stefano, Pascal Büttiker, Simon Weissenberger, Jiri Raboch, Martin Anders.
      While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.
    Keywords:  Alzheimer’s disease; Glucagon-like Peptide 1; Mitochondria; Neurodegenerative disease; Oxidative phosphorylation; Parkinson’s disease; Semaglutide
    DOI:  https://doi.org/10.1016/j.yfrne.2025.101217
  39. Mol Biol Cell. 2025 Oct 08. mbcE25060302
    The biophysical mechanism of mitochondrial pearling.
    Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall.
      Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, "beads-on-a-string" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of "pearls" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.
    DOI:  https://doi.org/10.1091/mbc.E25-06-0302
  40. Haematologica. 2025 Oct 09.
    Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids.
    Giacomo Roman, Knut H Lauritzen, Sean P Harrison, Anindita Bhattacharya, Marianne Seierstad Andresen, Marie-Christine Mowinckel, Barbora Smolkova, Carola E Henriksson, Heidi Glosli, Nina Iversen, Bernd Thiede, Gareth J Sullivan, Runar Almaas, Per Morten Sandset, Benedicte Stavik, Maria E Chollet.
      Coagulation factor (F) VII deficiency is the most frequent among the rare, inherited bleeding disorders and is predominantly caused by missense mutations in the F7 gene. The disease phenotype ranges from asymptomatic cases to extremely severe hemorrhagic forms, requiring prophylactic injections with plasma-derived or recombinant FVII concentrates. In response, we have developed an autologous cell-based approach that corrects the disease-causing mutation in patient-derived induced pluripotent stem cells (iPSCs) and generates therapeutic, three-dimensional hepatic organoids (HOs). We report the CRISPRmediated correction of homozygous c.718G>C (p.G240R), a missense mutation associated with a severe, life-threatening bleeding phenotype. The HOs contain all liver cell types and exhibit key liver functions, including coagulation factor production. After correction, our data indicate that the patient-derived HOs secrete consistent amounts of functional FVII protein, resulting in improved thrombin generation times. These results represent a significant milestone toward the establishment of an autologous cell-based therapy for patients with FVII- and other coagulation factor deficiencies.
    DOI:  https://doi.org/10.3324/haematol.2025.288046
  41. J Respir Biol Transl Med. 2025 ;2(3):
    Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.
    Le Xu, Chunting Tan, Nicole Talaba, Andrew Sou, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.
      Congenital Diaphragmatic Hernia (CDH) is a rare neonatal disorder causing diaphragmatic defects and cardiopulmonary hypoplasia, traditionally attributed to mechanical compression from organ herniation. However, emerging evidence suggests genetic mutations may independently impair lung development, prompting debate over CDH etiology. Here, we investigated the requirement of mitochondrial function guarded by LON peptidase 1 (Lonp1), a CDH risk gene, in either diaphragm or lung development. Lonp1 loss in skeletal muscles of the diaphragm led to its thinning and membranization, recapitulating the pathology of sac-type CDH. On the other hand, lung-specific inactivation caused severe hypoplasia with defective branching morphogenesis, independent of diaphragm anomalies. Molecularly, Lonp1 disruption dysregulated key transcription factors and signaling pathways known to be critical for early lung development. Our findings here revealed that mitochondrial defects contribute to the pathogenesis of CDH in an organ and cell type specific manner, opening new avenues for drug and therapeutic development.
    Keywords:  CDH; Diaphragm; FGF10; LONP1; Lung; Mitochondria; SHH
    DOI:  https://doi.org/10.70322/jrbtm.2025.10008
  42. Cell Death Dis. 2025 Oct 06. 16(1): 700
    PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease.
    Shiyi Yin, Yibo Zhai, Run Song, Jiannan Wu, Yongjiang Zhang, Miao Yu, Hongxia Ma, Mengmeng Shen, Xiaoyi Lai, Weina Jin, Yunqi Xu, Junqiang Yan.
      Parkinson's disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP+/MPTP models, PARL depletion amplified BAX activation and caspase-3 cleavage, driving neuronal death. Mechanistically, mitochondrial translocation of Nur77 stabilized PARL-BCL-2 complexes, suppressing apoptosis. AlphaFold2-guided structural modeling uncovered a PARL α-helix essential for Nur77 binding. Disrupting this interface abolished BCL-2 stabilization. Parl knockdown exacerbated motor/cognitive deficits in MPTP mice, rescued by Nur77 overexpression. Subcellular tracking demonstrated Nur77 nuclear-cytoplasmic shuttling dynamically regulates PARL-BCL-2 assembly, while co-immunoprecipitation confirmed Nur77 knockdown dissociates this complex. Our findings define the Nur77-PARL axis as a critical mitochondrial gatekeeper in PD, where PARL serves dual roles as a Lewy body constituent and apoptosis regulator. Reduced circulating PARL levels may reflect disease progression, while the Nur77-PARL structural interface offers a therapeutic target for neuroprotection. This study bridges Lewy body biology with mitochondrial apoptosis. It proposes biomarker-driven strategies to modulate BCL-2-dependent neuronal survival in PD. Schematic summary. In normal neuronal cells, PARL can inhibit the release of apoptotic signals by interacting with Nur77. In the MPP+-induced PD model, PARL expression is reduced inhibits the apoptosis of dopaminergic neurons, and reduces cell viability. Mechanistic schema: Normal state: PARL-Nur77 complex stabilizes mitochondrial membrane integrity, inhibiting BCL-2 ubiquitination. MPP+ injury: PARL downregulation disrupts Nur77 binding, triggering BAX oligomerization and caspase-3 activation. Therapeutic rescue: Nur77 overexpression restores PARL-mediated anti-apoptotic signaling.
    DOI:  https://doi.org/10.1038/s41419-025-08035-8
  43. Mol Ther Nucleic Acids. 2025 Dec 09. 36(4): 102717
    Exploring CRISPR-Cas: The transformative impact of gene editing in molecular biology.
    Vivek Pandey, Shivani Sharma, Yuba Raj Pokharel.
      This review traces the evolution of clustered regularly interspaced short palindromic repeats (CRISPR) technology from a prokaryotic immune mechanism to a versatile tool for precise genome engineering. We compare CRISPR with traditional gene-editing methods like RNA interference (RNAi), zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), emphasizing its advantages in target specificity, multiplexing, and ease of design. We examine various Cas enzyme classes, engineered variants, and their applications in dissecting genetic alterations at the cellular level. The review further explores CRISPR's expanding role in developing disease models using tissues, organoids, and animal systems, enhancing our understanding of disease mechanisms. Finally, we discuss CRISPR's emerging applications in diagnostics and its transformative impact on immunotherapy and cell-based cancer treatments.
    Keywords:  CRISPR-Cas systems; Cas enzyme variants; MT: RNA/DNA Editing; cancer gene therapy; genetic engineering; nucleic acid diagnostics
    DOI:  https://doi.org/10.1016/j.omtn.2025.102717
  44. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122
    STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis
    DOI:  https://doi.org/10.1073/pnas.2508809122
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