bims-curels Biomed News
on Leigh syndrome
Issue of 2025–07–13
nine papers selected by
Cure Mito Foundation
  1. The Role of Estrogen in Mitochondrial Disease.
  2. Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies.
  3. The xenobiotic detoxification pathway - glycine conjugation - is downregulated in a mouse model of Leigh syndrome.
  4. Remembering What It's Like to Be a Patient.
  5. How are patient partners involved in health service research? A scoping review of reviews.
  6. Transabdominal ultrasound guided AAV9-GFP delivery in fetal pigs: a translational and minimally invasive model for in utero fetal gene therapy.
  7. Unlocking the potential of mitochondrial transplantation: overcoming challenges and paving the way for routine therapeutic application.
  8. RareInsight simplifies the communication of genetic results for rare disease patients.
  9. Review: Limb-girdle muscular dystrophies (LGMDs) existing registries and natural history studies: Where do we stand?
  1. Cell Mol Neurobiol. 2025 Jul 11. 45(1): 68
    The Role of Estrogen in Mitochondrial Disease.
    Xi Huang, Cun-Hui Pan, Fei Yin, Jing Peng, Li Yang.
      This review aims to investigate the potential role of estrogen in various mitochondrial diseases, such as Leber's Hereditary Optic Neuropathy and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes, focusing on its effects on aging, oxidative stress, mitochondrial biogenesis, and mitophagy. Mitochondrial diseases have become important in modern medical research due to their complex genetic background and diverse clinical manifestations. Studies in recent years have shown that estrogen plays an essential role in physiological regulation and may also affect the health status of cells by regulating mitochondrial function, which in turn affects the occurrence and development of diseases. However, there is still a lack of systematic review of estrogen's specific mechanisms and roles in these diseases. This review will synthesize the relevant literature to explore the association between estrogen and mitochondrial diseases and its possible therapeutic prospects, aiming to provide a theoretical basis and reference for future research.
    Keywords:  Aging; Estrogen; Mitochondrial biogenesis; Mitochondrial disease; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s10571-025-01592-8
  2. Front Aging. 2025 ;6 1585508
    Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies.
    Dalia M Miller, Stephen L Archer, Kimberly J Dunham-Snary.
      Mitochondrial-driven diseases encompass a diverse group of single-gene and complex disorders, all linked to mitochondrial dysfunction, with significant impacts on human health. While there are rare mitochondrial diseases in which the primary defect resides in mutations in mitochondrial DNA, it is increasingly clear that acquired mitochondrial dysfunction, both genetically- and epigenetically-mediated, complicates common complex diseases, including diabetes, cardiovascular disease and ischemia reperfusion injury, cancer, pulmonary hypertension, and neurodegenerative diseases. It is also recognized that mitochondrial abnormalities not only act by altering metabolism but, through effects on mitochondrial dynamics, can regulate numerous cellular processes including intracellular calcium handling, cell proliferation, apoptosis and quality control. This review examines the crucial role of preclinical models in advancing our understanding of mitochondrial genetic contributions to these conditions. It follows the evolution of models of mitochondrial-driven diseases, from earlier in vitro and in vivo systems to the use of more innovative approaches, such as CRISPR-based gene editing and mitochondrial replacement therapies. By assessing both the strengths and limitations of these models, we highlight their contributions to uncovering disease mechanisms, identifying therapeutic targets, and facilitating novel discoveries. Challenges in translating preclinical findings into clinical applications are also addressed, along with strategies to enhance the accuracy and relevance of these models. This review outlines the current state of the field, the future trajectory of mitochondrial disease modeling, and its potential impact on patient care.
    Keywords:  CRISPR/Cas9; conplastic mouse; cybrid; mitochondrial replacement therapy (MRT); mitochondrial-driven diseases; mitochondrial-nuclear eXchange (MNX) mice; organoid; preclinical models
    DOI:  https://doi.org/10.3389/fragi.2025.1585508
  3. Biochem Biophys Res Commun. 2025 Jul 01. pii: S0006-291X(25)00993-3. [Epub ahead of print]777 152278
    The xenobiotic detoxification pathway - glycine conjugation - is downregulated in a mouse model of Leigh syndrome.
    Belinda R Fouché, Zander Lindeque, Francois van der Westhuizen, Marianne Venter, Rencia van der Sluis.
      Leigh syndrome (LS), a primary mitochondrial disease frequently caused by complex I (CI) deficiency, has been associated with hepatic dysfunction and impaired metabolic homeostasis. Despite this, the impact of mitochondrial dysfunction on hepatic xenobiotic detoxification pathways remains poorly understood. This study investigated the glycine conjugation pathway-central to the metabolism of dietary xenobiotics such as benzoate, salicylate, and medium-chain fatty acids (MCFAs)-in a whole-body Ndufs4 knockout (Ndufs4-/-) mouse model of LS. Transcriptomic analysis revealed a significant downregulation of the xenobiotic/medium chain fatty acid: CoA ligases (Acsm1 and Acsm2) and glycine N-acyltransferase (Glyat) in the livers of Ndufs4-/- mice, suggesting impaired activation and conjugation of xenobiotics. This was corroborated by reduced GLYAT (EC2.3.1.13) enzymatic activity and a marked decrease in hepatic hexanoylglycine levels. These findings imply that CI deficiency attenuates glycine conjugation capacity, potentially compromising the liver's ability to metabolise xenobiotic and dietary substrates. Given the role of glycine conjugation in detoxification, our data highlight a metabolic vulnerability in LS that may influence dietary and pharmacological interventions. Adjusting dietary intake of conjugation substrates may therefore be crucial in the clinical management of mitochondrial disease.
    Keywords:  ACSM; GLYAT; Glycine N-Acyltransferase; Glycine conjugation; Leigh syndrome; Xenobiotic detoxification; Xenobiotic/medium chain fatty acid: CoA ligases
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152278
  4. Fam Pract Manag. 2025 Jul;32(4): 4
    Remembering What It's Like to Be a Patient.
    James DomDera.
      
  5. Res Involv Engagem. 2025 Jul 08. 11(1): 78
    How are patient partners involved in health service research? A scoping review of reviews.
    Sarah Cecilie Tscherning, Annesofie Lunde Jensen, Hilary Louise Bekker, Tina Wang Vedelø, Jeanette Finderup, Gitte Susanne Rasmussen, Jakob Appel Østergaard, Flemming Otto Jensen, Lotte Ørneborg Rodkjaer.
      
    Keywords:  Health services research; Patient and public involvement; Patient engagement; Patient involvement; Patient participation; Patient partner; Scoping review
    DOI:  https://doi.org/10.1186/s40900-025-00755-7
  6. Gene Ther. 2025 Jul 11.
    Transabdominal ultrasound guided AAV9-GFP delivery in fetal pigs: a translational and minimally invasive model for in utero fetal gene therapy.
    Alessia Di Donfrancesco, Alessia Adelizzi, Anastasia Giri, Roberto Duchi, Simona Boito, Maria Barandalla, Giulia Massaro, Chiara Santanatoglia, Enrica Cappellozza, Andrea Perota, Ivano Di Meo, Valeria Tiranti, Emanuela Bottani, Cesare Galli, Nicola Persico, Dario Brunetti.
      In utero fetal gene therapy (IUFGT) has the potential to correct severe monogenic disorders before irreversible damage occurs. Despite promising results in small and large animal models, its translation to clinical practice remains limited by technical challenges, safety concerns, and the lack of standardized protocols in relevant disease models species. We established and validated a minimally invasive, ultrasound-guided approach for systemic gene delivery in fetal pigs using a self-complementary AAV9 vector encoding GFP under a CAG promoter. Injections were performed at different gestational ages (GA 80 and GA 108) via intracardiac or umbilical venous routes. Postnatal outcomes were monitored, and transgene biodistribution and expression were assessed by qPCR, ddPCR, immunofluorescence, and Western blotting. Inflammatory response, toxicity, and maternal safety were evaluated through cytokine profiling and histological analyses. The procedure was well tolerated, with no significant maternal morbidity or adverse obstetric outcomes beyond one preterm delivery. Biodistribution analysis revealed widespread vector presence in peripheral tissues, with robust GFP expression in liver and heart. Importantly, there was no evidence of significant tissue toxicity, necrosis, or fibrosis in any of the organs analyzed. Mild increases in pro-inflammatory cytokines (GM-CSF, GRO-α, IFN-γ) were observed but were not associated with histopathological changes. No anti-AAV9 capsid antibodies were detected in sera from piglets or sows, suggesting a minimal immune response to the vector. These findings demonstrate the safety, feasibility, and efficacy of ultrasound-guided IUFGT in pigs, supporting its potential as a translational platform for therapeutic gene delivery in fetuses affected by severe congenital diseases. This model offers a valuable framework for further preclinical development of prenatal interventions, particularly for disorders with early onset, such as mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41434-025-00551-8
  7. Cytotechnology. 2025 Aug;77(4): 139
    Unlocking the potential of mitochondrial transplantation: overcoming challenges and paving the way for routine therapeutic application.
    Amaneh Mohammadi Roushandeh, Kazuo Tomita, Yoshikazu Kuwahara, Nima Najafi-Ghalehlou, Tomoaki Sato, Mehryar Habibi Roudkenar.
      Mitochondrial medicine has shown great promise as a therapeutic approach for treating currently incurable diseases. Preclinical studies highlight its safety and efficacy, but significant challenges remain in translating these therapies from bench to bedside. Key unresolved issues include understanding the mechanisms behind the reparative potential of transplanted mitochondria, such as their viability and functionality in an extracellular environment, especially under elevated calcium ion concentrations. Additionally, challenges related to mitochondrial sourcing, delivery methods, and ethical considerations need to be addressed for broader clinical adoption. This review analyses these challenges and explores strategies to overcome them, including refining mitochondrial sourcing, delivery techniques, and storage solutions. We also emphasise the need for rigorous ethical guidelines and regulatory frameworks to ensure safe and global implementation, paving the way for mitochondrial medicine's broader clinical use.
    Keywords:  Mitochondrial biology; Mitochondrial dysfunction; Mitochondrial medicine; Mitochondrial transplantation; Regenerative medicine
    DOI:  https://doi.org/10.1007/s10616-025-00805-8
  8. Sci Rep. 2025 Jul 08. 15(1): 24442
    RareInsight simplifies the communication of genetic results for rare disease patients.
    Kimberly C Coetzer, Firas Zemzem, Eva Akurut, Gideon Akuamoah Wiafe, Olaitan I Awe.
      Following a confirmed genetic diagnosis, rare disease patients and their families encounter significant challenges in accessing diagnostic information and support. Patients and non-specialists are increasingly expected to interpret and share test results; however, existing standards are primarily designed for specialists. These standards fail to address the needs of resource-limited populations where low genomic literacy hampers accurate dissemination of genetic results. This research introduces RareInsight, an open-source, interactive dashboard designed to enhance the accessibility, comprehension, and collaboration of genetic data among patients, caregivers, clinicians, and researchers. Developed using shinydashboard, RareInsight was evaluated using whole exome sequencing data from skeletal dysplasia patients. It allows users to input and view Variant Call Format files and includes a searchable ClinVar variant table with filtering options, providing access to multiple resources based on search terms. RareInsight aims to simplify the dissemination of complex genetic information beyond the clinical setting. This dashboard serves as a pilot study demonstrating the potential of patient-centered interactive dashboards for the rare disease community.
    Keywords:  Bioinformatics; Clinical dashboard; Genetic testing; Rare diseases; Shinydashboard
    DOI:  https://doi.org/10.1038/s41598-025-09744-y
  9. J Neuromuscul Dis. 2025 Jul 07. 22143602251355316
    Review: Limb-girdle muscular dystrophies (LGMDs) existing registries and natural history studies: Where do we stand?
    Elena Faedo, Iman Tahiri, Christophe Alimi, Hussein Shoaito, Gianmarco Severa, Sophie Olivier, Stephane Degove, Isabelle Richard, Edoardo Malfatti.
       INTRODUCTION: Limb-Girdle Muscular Dystrophies (LGMDs) are heterogeneous inherited disorders with no cure, including 29 recessive (LGMDR) and 5 dominant forms (LGMDD), characterized by proximal muscle weakness. Finding a cure for LGMD is difficult due to the their slow evolution for which comprehensive data collection through registries, network, and natural history studies is pivotal.
    METHODS: We conducted a review following PRISMA guidelines searching in PubMed, Scopus, and Web of Science for articles published between 2000-2025, focusing on LGMD registries, networks, and natural history studies. We included observational studies, cohort designs, and registry-based studies.
    RESULTS: Among 443 records, 38 studies were included, 10 registries, 4 networks, and 17 natural history studies respectively. Registries varied in scope, with many focused on specific LGMD subtypes. Natural history studies were predominantly subtype-specific, poorly linked to registries. Only 12 studies were connected to registries or networks, and most performed in Europe and North America.
    DISCUSSION: Registries, networks, and natural history studies showed considerable design variability, leading to challenges with data interoperability and underscoring the need for standardization. Despite regional coverage, low-income countries are underrepresented in the data. The limited linkage between natural history studies and registries presents a missed opportunity to leverage well-characterized cohorts. Many registries and networks remain unpublished, limiting available data for global research.
    CONCLUSION: Registries are crucial, benefiting patients, clinicians, researchers, and industries. The scarcity of natural history studies hinders the development of centralized datasets. Standardizing registry design, improving data interoperability, and enhancing patient diversity are critical to boost LGMD research.
    Keywords:  data collection; limb girdle muscular dystrophy LGMD; natural history studies; registries
    DOI:  https://doi.org/10.1177/22143602251355316
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒13 at 21:09.