bims-curels Biomed News
on Leigh syndrome
Issue of 2025–03–30
sixteen papers selected by
Cure Mito Foundation
  1. Mitochondrial DNA Pathogenic Variants in Ophthalmic Diseases: A Review.
  2. Adult-onset Leigh syndrome with recurrent seizures and peripheral neuropathy due to the 9176T > C mutation: a case report and literature review.
  3. Mitochondrial DNA variants revealed by whole exome sequencing: from screening to diagnosis and follow-up.
  4. Diverse Phenotypes of Mitochondrial Disease With Varying Levels of Heteroplasmy.
  5. Mitochondrial Retinopathy Due to MT-TL1 Mutation: The Role of Heteroplasmy. A Case Report.
  6. Evaluation of the Patient Innovation Partner Role: Perceived Benefits, Structures, Supports, and Recommendations for Lived Experience Engagement in Healthcare Innovation Teams.
  7. Efficacy and Safety of Photobiomodulation in MELAS: Protocol for a Series of N-of-1 Trials.
  8. Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments.
  9. Application of rapid clinical exome sequencing technology in the diagnosis of critically ill pediatric patients with suspected genetic diseases.
  10. Organoids as 3D Models for Studying Exogenous Mitochondrial Transplantation.
  11. Clinical characteristics and long-term prognosis of 150 children with MELAS syndrome in China.
  12. The People's Review protocol: planning an innovative study powered by the public.
  13. A New Perspective on the Role of Alterations in Mitochondrial Proteins Involved in ATP Synthesis and Mobilization in Cardiomyopathies.
  14. A leigh syndrome mutation perturbs long-range energy coupling in respiratory complex I.
  15. A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX.
  16. "My full-time unpaid role": Understanding the (extra)ordinary work of founders of rare disease organisations.
  1. Genes (Basel). 2025 Mar 17. pii: 347. [Epub ahead of print]16(3):
    Mitochondrial DNA Pathogenic Variants in Ophthalmic Diseases: A Review.
    Khaled K Abu-Amero, Bashaer Almadani, Shereen Abualkhair, Syed Hameed, Altaf A Kondkar, Andrea Sollazzo, Angeli Christy Yu, Massimo Busin, Giorgio Zauli.
      Mitochondria are vital organelles responsible for ATP production and metabolic regulation, essential for energy-intensive cells such as retinal ganglion cells. Dysfunction in mitochondrial oxidative phosphorylation or mitochondrial DNA (mtDNA) pathogenic variants can disrupt ATP synthesis, cause oxidative stress, and lead to cell death. This has profound implications for tissues such as the retina, optic nerve, and retinal pigment epithelium, which are dependent on robust mitochondrial function. In this review, we provide a comprehensive compilation of pathogenic variants in the mtDNA associated with various ophthalmic diseases, including Leber's hereditary optic neuropathy, chronic progressive external ophthalmoplegia, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, among others. We highlight the genetic variants implicated in these conditions, their pathogenic roles, and the phenotypic consequences of mitochondrial dysfunction in ocular tissues. In addition to well-established mutations, we also discuss the emerging evidence of the role of mtDNA's variants in complex multifactorial diseases, such as non-arteritic anterior ischemic optic neuropathy, primary open-angle glaucoma, and age-related macular degeneration. The review aims to serve as a valuable resource for clinicians and researchers, providing a detailed overview of mtDNA pathogenic variants and their clinical significance in the context of mitochondrial-related eye diseases.
    Keywords:  DNA pathogenic variant; mitochondria; ophthalmology
    DOI:  https://doi.org/10.3390/genes16030347
  2. BMC Neurol. 2025 Mar 26. 25(1): 128
    Adult-onset Leigh syndrome with recurrent seizures and peripheral neuropathy due to the 9176T > C mutation: a case report and literature review.
    Yashi Liao, Yaxin Lai, Xinxin Chen, Shanshan Zhao.
       BACKGROUND: Leigh syndrome (LS) is an inherited form of mitochondrial encephalopathy associated with various gene mutations of the oxidative phosphorylation system, typically occurring in infancy or early childhood and resulting in disability or even death. However, few late-onset cases have been reported.
    OBJECTIVE: The objective of this case report was to investigate the radiological and clinical characteristics of an adult patient diagnosed with Leigh syndrome.
    CASE PRESENTATION: This article describes a patient who presented with recurrent generalized seizures, peripheral neuropathy and hypertension and was ultimately diagnosed with Leigh syndrome with a mitochondrial gene variant, c.9176T > C (p.Leu217Pro), in 20,315 of the MT-ATP6 gene. Here, we discuss the possible pathogenesis of its clinical manifestations according to the related literature and review the current therapeutic approaches and prognosis of LS.
    CONCLUSION: A possible diagnosis of LS should be taken into consideration when patients with characteristic neuroimaging findings of LS demonstrate recurrent seizures, peripheral neuropathy, or hypertension, and genetic analysis should be carried out for differential diagnosis.
    Keywords:  Basal ganglia; Hypertension; Leigh syndrome; MT-ATP6 gene; Mitochondrial diseases; Peripheral neuropathy; Recurrent seizure
    DOI:  https://doi.org/10.1186/s12883-025-04135-2
  3. Neurogenetics. 2025 Mar 26. 26(1): 38
    Mitochondrial DNA variants revealed by whole exome sequencing: from screening to diagnosis and follow-up.
    Sebastian Skoczylas, Tomasz Płoszaj, Karolina Gadzalska, Monika Gorządek, Paulina Jakiel, Ewa Juścińska, Maria Malarska, Magdalena Traczyk-Borszyńska, Hanna Biezynska, Magdalena Rychlik, Agata Pastorczak, Agnieszka Zmysłowska.
      Mutations in mitochondrial DNA play a crucial role in several diseases, but interpreting the clinical significance of mitochondrial DNA variants is challenging due to heteroplasmy, age-related loss of variants and evolving phenotypes. The aim of study was to identify mitochondrial pathogenic variants and explore their potential future association with specific phenotypes in patients during their lifetime, for both known and novel variants. We used a Python pipeline to analyse exome sequencing data from 418 patients (median age: 15 years; 52.9% males and 47.1% females), mostly diagnosed with neurological disorders, developmental and intellectual disabilities, behavioural and sensory disorders, cardiovascular and metabolic abnormalities, renal diseases and others. Screening identified 1,000 unique variants with heteroplasmy levels greater than 10% and 192 unique variants with 1-10% heteroplasmy, excluding hypervariable regions. Among these variants, four confirmed pathogenic variants were detected according to MITOMAP (m.1555 A > G, m.3243 A > G, m.9035T > C, and m.11778G > A), each identified in one patient. The application of pathogenicity and frequency criteria led to the identification of three unique variants and one in monozygotic twin sister with low levels of heteroplasmy, which were confirmed by next-generation sequencing. Finally, one of them, the variant m.15897G > A, was recognised as likely pathogenic (PP3, PS2). Our study highlights the complexity of diagnosing mitochondrial diseases associated with mtDNA mutations and emphasises the need for a comprehensive genotype-phenotype approach to correctly identify causal variants.
    Keywords:  Mitochondrial diseases; Whole exome sequencing; mtdna; mtdna variants
    DOI:  https://doi.org/10.1007/s10048-025-00820-z
  4. JCEM Case Rep. 2025 Apr;3(4): luaf020
    Diverse Phenotypes of Mitochondrial Disease With Varying Levels of Heteroplasmy.
    Rebecca John, Aaron Chapla, Geeta Chacko, Sangeetha Yoganathan, Maya Mary Thomas, Nihal Thomas.
      Mitochondrial diseases have a wide spectrum of clinical presentations. Heteroplasmy, the presence of wild type and mutated mitochondrial deoxyribonucleic acid (DNA) in a single cell, is typical of mitochondrial disorders. It can show varying levels between cells of the same tissue, between organs in a single individual as well as between members of the same family. We describe below a woman who presented to us for management of pancreatic diabetes. Her daughter had a history of recurrent bouts of myopathy; evaluation was suggestive of having a mitochondrial etiology. Subsequently, mitochondrial genetic testing revealed positivity for m.3243A>G variant with a heteroplasmy of 45% in the blood in the daughter and 15% in the proband. We highlight how differences in the heteroplasmy and threshold levels among members of the same family resulted in a variable spectrum of clinical disease. Family screening of members identified with mitochondrial disease is of utmost significance to ensure early diagnosis and therapy.
    Keywords:  diabetes mellitus; heteroplasmy; mitochondrial diseases; muscular diseases
    DOI:  https://doi.org/10.1210/jcemcr/luaf020
  5. Cesk Slov Oftalmol. 2025 ;81(Ahead of Print): 1-4
    Mitochondrial Retinopathy Due to MT-TL1 Mutation: The Role of Heteroplasmy. A Case Report.
    Mauricio Arango, Sarita Restrepo, Antonia Maria Orrego, Sara Turizo, Karol Quintero-Lizcano.
       OBJECTIVE: To report a case of mitochondrial retinopathy, highlighting its clinical and imaging findings, the importance of genetic confirmation, and the possible implications of heteroplasmy in this disease.
    MATERIAL AND METHODS: Case report of a mitochondrial retinopathy secondary to m.3243A>G mutation in the MT-TL1 gene.
    RESULTS: A 32-year-old woman presented with bilateral vision loss, photophobia, and sensorineural hearing loss for more than 3 years. Best corrected visual acuity (BCVA) was 20/60 in the right eye (OD) and 20/25 in the left eye (OS). Fundus examination revealed multiple macular subretinal yellow-white deposits and central chorioretinal atrophy, without edema, hemorrhage, or subretinal fluid in the RE, and juxtafoveal atrophy with retinal pigment epithelium (RPE) metaplasia in the OS. Multimodal imaging raised suspicion of retinal dystrophy, and genetic testing confirmed a mitochondrial retinopathy secondary to the m.3243A>G mutation in the MT-TL1 gene.
    CONCLUSIONS: Bilateral and symmetric RPE atrophic changes in young individuals, especially when associated with systemic symptoms, should prompt a comprehensive evaluation, including multimodal imaging and genetic testing. Identifying causative mutations and understanding the dynamics of mitochondrial DNA in the pathogenesis of these diseases is crucial for improving diagnosis and suggesting potential therapeutic strategies, including gene therapy.
    Keywords:  Heteroplasmy; MT-TL1 gene; m.3243A>G mutation; mitochondrial disease
    DOI:  https://doi.org/10.31348/2025/8
  6. Health Expect. 2025 Apr;28(2): e70194
    Evaluation of the Patient Innovation Partner Role: Perceived Benefits, Structures, Supports, and Recommendations for Lived Experience Engagement in Healthcare Innovation Teams.
    Shoshana H Bardach, Amanda Perry, Terry Sturke, Randy Stevens, Milan F Satcher.
       BACKGROUND: Patient engagement plays a valuable role in health research and quality improvement. While prior research highlights some principles and key considerations for patient involvement in these efforts, there is a limited understanding of how best to structure and support this engagement, especially from the patient perspective and for healthcare innovation projects.
    METHODS: Transcripts and notes from semi-structured debrief interviews with patient partners (n = 14) and team leads (n = 22) of 14 healthcare innovation projects conducted between 2020 and 2023 were analyzed thematically to identify perceived benefits, structures and supports that shape lived-experience engagement, and recommendations for future patients' participation in healthcare innovation teams.
    RESULTS: Lived-experience engagement was perceived as highly valuable to project teams and rewarding to the patients themselves. Approaches for structuring and supporting the patient role shaped engagement, highlighting several strategies (e.g., providing patient partners with opportunities to reflect and prepare, having smaller check-ins, truly getting to know the patient, and offering opportunities for in-person connection) to enhance the experience and ameliorate challenges. Patients also emphasized the importance of sharing their perspectives to fully realize the benefits of their engagement.
    CONCLUSION: These findings highlight the importance of recognizing the bidirectional benefits of patient engagement within project teams. Taking opportunities to check in with patients throughout the project period, both formally and informally, regarding their preferences for involvement and experiences on the team would enable real-time feedback and adjustments to optimize patient partner engagement.
    PATIENT OR PUBLIC CONTRIBUTION: Since its inception, the Susan and Richard Levy Healthcare Delivery Incubator has incorporated patient and public involvement into the design and operations of its healthcare innovation projects. While the conceptualization of this analysis did not engage patients or the public, patients and individuals with lived experience provided the data. Further, three patient partners were engaged in the review of the findings, two of whom also actively contributed to the preparation of the manuscript by reviewing drafts, adding content, and making revisions.
    Keywords:  healthcare innovation; human‐centered design; lived experience; patient partner; quality improvement
    DOI:  https://doi.org/10.1111/hex.70194
  7. J Clin Med. 2025 Mar 17. pii: 2047. [Epub ahead of print]14(6):
    Efficacy and Safety of Photobiomodulation in MELAS: Protocol for a Series of N-of-1 Trials.
    E-Liisa Laakso, Tatjana Ewais, Katie McMahon, Josephine Forbes, Liza Phillips.
      Background: There is no cure for mitochondrial diseases which manifest in numerous ways including fatigue, muscle weakness, and exercise intolerance. Medical treatment varies and focuses on managing symptoms. Photobiomodulation (PBM) can decrease mitochondrial damage thereby increasing energy production and decreasing cell death. This pilot study will apply PBM to people with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) to examine the safety of application, and if changes occur in symptoms and signs after cross-over application/withdrawal of a sham or active PBM treatment including a two-week period of washout. Methods: This study is an exploratory, prospective series N-of-1 (single patient) studies. The protocol is guided by the CONSORT extension for reporting N-of-1 trials (CENT 2015), chosen due to the rarity of mitochondrial diseases, the fluctuating symptomology, and heterogeneity of the clinical presentation. The primary outcome is patient-reported fatigue assessed using the Checklist of Individual Strength and with concomitant evaluation of safety. Secondary measures are of depression, anxiety and stress, sleepiness, physical activity, blood lactate and creatine kinase, physical measures of sit-to-stand, and heel raise capability. Mitochondrial function will be evaluated using hydrogen magnetic resonance spectroscopy for lactate. PBM will be a participant-administered, home-based therapy using a multiple diode flexible array (BeniLight iLED-Pro Multi-Wave Multi-Pulse belt; 465 nm, 660 nm, 850 nm; average irradiance 5.23 mW/cm2; total joules: 770.1 J/treatment, all sites; 5 KHz; 20% duty ratio) over the anterior thigh muscles, posterior calf muscles and abdomen for 10 min to each site, three times/week. The safety of the intervention will be assessed. Descriptive statistics, causal analyses of time series data and dynamic modelling will be applied as relevant to the variables collected. Hydrogen magnetic resonance spectra will be acquired and averaged to obtain the content of the targeted hydrogen levels. Discussion: The study will provide guidance on whether and how to progress to a larger, randomised cohort study with sham control.
    Keywords:  fatigue; lactic acidosis; mitochondrial disease; mitochondrial encephalomyopathy; stroke-like episodes
    DOI:  https://doi.org/10.3390/jcm14062047
  8. Biomedicines. 2025 Mar 17. pii: 733. [Epub ahead of print]13(3):
    Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments.
    Giuseppe Magro, Vincenzo Laterza, Federico Tosto.
      Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment.
    Keywords:  Leigh syndrome; genetics; neurology; preclinical research; therapy
    DOI:  https://doi.org/10.3390/biomedicines13030733
  9. Front Genet. 2025 ;16 1526077
    Application of rapid clinical exome sequencing technology in the diagnosis of critically ill pediatric patients with suspected genetic diseases.
    Xuejun Ouyang, Yu Zhang, Tian Yu, Qian Zhang, Lei Xu, Victor Wei Zhang, Bin Wang.
       Purpose: This study evaluates the efficacy of rapid clinical exome sequencing (CES) and mitochondrial DNA (mtDNA) sequencing for diagnosing genetic disorders in critically ill pediatric patients.
    Methods: A multi-centre investigation was conducted, enrolling critically ill pediatric patients suspected of having genetic disorders from March 2019 to December 2020. Peripheral blood samples from patients and their parents were analyzed using CES (proband-parent) and mtDNA sequencing (proband-mother) based on Next-Generation Sequencing (NGS) technology.
    Results: The study included 44 pediatric patients (24 males, 20 females) with a median age of 27 days. The median turnaround time for genetic tests was 9.5 days. Genetic disorders were diagnosed in 25 patients (56.8%): 5 with chromosome microduplication/deletion syndromes (11.3%), 1 with UPD-related disease (2.3%), and 19 with monogenic diseases (43.2%). De novo variants were identified in nine patients (36.0%). A neonate was diagnosed with two genetic disorders due to a homozygous SLC25A20 variant and an MT-TL1 gene variation.
    Conclusion: Rapid genetic diagnosis is crucial for critically ill pediatric patients with suspected genetic disorders. CES and mtDNA sequencing offer precise and timely results, guiding treatment and reducing mortality and disability, making them suitable primary diagnostic tools.
    Keywords:  clinical exome sequencing; critical illness; mtDNA sequencing; pediatric; rapid genetic diagnosis
    DOI:  https://doi.org/10.3389/fgene.2025.1526077
  10. Adv Exp Med Biol. 2025 Mar 26.
    Organoids as 3D Models for Studying Exogenous Mitochondrial Transplantation.
    Ismail Eş, Oner Ulger.
      Mitochondria play a critical role in cellular communication, cell proliferation, and apoptosis, which make them essential to maintaining cellular health. Recently, mitochondrial transplantation has emerged as a promising therapeutic approach to treat conditions such as ischemia, neurodegenerative diseases, and cardiovascular disorders by restoring mitochondrial function in damaged cells. Despite its potential, understanding mitochondrial behavior in vivo remains challenging; however, organoid models, which are three-dimensional structures derived from stem cells that mimic human tissues, offer a solution to study mitochondrial function and transplantation strategies under controlled conditions. These models are particularly necessary in studies, as they can replicate disease conditions and consequently enable researchers to investigate mitochondrial dynamics and therapeutic integration. Developing organoid systems optimized for mitochondrial transplantation requires exploring factors that influence mitochondrial uptake, refining transplantation strategies, and understanding their role in cellular regeneration in order to advance in the field of mitochondrial research.
    Keywords:  3D cell culture models; Delivery methods in organoids; Mitochondria; Mitochondrial transplantation; Organoids
    DOI:  https://doi.org/10.1007/5584_2025_857
  11. J Neurol. 2025 Mar 21. 272(4): 280
    Clinical characteristics and long-term prognosis of 150 children with MELAS syndrome in China.
    Chaolong Xu, Sisi Dai, Huafang Jiang, Zhimei Liu, Yunxi Zhang, Tianyu Song, Ying Zou, Xin Duan, Yang Liu, Minhan Song, Zixuan Zhang, Tongyue Li, Fang Fang.
       OBJECTIVE: The aim was to summarise the clinical characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), evaluate patient survival status, and identify prognostic factors.
    METHODS: This retrospective study enrolled 150 children with MELAS from 07/2004 to 07/2023. The patients were followed up for a median of 3.37 years (IQR: 2.07-6.16 years). Disease burden was assessed using the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), and Spearman's correlation coefficient was used to analyse factors affecting disease severity. The Kaplan-Meier and Cox proportional methods were used for survival analysis.
    RESULTS: Overall, 150 patients (73 male) were enrolled, of whom 118 were followed up and 22 died. The mean age at onset was 8.2 years (0.4-15.3), and stroke-like episodes were the most common initial symptoms (54%). Among the surviving patients, 78 completed the NPMDS (mean score: 23.6 ± 6.7 points), and 71.8% (56/78) had moderate-to-severe disease (NPMDS score ≥ 15 points). The NPMDS score was positively correlated with disease duration (r = 0.41, P < 0.001) and negatively correlated with age at onset (r =  -0.26, P < 0.01). Among 48 patients who received long-term oral L-arginine and anti-seizure medications (ASMs), 56.3% (27/48) experienced reductions in seizures and stroke-like episodes. The 10- and 15-year survival rates were 65.3% and 34.5%, respectively. Muscle weakness was an independent risk factor for death (HR = 4.83, 95% CI 1.32-17.68; P = 0.017).
    CONCLUSIONS: This study had the largest cohort and longest follow-up of pediatric MELAS. Early onset was associated with severe disease, while muscle weakness was associated with a worse prognosis. Early identification and effective management of stroke-like episodes and seizures are crucial to reduce the disease burden.
    Keywords:  Disease burden; Lactic acidosis and stroke-like episodes; Mitochondrial encephalomyopathy; Newcastle Pediatric Mitochondrial Disease Scale; Survival analysis
    DOI:  https://doi.org/10.1007/s00415-025-13009-z
  12. Res Involv Engagem. 2025 Mar 25. 11(1): 28
    The People's Review protocol: planning an innovative study powered by the public.
    Éle Quinn, Shoba Dawson, Jeremy Holt, Shahed Hossain, Patricia Logullo, Ann O'Brien, Maureen Smith, Derek Stewart, Shaun Treweek, Charlene Young, Chris Noone, David Moher, Sinéad M Hynes.
       BACKGROUND: Systematic reviews provide the best quality evidence about the effectiveness of health treatments. However, systematic reviews and the important role they play in healthcare are not well understood beyond the walls of academia and healthcare. Systematic reviews can help the public make more informed health choices, based on the best available evidence. The People's Review aims to provide an opportunity to members of the public to plan and complete a full systematic review online in a supportive and engaging manner. It will be a learning-by-doing experience to support the public's understanding of what reviews are, how they are done, why they matter, and how they can be used to support everyday health decisions.
    METHODS: In The People's Review the public will conduct a full systematic review, deciding the review question, planning the review, working on the parts of the review, and deciding how to share the review findings, in a 'learning by doing' process. The review will be conducted online in eight stages using Cochrane Crowd, an existing citizen science platform. The team working behind-the-scenes of The People's Review will design, produce, and share learning material to support the public's understanding at each stage of the review.
    DISCUSSION: Involving the public in a systematic review online will enable members of the public to understand and use systematic reviews in everyday health choices. It provides the public with a unique 'learning by doing' opportunity to get to grips with what systematic reviews are and how they are produced. This article describes how we plan to involve the public in The People's Review. It is not a protocol for the systematic review itself - this will be published separately once the project has commenced, and the public have decided the review question.
    Keywords:  Citizen science; Evidence synthesis; Evidence-based healthcare; Health research; Making sense of science; Patient and public involvement (PPI); Public partners; Systematic review; learning by doing
    DOI:  https://doi.org/10.1186/s40900-025-00682-7
  13. Int J Mol Sci. 2025 Mar 19. pii: 2768. [Epub ahead of print]26(6):
    A New Perspective on the Role of Alterations in Mitochondrial Proteins Involved in ATP Synthesis and Mobilization in Cardiomyopathies.
    Melissa Vázquez-Carrada, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Daniel Uribe-Ramírez, Deyamira Matuz-Mares.
      The heart requires a continuous energy supply to sustain its unceasing contraction-relaxation cycle. Mitochondria, a double-membrane organelle, generate approximately 90% of cellular energy as adenosine triphosphate (ATP) through oxidative phosphorylation, utilizing the electrochemical gradient established by the respiratory chain. Mitochondrial function is compromised by damage to mitochondrial DNA, including point mutations, deletions, duplications, or inversions. Additionally, disruptions to proteins associated with mitochondrial membranes regulating metabolic homeostasis can impair the respiratory chain's efficiency. This results in diminished ATP production and increased generation of reactive oxygen species. This review provides an overview of mutations affecting mitochondrial transporters and proteins involved in mitochondrial energy synthesis, particularly those involved in ATP synthesis and mobilization, and it examines their role in the pathogenesis of specific cardiomyopathies.
    Keywords:  ATP synthesis; cardiomyopathies; mitochondria; mitochondrial DNA; point mutations
    DOI:  https://doi.org/10.3390/ijms26062768
  14. Chem Sci. 2025 Mar 21.
    A leigh syndrome mutation perturbs long-range energy coupling in respiratory complex I.
    Franziska Hoeser, Patricia Saura, Caroline Harter, Ville R I Kaila, Thorsten Friedrich.
      Respiratory complex I is a central enzyme of cellular energy metabolism that couples electron transfer with proton translocation across a biological membrane. In doing so, it powers oxidative phosphorylation that drives energy consuming processes. Mutations in complex I lead to severe neurodegenerative diseases in humans. However, the biochemical consequences of these mutations remain largely unknown. Here, we use the Escherichia coli complex I as a model to biochemically characterize the F124LMT-ND5 mutation found in patients suffering from Leigh syndrome. We show that the mutation drastically perturbs proton translocation and electron transfer activities to the same extent, despite the remarkable 140 Å distance between the mutated position and the electron transfer domain. Our molecular dynamics simulations suggest that the disease-causing mutation induces conformational changes that hamper the propagation of an electric wave through an ion-paired network essential for proton translocation. Our findings imply that malfunction of the proton translocation domain is entirely transmitted to the electron transfer domain underlining the action-at-a-distance coupling in the proton-coupled electron transfer of respiratory complex I.
    DOI:  https://doi.org/10.1039/d4sc04036h
  15. Front Pharmacol. 2025 ;16 1516126
    A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX.
    Ralf J Ludwig, Matthew Anson, Henner Zirpel, Diamant Thaci, Henning Olbrich, Katja Bieber, Khalaf Kridin, Astrid Dempfle, Philip Curman, Sizheng S Zhao, Uazman Alam.
      Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX's federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.
    Keywords:  Kaplan–Meier estimator; TriNetX; cohort study; drug discovery; real-world data
    DOI:  https://doi.org/10.3389/fphar.2025.1516126
  16. Soc Sci Med. 2025 Mar 14. pii: S0277-9536(25)00288-6. [Epub ahead of print]372 117958
    "My full-time unpaid role": Understanding the (extra)ordinary work of founders of rare disease organisations.
    Rebecca Dimond, Jamie Lewis.
      Rare disease organisations can play a crucial role in shaping the medical and scientific landscape. This article draws from interviews with sixteen founders of UK-based, rare disease organisations, all of whom were patients, parents or family members, to understand their experiences and commitment to the organisation and its community. First, we explore the work involved in creating a professional community and addressing the challenge of expert capacity-building for rare diseases. We then utilise the concept of 'translation' to emphasise the efforts of founders at an intermediate stage, for example encouraging health professionals to collaborate and realise that a project is achievable. Third, we consider the personal implications for the founders in their efforts to develop and sustain the organisation. Founders' biographies are intimately entwined with the establishment and development of their organisation, and we highlight how they are fundamentally shaped by the necessity of their hard work, skills and passion. Finally, we recognise that although some of the efforts of founders are undervalued both socially and economically, the founders themselves understand their work and role as crucial to the organisation's long-term success.
    DOI:  https://doi.org/10.1016/j.socscimed.2025.117958
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