bims-curels Biomed News
on Leigh syndrome
Issue of 2025–10–19
twelve papers selected by
Cure Mito Foundation
  1. Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
  2. Ethical challenges in extending mitochondrial replacement therapy (MRT) for overcoming poor egg quality in older women without mitochondrial diseases.
  3. Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
  4. A patient experience of preimplantation genetic testing.
  5. OPTIMIZATION OF ILLUMINA® NEXTERA™ XT LIBRARY PREPARATION FOR THE MITOCHONDRIAL GENOME SEQUENCING AND CONFIRMATORY SANGER SEQUENCING.
  6. Breathing new life into male fertility: the potential of mitochondrial transplantation.
  7. From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
  8. Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
  9. Patient passports for rare diseases: results of a pilot study.
  10. I-ETL: an interoperability-aware health (meta)data pipeline to enable federated analyses.
  11. Out of Sync? Rare Genetic Disease and the Chronopolitics of Care.
  12. "I read a bit of information": Epistemic markers as a resource for enacting patients' agency.
  1. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 10. pii: S0925-4439(25)00418-1. [Epub ahead of print]1872(2): 168070
    Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria.
    Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Marta Zaninello, Esther Barth, Matteo Veronese, Richard Rodenburg, Elena I Rugarli, Susanne Brodesser, Susanne Arnold, Ulrich Brandt.
      Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, how molecular causes ultimately present as a clinical phenotype is poorly understood. To address this conundrum starting from the molecular defect, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40 % of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by ∼20 kJ∙mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.
    Keywords:  Active/deactive transition; Complex I; Complexome profiling; Mitochondria; Mitochondrial disease; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168070
  2. J Assist Reprod Genet. 2025 Oct 18.
    Ethical challenges in extending mitochondrial replacement therapy (MRT) for overcoming poor egg quality in older women without mitochondrial diseases.
    Alexis Heng Boon Chin, Adrian Villalba, Ido Alon, Ningyu Sun, Jiao Yang.
      Recently, eight healthy human offspring were born through mitochondrial replacement therapy (MRT) with pronuclear transfer (PNT), aimed at preventing the transmission of pathological mitochondrial DNA (mtDNA) mutations. These encouraging preliminary results on the safety of MRT, accompanied by some early neonatal findings and ongoing follow-ups, open up the possibility for its broader application in addressing age-related female infertility by enhancing oocyte quality in older women, commonly referred to as ooplasmic donation or ooplasmic transfer. Because female fertility declines sharply with age, and not all women choose to undergo elective egg freezing (oocyte cryopreservation), there will always be a substantial number of older female IVF patients who are unable to conceive with their own oocytes. For such patients, enabling them to conceive genetically related offspring via MRT would be a far more preferable alternative to conventional egg donation, which disrupts the continuity of maternal genetic lineage. However, extending the use of MRT from the prevention of mitochondrial diseases to the treatment of age-related infertility raises numerous ethical issues. A significant challenge lies in balancing the aspirations of infertile older women to have genetically related offspring with the medical risks and ethical concerns associated with the MRT procedure. To navigate these ethical challenges, some policy recommendations are proposed, including (i) MRT should be conducted in clinical trials until its long-term safety is validated, (ii) rigorous patient counseling to ensure informed consent, (iii) stringent regulations to govern egg donation for MRT, and (iv) implementation of an internationally recognized ethical and regulatory framework for MRT.
    Keywords:  Advanced reproductive age; Female infertility; Genome; Mitochondrial donation; Mitochondrial replacement techniques; Ooplasm
    DOI:  https://doi.org/10.1007/s10815-025-03713-0
  3. Adv Ophthalmol Pract Res. 2025 Nov-Dec;5(4):5(4): 278-284
    Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy.
    Shanshan Cao, Yong Liu, Mingming Sun, Yuan Zhang, Yonghua Sun, Quangang Xu, Shihui Wei, Huanfen Zhou.
       Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder primarily caused by mutations in MT-ND1, MT-ND4, and MT-ND6, leading to retinal ganglion cell degeneration and severe vision loss. While 90%-95% of cases involve three common mutations (m.11778G ​> ​A, m.3460G ​> ​A, m.14484T ​> ​C), the genetic and clinical profiles of rare mutations remain poorly characterized, contributing to diagnostic challenges.
    Methods: This cohort study analyzed 26 genetically confirmed LHON patients harboring rare mitochondrial DNA (mtDNA) mutations. Patients underwent best-corrected visual acuity (BCVA), optical coherence tomography (OCT) measurements (peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer [GCL] thickness), and neuroimaging findings. Prognostic outcomes were compared between pediatric (≤16 years) and adult (>16 years) subgroups.
    Results: The cohort (male:female ​= ​4.2:1) exhibited a median onset age of 17 years (range:4-42), with 30.77% unilateral involvement. Rare mutations were distributed in MT-ND4(34.62%,m.11696G ​> ​A), MT-ND1(34.62%,including m.3733G ​> ​A/m.3866T ​> ​C), and MT-ND6 (23.08%, m.14502T>C), with 26.92% harboring dual mutations. Younger patients showed significantly better visual recovery (59.09% vs. 22.73% achieving BCVA ≥ 0.3, P ​= ​0.014), despite comparable baseline vision and structural OCT parameters (pRNFL/GCL thickness, all P ​> ​0.05). T2 hyperintensity in the optic nerve magnetic resonance imaging (MRI) was present in 38.46% of cases.
    Conclusions: Our study probes into the clinical and genetic diversity of LHON with rare mtDNA mutations, revealing varied clinical presentations, such as more frequent unilateral involvement and enhanced optic nerve T2 MRI signals. Visual recovery was significantly better in the younger cohort. These results suggest the need for broader genetic testing in atypical LHON cases and offer insights into better prognostic strategies for new therapies.
    Keywords:  Leber's hereditary optic neuropathy; Maternal inheritance; Mitochondrial DNA; Rare mutation
    DOI:  https://doi.org/10.1016/j.aopr.2025.08.001
  4. Fertil Steril. 2025 Nov 01. pii: S0015-0282(25)00179-7. [Epub ahead of print]124(5 Pt 1): 904-905
    A patient experience of preimplantation genetic testing.
    Emily A Ferenczi.
      
    DOI:  https://doi.org/10.1016/j.fertnstert.2025.03.030
  5. Med Glas (Zenica). 2025 Aug 25. 22(2): 191-194
    OPTIMIZATION OF ILLUMINA® NEXTERA™ XT LIBRARY PREPARATION FOR THE MITOCHONDRIAL GENOME SEQUENCING AND CONFIRMATORY SANGER SEQUENCING.
    Nejira Handžić, Dino Pećar, Selma Durgut, Naida Mulahuseinović, Ivana Čeko, Adna Ašić, Mirza Izmirlija, Sabina Šegalo, Lana Salihefendić, Rijad Konjhodžić.
       AIM: Due to increasing use of mitochondrial DNA (mtDNA) sequencing in both forensic practice and clinical disease research, this study explores the optimization of the next-generation sequencing (NGS) method for whole mitochondrial genome analysis on the Illumina MiSeq platform.
    METHODS: Initial attempts using pre-made commercial primers were unsuccessful, leading to the design of novel custom-designed primers in our laboratory and optimization of sequencing chemistry and protocols. A comprehensive protocol was developed, involving long-range amplification, enzymatic fragmentation, and the use of IDT® for Illumina DNA/RNA UD Indexes and MiSeq Reagent Nano Kit v2 (300 cycles), whereby DNA extraction, quantification, and library preparation were all performed according to optimized protocols.
    RESULTS: Successful amplification was confirmed using gel electrophoresis and Agilent Bioanalyzer, with optimized conditions yielding clear, specific amplicons 9.8 and 8.5 kb in length. Sequencing results demonstrated high-quality reads with an average coverage depth of 742x and a GC content of 43-45%. The study highlights the efficiency of custom primers and individual library normalization for reliable mtDNA sequencing.
    CONCLUSION: These findings advance the application of NGS in forensic and clinical settings by enhancing the detection of rare mutations and mitochondrial heteroplasmy, paving the way for routine mtDNA analysis using NGS technology.
    Keywords:  mitochondrial genome; mutations; next-generation sequencing
    DOI:  https://doi.org/10.17392/1950-22-02
  6. Mol Biol Rep. 2025 Oct 17. 52(1): 1043
    Breathing new life into male fertility: the potential of mitochondrial transplantation.
    Bunty Sharma, Akshat Ashutosh Jha, Shafiul Haque, Hardeep Singh Tuli, Kawaljit Singh Kaura, Ujjawal Sharma.
      Male infertility affects about 7% of men worldwide. Along with this disease also comes stigma and taboo that overshadow its emotional and psychological impacts. Despite its widespread prevalence, many cases of male infertility remain idiopathic. This review illustrates the use of mitochondrial transfer in addressing male fertility issues, particularly in situations where sperm movement is hindered and there are problems with mitochondrial function. Various factors can trigger male infertility, such as problems with sperm quality or quantity, genetic disorders, hormonal imbalances, testicular injuries, infections, or lifestyle habits. Stress, anxiety, and depression are parameters that can make matters worse by disrupting hormone levels and sperm production. Currently, there's no reliable treatment for mitochondrial dysfunction, which plays a role in oxidative stress and lower ATP production. Mitochondrial transfer works by injecting healthy mitochondria into deficient cells; this, in turn, improves ATP production and reduces oxidative stress. This leads to improvements in sperm motility and viability. The technique has already been used and found effective in improving embryo quality in human oocytes, which shows its potential application in male infertility treatments. Therefore, in the present review, we discussed the mechanisms used for mitochondrial transfer, intercellular communication pathways, purification, and delivery techniques that can enhance therapeutic outcomes. By consolidating recent advances in this domain, we aim to present a comprehensive overview of mitochondrial transfer as an innovative intervention in the management of male infertility. The ultimate goal is to transform male infertility from a challenging condition into a manageable one. This will offer new hope to affected individuals and couples through advanced reproductive technologies and targeted therapeutic interventions.
    Keywords:  Infertility; Male fertility; Mitochondrial transplantation; Sperm motility; Therapeutic application
    DOI:  https://doi.org/10.1007/s11033-025-11158-y
  7. Mol Cell Biol. 2025 Oct 17. 1-27
    From Biogenesis to Breakdown: How Protein Biogenesis and Quality Control Failures Drive Mitochondrial Disease.
    Phoebe J Leeming, Julia Mercuri-Svik, Diana Stojanovski.
      Mitochondria rely on the coordinated function of over 1000 proteins, most of which are nuclear-encoded, synthesized in the cytosol, and imported into distinct mitochondrial sub-compartments. Thirteen additional proteins are synthesized within the organelle itself, forming core components of the oxidative phosphorylation (OXPHOS) system. Once inside, mitochondrial precursors undergo precise maturation, folding, and assembly, supported by specialized factors that ensure their function. These processes are safeguarded by an intricate network of chaperones, proteases, and disaggregases that maintain proteome integrity. Protein biogenesis and quality control are deeply interconnected, operating continuously to preserve mitochondrial function. Disruption at any stage, whether in import, folding, assembly, or degradation, can lead to proteotoxic stress and mitochondrial dysfunction, underlying a wide spectrum of mitochondrial diseases. Despite progress in characterizing many of these pathways in human cells, large gaps in knowledge remain. A complete understanding of protein biogenesis and surveillance mechanisms is essential to uncover how their dysregulation drives disease. This knowledge will be foundational for interpreting pathogenic mutations, predicting disease mechanisms, and ultimately guiding therapeutic strategies aimed at restoring mitochondrial proteostasis and health.
    Keywords:  Mitochondria; mitochondrial disease; protein import; protein quality control
    DOI:  https://doi.org/10.1080/10985549.2025.2566671
  8. Nature. 2025 Oct;646(8085): 530-532
    Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
    Gemma Conroy.
      
    Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Diseases; Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-03307-x
  9. Eur J Hum Genet. 2025 Oct 14.
    Patient passports for rare diseases: results of a pilot study.
    Jo Balfour, Vaila Morrison, Lydia Seed, Joseph Clymer, Emma Warnants, Abigail Lampkin, Sarah M Leiter, Gemma Chandratillake.
      For individuals with rare diseases, complex needs requiring multidisciplinary management can cause disjointed healthcare and challenges communicating with healthcare professionals (HCPs). 'Patient passports' support communication and healthcare coordination by sharing healthcare information with HCPs, reducing burden on patients/caregivers. Currently, no widely adopted passport addresses the multifaceted needs of patients with rare diseases. This pilot study was a service evaluation of a rare-disease-specific patient passport, co-designed with patients and HCPs. Patients/caregivers completed surveys before ('pre-passport') and after ('post-passport') using the passport. HCPs were surveyed on their perception of the passport. Of 157 'pre-passport' survey respondents, 96.2% spent considerable time explaining medical needs to new care teams; 65.6% found communicating care needs challenging. Nearly all respondents (99.4%) believed a document presenting relevant healthcare information would be helpful. Among 55 'post-passport' survey respondents, 85.1% used the passport during care interactions; 72.2% found it eased communication with unfamiliar teams, and 64.2% felt more confident communicating their needs. Over half (53.8%) felt the passport helped access needed care, 67.9% found it more useful than existing tools, and 75.9% were highly likely to recommend it to peers. All 31 HCP respondents listed perceived benefits, including improved HCP-patient/caregiver communication; some noted a preference for formal endorsement. By alleviating patient/caregiver-HCP communication challenges, this rare-disease-specific patient passport can enhance healthcare coordination and patient experiences. Participants' use of the passport during interactions with care teams and likelihood of recommendation to peers support its widespread integration. Further work to assess usability across healthcare settings and to gain formal endorsement is warranted.
    DOI:  https://doi.org/10.1038/s41431-025-01930-w
  10. BMC Med Inform Decis Mak. 2025 Oct 13. 25(1): 375
    I-ETL: an interoperability-aware health (meta)data pipeline to enable federated analyses.
    Nelly Barret, Anna Bernasconi, Boris Bikbov, Pietro Pinoli.
       BACKGROUND: Clinicians are interested in better understanding complex diseases, such as cancer or rare diseases, so they need to produce and exchange data to mutualize sources and join forces. To do so and ensure privacy, a natural way consists in using a decentralized architecture and Federated Learning algorithms. This ensures that data stays in the organization in which it has been collected, but requires data to be collected in similar settings and similar models. In practice, this is often not the case because healthcare institutions work individually with different representations and raw data; they do not have means to normalize their data, and even less to do so across centers. For instance, clinicians have at hand phenotypic, clinical, imaging and genomic data (each individually collected) and want to better understand some diseases by analyzing them together. This example highlights the needs and challenges for a cooperative use of this wealth of information.
    METHODS: We designed and implemented a framework, named I-ETL, for integrating highly heterogeneous healthcare datasets of hospitals in interoperable databases. Our proposal is twofold: ([Formula: see text]) we devise two general and extensible conceptual models for modeling both data and metadata and ([Formula: see text]) we propose an Extract-Transform-Load (ETL) pipeline ensuring and assessing interoperability from the start.
    RESULTS: By conducting experiments on open-source datasets, we show that I-ETL succeeds in representing various health datasets in a unified way thanks to our two general conceptual models. Next, we demonstrate the importance of blending interoperability as a first-class citizen in integration pipelines, ensuring possible collaboration between different centers.
    CONCLUSION: As a framework, I-ETL contributes to integrate and improve interoperability between healthcare institutions. When used in a decentralized federated platform, it eases the federated analysis of the different hospital databases and helps clinicians to obtain insights and knowledge on medical conditions of interest.
    Keywords:  Data model; FAIR principles; Federated Learning; Healthcare; Heterogeneous data
    DOI:  https://doi.org/10.1186/s12911-025-03188-0
  11. Sociol Health Illn. 2025 Nov;47(8): e70106
    Out of Sync? Rare Genetic Disease and the Chronopolitics of Care.
    Catherine Coveney.
      Drawing on the experiences of parents of children diagnosed with Noonan Syndrome, I examine how living in and between multiple temporalities of care impacts parents' sense of temporal autonomy and social inclusion. Employing the concept of 'crip time', I connect everyday choreographies of care with their temporal politics to analyse the chronopolitics of care in the context of rare genetic disease, crafting theoretical synergies between the sociology of health and illness, critical disabilities studies and the sociology of temporality. I argue that care time is crip time, requiring parents to juggle competing temporal rhythms that deviate from the chrononormative time order. Parents describe good care as making time and giving time to be with their child to meet their embodied care needs. Meanwhile, the inflexible and unpredictable nature of medical time can be experienced as oppressive and disruptive to the family's care rhythms. Temporal conflicts can create a sense of disconnection, leaving family's feeling out of sync, socially and emotionally. I suggest the need for a new focus on the chronopolitics of care within formal and informal care relations, to support parent carers to regain their temporal autonomy and a regain a shared sense of time and community.
    Keywords:  care; caregiving; chronopolitics; crip time; disability; lived experience; noonan syndrome; rare genetic disease; temporalities
    DOI:  https://doi.org/10.1111/1467-9566.70106
  12. Soc Sci Med. 2025 Oct 06. pii: S0277-9536(25)00970-0. [Epub ahead of print]386 118639
    "I read a bit of information": Epistemic markers as a resource for enacting patients' agency.
    Aleksandr Shirokov.
      As access to online health information grows, patients increasingly arrive at medical consultations informed but uncertain about how to display their knowledge without undermining the doctor's authority. This paper examines how patients navigate this tension by analyzing 151 video-recorded Russian-language consultations using Conversation Analysis. Focusing on the use of epistemic markers like "I read," "I heard," and "I was told," the study shows how patients perform delicate actions such as treatment requests, diagnostic assertions, and resistance to medical advice. By using the epistemic markers, patients construct these actions as actions they have limited rights to engage in, displaying their orientation to the doctor's authority. Epistemic markers allow patients to simultaneously achieve two things that can be seen as contradictory to each other: acknowledging the authority of the doctor while also asserting their own agency and doing actions they are not expected to have authority to do. The study expands the understanding of patient agency in clinical encounters, particularly in underexamined non-English-speaking contexts, and contributes to research on how interactional asymmetry is (re)produced in healthcare settings.
    Keywords:  Asymmetry; Conversation analysis; Diagnostic assertions; Doctor-patient interaction; Epistemic markers; Treatment requests; Video-recorded consultations
    DOI:  https://doi.org/10.1016/j.socscimed.2025.118639
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