bims-curels Biomed News
on Leigh syndrome
Issue of 2026–02–15
fourteen papers selected by
Cure Mito Foundation
  1. Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations.
  2. Short telomeres in mitochondrial DNA depletion disorders.
  3. Remimazolam-based anesthesia with intraoperative motor evoked potential monitoring in a patient with Leigh syndrome undergoing scoliosis surgery: a case report.
  4. Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.
  5. Gene Therapy Techniques and Delivery Methods (Review).
  6. Statistical interpretation of mtDNA matches in two uncommon types of forensic cases.
  7. Single-cell mitochondrial lineage tracing: Opportunities and challenges.
  8. A Review Exploring the Translational Perspective of Artificial Intelligence in Drug Discovery and Formulation Development.
  9. Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.
  10. A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
  11. What do public contributors with lived experience know and think about open research? 'Nobody should look at results and think "how did they arrive at that?"'.
  12. Exploring Caregivers' Experiences with Diagnostic Uncertainty During a Hospitalization: A Qualitative Study.
  13. ASSOCIATION ANALYSIS OF MITOCHONDRIAL HETEROPLASMIC VARIANTS AND CARDIOMETABOLIC TRAITS.
  14. Charged Topics in Medical Education: Students' Perspectives on Power, Voices, and Faculty Engagement.
  1. J Genet Genomics. 2026 Feb 08. pii: S1673-8527(26)00047-0. [Epub ahead of print]
    Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations.
    Huiying Li, Cheng Ai, Xiaofen Jin, Jing Wang, Jun Yu, Yinlong Gao, Douglas C Wallace, Min-Xin Guan.
      Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy. Here, we investigate the mechanism underlying the interaction between nuclear modifier and mtDNA mutation(s) that manifests optic neuropathy in vivo to develop an effective therapeutic approach for this disease using mouse models bearing LHON-linked Yars2G186V or COIV421A mutation alone and double mutations. Yars2G186V alters mitochondrial translation and assembly and activities of complex I, III, and IV, while COIV421A reduces complex IV activity. However, a single Yars2G186V or COIV421A mutation causes mild declines in ATP production and yields relatively mild degeneration of retinal ganglion cells (RGCs). Notably, the synergy between COIV421A and Yars2G186V mutations aggravates mitochondrial dysfunction and oxidative stress. Interestingly, COIV421A mainly promotes apoptosis, and Yars2G186V contributes to ferroptosis. The combination of two mutations accelerates the degeneration of RGCs and photoreceptors. Strikingly, AAV-mediated Yars2 expression in the mouse retina carrying both Yars2G186V and COIV421A mutations corrects the defective translation and ferroptosis arising from the Yars2G186V mutation and remarkably improves mitochondrial function and causes morphologic and functional recovery of RGCs and photoreceptors. These findings provide mechanistic insights into the pathophysiology of LHON arising from nuclear modifiers and mtDNA mutation(s) and potential therapeutic strategies for LHON and other mitochondrial diseases.
    Keywords:  Apoptosis; Ferroptosis; Gene therapy; Mitochondrial DNA mutation; Mitochondrial tyrosyl-tRNA synthetase; Optic neuropathy; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.jgg.2026.02.003
  2. Mitochondrion. 2026 Feb 10. pii: S1567-7249(26)00021-8. [Epub ahead of print]88 102131
    Short telomeres in mitochondrial DNA depletion disorders.
    Yumi Dille, Emmanouil Rampakakis, Geraldine Aubert, Christelle Dassi, William Mannherz, Saoussen Berrahmoune, Myriam Srour, Daniela Buhas, Suneet Agarwal, Kenneth A Myers.
      Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, sometimes leading to catastrophic multisystem failure. In a cohort of patients with MDDs, we measured telomere length in lymphocytes, granulocytes, T cells, and B cells, and compared to healthy controls. Telomere length was shorter overall in patients with MDDs, with the most significant differences observed in granulocytes. The observation that mtDNA depletion is associated with shorter telomeres may provide insight into MDD pathophysiology. Telomere length may have potential as a biomarker in mitochondrial disease, but further study is needed.
    Keywords:  C10orf2; DGUOK; Mitochondrial DNA depletion disorders; POLG; RRM2B; SUCLA2; SUCLG1; TK2; TYMP; Telomere length; Telomeres
    DOI:  https://doi.org/10.1016/j.mito.2026.102131
  3. JA Clin Rep. 2026 Feb 13.
    Remimazolam-based anesthesia with intraoperative motor evoked potential monitoring in a patient with Leigh syndrome undergoing scoliosis surgery: a case report.
    Takahiro Kuwabara, Takahiro Tamura, Masashi Takakura, Tasuku Fujii, Kanako Ozeki, Koichi Akiyama.
      
    Keywords:  Leigh syndrome; Mitochondrial encephalomyopathy; Motor evoked potential monitoring; Remimazolam
    DOI:  https://doi.org/10.1186/s40981-026-00851-x
  4. Int J Mol Sci. 2026 Jan 29. pii: 1375. [Epub ahead of print]27(3):
    Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.
    Savas Baris, Rojan Ipek, Saniye Tugba Baris, Ibrahim Baris.
      Biallelic variants in NDUFS6, encoding an accessory subunit of mitochondrial complex I, were initially associated with lethal neonatal mitochondrial encephalopathy and Leigh syndrome. Recent studies have demonstrated that NDUFS6 variants can also cause childhood- or adolescent-onset axonal neuropathy and Charcot-Marie-Tooth (CMT)-like phenotypes, indicating marked clinical heterogeneity. Here, we report a patient with a novel homozygous truncating NDUFS6 variant presenting with a neuropathy-predominant phenotype accompanied by epilepsy, in the absence of neonatal metabolic decompensation. The patient presented with childhood-onset progressive gait abnormality, pes cavus deformity, distal weakness requiring Achilles tendon-release surgery, pyramidal signs, urinary incontinence, and focal epileptiform EEG findings. Brain MRI showed bilateral lenticular nucleus abnormalities. Whole-exome sequencing identified a novel homozygous NDUFS6 nonsense variant (c.130C>T, p.Gln44*). While neuropathy has previously been reported primarily in association with the recurrent splice-site variant c.309+5G>A, our findings demonstrate that truncating NDUFS6 mutations can also underlie a neuropathy-predominant phenotype. Together with previously published cases, our findings support a phenotypic heterogeneity ranging from lethal encephalopathy to neuropathy and reinforce the role of NDUFS6 as a disease-causing gene for inherited peripheral neuropathy. These data support inclusion of NDUFS6 among established neuropathy and Charcot-Marie-Tooth genes.
    Keywords:  CMT; NDUFS6; epilepsy; neuropathy
    DOI:  https://doi.org/10.3390/ijms27031375
  5. Sovrem Tekhnologii Med. 2025 ;17(6): 56-67
    Gene Therapy Techniques and Delivery Methods (Review).
    E I Shchukina, I O Mazunin, I I Eremin, A A Moskalev.
      Gene therapy has evolved into a sophisticated field encompassing diverse precision editing platforms and advanced delivery systems capable of addressing complex genetic disorders and age-related pathologies. This comprehensive review examines the current landscape of gene therapeutic technologies, including CRISPR-based genome editing, base editing systems, prime editing platforms, and emerging DNA polymerase-based editors alongside their corresponding delivery methodologies. The review encompasses viral vectors, including tissue-specific adeno-associated virus serotypes, non-viral delivery systems such as ionizable lipid nanoparticles and virus-like particles, and innovative platforms, including exosome-based delivery and the SEND system. We examine therapeutic applications spanning nuclear genome editing, mitochondrial genome modification, RNA editing, and epigenetic modulation, demonstrating the expanding scope of gene therapy beyond traditional monogenic disorders. Critical analysis reveals that while fundamental technological capabilities have been established, significant challenges remain in manufacturing scalability, long-term safety assessment, delivery across physiological barriers, and optimization of editing efficiency in post-mitotic tissues. The integration of artificial intelligence approaches for predictive analysis and rational vector design represents a promising avenue for addressing current limitations. This review concludes that successful clinical implementation requires systematic resolution of manufacturing, safety, and delivery challenges alongside the development of standardized protocols for patient stratification and robust regulatory frameworks that accommodate rapid technological innovation while ensuring patient safety.
    Keywords:  CRISPR genome editing; RNA editing; adeno-associated virus vectors; base editing; epigenome editing; gene therapy; lipid nanoparticles; mitochondrial genome editing; prime editing
    DOI:  https://doi.org/10.17691/stm2025.17.6.06
  6. Forensic Sci Int Genet. 2026 Feb 03. pii: S1872-4973(26)00025-6. [Epub ahead of print]83 103444
    Statistical interpretation of mtDNA matches in two uncommon types of forensic cases.
    Gloria Dimick, Mitchell M Holland, Walther Parson, Michael Krawczak.
      Mitochondrial DNA (mtDNA) analysis is a frequently used tool for determining the potential origin of biological traces found at crime scenes. The method typically involves comparing the genetic profile of the trace with that of a suspect. While a mismatch between the two profiles usually leads to the exclusion of the suspect, the evidential value of a match is sometimes difficult to grasp. This is particularly true in cases that are more complex than a simple trace-suspect comparison. We considered two such scenarios and developed means for appropriate statistical interpretation of the respective mtDNA results. One scenario requires the evaluation of a composite hypothesis about trace donorship in multiple cases involving an mtDNA profile match with one and the same suspect. The other scenario calls for the consideration of a second mtDNA profile found at the crime scene that matches a matrilineally unrelated contact person of the suspect. For both scenarios, we propose formally linked mathematical methods for interpreting the mtDNA data which, under certain assumptions, allow valid quantification of the evidential value of the latter for or against the suspect. Furthermore, we illustrate the application of both methods with example calculations under realistic assumptions about the required parameters.
    Keywords:  Evidential value; Likelihood ratio; Match probability; Mitochondrial DNA; Trace donorship
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103444
  7. Quant Biol. 2026 Mar;14(1): e70018
    Single-cell mitochondrial lineage tracing: Opportunities and challenges.
    Siqi Li, Kun Wang, Xin Wang, Zheng Hu.
      Lineage tracing using endogenous mitochondrial DNA (mtDNA) variants holds great promise for reconstructing the lineage histories of individual cells, with broad applications in oncology, developmental biology, and regenerative medicine. Unlike synthetic DNA barcoding techniques, mitochondrial lineage tracing does not require genetic engineering of exogenous genetic markers, and thus is particularly suitable for human clinical samples. Various experimental and computational methods have been developed to profile mtDNA variants from single-cell genomic, transcriptomic, and epigenomic sequencing data. Despite the technical advances, several challenges still limit the robustness of single-cell mitochondrial lineage tracing, such as random genetic drift, genetic bottlenecks, informative variant identification, and low mtDNA coverage. In this review, we systematically examine current experimental and computational approaches for analyzing mtDNA variants in single cells and discuss current challenges and future technical developments aimed at enhancing the robustness and applicability of single-cell mitochondrial lineage tracing.
    Keywords:  lineage tracing; mtDNA variants; phylogenetic reconstruction; single‐cell genomics
    DOI:  https://doi.org/10.1002/qub2.70018
  8. Ann Pharm Fr. 2026 Feb 05. pii: S0003-4509(26)00007-6. [Epub ahead of print]
    A Review Exploring the Translational Perspective of Artificial Intelligence in Drug Discovery and Formulation Development.
    Babita Agarwal, Saurabh Gaware, Namdev More, Rushikesh Shinde, H N Shivakumar, Sachin Jagdale.
      The drug development pipeline remains extraordinarily complex, costly, and time-intensive, typically requiring 10-15 years and $2-3 billion per approved drug. This review presents a translational perspective on how artificial intelligence (AI) and machine learning (ML) are renovating pharmaceutical R&D across the entire value chain while maintaining rigorous safety and efficacy standards. In drug discovery, deep learning platforms enable virtual screening of billion-compounds, reducing target identification from years to months while improving hit rates by 30-50%. Preclinical development benefits from AI-powered toxicity prediction, potentially eliminating 40% of animal testing through accurate in silico models. Clinical trials are optimized through digital twin technology, reducing patient cohorts by 25-30% without compromising statistical power. Post-marketing surveillance is accelerated 100-fold through AI-driven real-world evidence analysis. Across the development lifecycle, AI delivers 30-60% time savings and 25-40% cost reductions while increasing success rates through enhanced predictive capabilities. Formulation development benefits from ML algorithms that optimize drug compositions and stability, reducing trial-and-error experimentation. However, challenges persist in data quality, algorithmic bias, and regulatory acceptance of AI-derived evidence. This review provides a balanced perspective on AI's transformative potential in drug discovery and various formulation developments, along with its limitations, offering a roadmap for successful implementation in pharmaceutical R&D.
    Keywords:  Artificial Intelligence; Drug Discovery; Formulation Development; Machine Learning; Regulatory Approvals
    DOI:  https://doi.org/10.1016/j.pharma.2026.01.007
  9. Arch Toxicol. 2026 Feb 07.
    Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.
    Busra Korkut Celikates, Sinem Ilgin, Melis Umay Yilmaz, Ozlem Atli Eklioglu.
      Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.
    Keywords:  Gentamicin; Mitochondrial dysfunction; Mitochondrial permeability transition pore; Nephrotoxicity; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s00204-026-04310-5
  10. Cell Rep. 2026 Feb 11. pii: S2211-1247(26)00036-7. [Epub ahead of print]45(2): 116958
    A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs.
    Ying Wang, Xinwan Su, Yu Chen, Yijian Chen, Chengyu Shi, Fangzhou Liu, Yuqi Ye, Panyi Sun, Manman Tan, Meng Yu, Ya Wang, Shanshan Xie, Jian Liu, Qingfeng Yan, Qiming Sun, Dante Neculai, Wei Liu, Jianzhong Shao, Yang Liu, Weiqiang Lin, Aifu Lin.
      Mitochondrial genetic diseases arise from mitochondrial DNA (mtDNA) defects, which gene therapy tools may rectify. However, delivering single-guide RNAs (sgRNAs) into mitochondria remains a challenge limiting CRISPR-mediated mtDNA therapy. Here, through network analysis of mitochondrion-localized long noncoding RNAs (lncRNAs) and RNA-binding proteins (RBPs), we found that lncRNA RP11-46H11.3 translocates into mitochondria via binding mitochondria-associated RBPs using its key RNA recognition motifs (RRMs); its derived 30 nt ST2-RNA mitochondrial targeting sequence (RMTS) showed the highest mitochondrial localization efficiency. We engineered the RMTS-CRISPR tool by fusing ST2-RMTS to sgRNA, verifying its ability to target and cleave mtDNA. Strikingly, our results demonstrated that RMTS-CRISPR could achieve heteroplasmic mtDNA shifting efficiencies of up to 26.37% in m.3243A>G mutant cell models and 26.79% in vivo, offering a technological approach for the correction of heterogeneous mtDNA mutations. Taken together, our findings reveal a CRISPR-based mitochondrial gene intervention strategy that may have applications in mitochondrial disorders.
    Keywords:  CP: genomics; CRISPR-Cas system; RNA recognition motif; mitochondrial DNA; mitochondrial disorder; organelle-associated RNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.116958
  11. J Neuropsychol. 2026 Feb 09.
    What do public contributors with lived experience know and think about open research? 'Nobody should look at results and think "how did they arrive at that?"'.
    Ellen Poliakoff, Hayley Shepherd, Ying Bai, Jade Pickering, Anne Ferrett, Peter Baimbridge, Graham Hanks, Emma Gowen.
      Involving people with lived experience in research (patient and public involvement or co-production) is one principle of open research (transparent research practices). Involvement of experts by experience helps ensure that clinical and health research is relevant, ethical and accessible. While public contributors are likely to view co-production as important, what do public contributors know and think about other open research practices (e.g., pre-registration, data sharing)? We carried out a mixed methods online survey investigating what public contributors already know and would like to know about different open research practices, working with public contributors to shape the study. The 64 participants had a range of lived experience, which they had contributed to research and were passionate about the benefits of co-production. Although many participants did not know the term 'open research', they rated specific practices as familiar and important, seeing the moral imperative. Participants described the balance of practical benefits (e.g., efficiency, transparency) and potential risks (e.g., data sharing, pre-prints). Some practices (e.g., pre-registration) were less well understood, and participants learnt more about open research from the survey. Most participants were interested to learn more, and over 70% indicated an interest in further training. Overall, there is a need and an opportunity to share accessible information and training about open research with those who contribute their lived experience to research. This has the potential to improve research involvement and co-production, as well as the quality and applicability of research more broadly.
    Keywords:  Co‐production; data sharing; involvement; open research; open science; transparency
    DOI:  https://doi.org/10.1111/jnp.70034
  12. Acad Pediatr. 2026 Feb 09. pii: S1876-2859(26)00025-2. [Epub ahead of print] 103243
    Exploring Caregivers' Experiences with Diagnostic Uncertainty During a Hospitalization: A Qualitative Study.
    Emily Kramer, Anna Kerr, Suzanne Reed.
       OBJECTIVE: Pediatric hospitalists commonly care for children with symptoms unable to be attributed to a unifying diagnosis. Although pediatric hospitalists prioritize patient- and family-centered care, very little is known about the communication of uncertainty on family-centered rounds. This study explores caregivers' perceptions of conversations regarding diagnostic uncertainty during family-centered rounds on a pediatric hospital medicine service.
    METHODS: This qualitative study was conducted at a single, freestanding, 700 bed, quaternary care children's hospital. We conducted 15 semi-structured interviews with a purposive sample of caregivers of children admitted with an uncertain diagnosis. Interviews explored caregivers' experiences throughout the diagnostic process and perceptions of conversations with the healthcare team on family-centered rounds. Interviews were recorded, transcribed verbatim, and deidentified. Three researchers independently coded transcripts using an inductive, thematic analysis approach.
    RESULTS: Data analysis yielded seven themes: the importance of inherent individual caregiver contextual factors, the presence of caregiver expectations, general team communication skills, interprofessional team dynamics, the value of a plan and symptom management, time as a barrier and facilitator, and development of a therapeutic alliance. Caregiver experiences and perceptions were mapped along a diagnostic model to demonstrate opportunities for improvement when medical providers are faced with diagnostic uncertainty.
    CONCLUSION: Understanding caregivers' experiences and perceptions of conversations regarding diagnostic uncertainty can assist medical providers in managing, communicating, and overcoming uncertainty. Results suggest uncertainty is complex and multilayered, however, uncertainty about a diagnosis can be overcome by providing symptom management and certainty in the plan and follow-up.
    Keywords:  Diagnostic; Uncertainty; qualitative
    DOI:  https://doi.org/10.1016/j.acap.2026.103243
  13. medRxiv. 2026 Jan 25. pii: 2026.01.23.26344724. [Epub ahead of print]
    ASSOCIATION ANALYSIS OF MITOCHONDRIAL HETEROPLASMIC VARIANTS AND CARDIOMETABOLIC TRAITS.
    TOPMed mtDNA working group
      Mitochondrial heteroplasmic variant has been increasingly recognized as a potential contributor to common complex diseases, yet its relationship with cardiometabolic disorders (CMDs) remains poorly understood. Leveraging deep whole-genome sequencing data from 16,882 participants across six multi-ancestry TOPMed cohorts, we systematically evaluated the associations between rare heteroplasmic variants and eight CMD traits, including body mass index (BMI), obesity, blood pressure, hypertension, blood glucose, diabetes, low-density lipoprotein (LDL), and hyperlipidemia. Using a previously developed statistical framework, we identified heteroplasmic variants according to three coding definitions and performed gene-based burden, SKAT, SKAT-O and ACAT-O tests within sixteen mitochondrial DNA (mtDNA) genes. We identified twelve significant gene-trait associations after Bonferroni correction, with consistent effect directions across coding definitions. The strongest association was observed between hyperlipidemia and heteroplasmic variants in CO1 gene (OR=0.28, 95% CI=(0.17, 0.46), p=3.4E-7) among EA (European Americans). Additional associations were detected for BMI, adjusted SBP (systolic blood pressure), BG (blood glucose), diabetes, and adjusted LDL. These findings highlight the contribution of heteroplasmic variation within mtDNA to cardiometabolic phenotypes and provide new insight into mitochondrial involvement in CMD pathophysiology.
    DOI:  https://doi.org/10.64898/2026.01.23.26344724
  14. Perspect Med Educ. 2026 ;15(1): 65-74
    Charged Topics in Medical Education: Students' Perspectives on Power, Voices, and Faculty Engagement.
    Maram Alkhatib, Shazia Samanani, Megan Murphy, Bridget O'Brien, Zareen Zaidi.
       Introduction: Medical education learning environments involve charged topics at the intersection of social, political, and cultural domains. Growing student diversity and political polarization add complexity to the discussion of charged topics, yet current literature lacks insight into student perspectives. This study explores how medical students position themselves during charged topic discussions and their preferences for educators' engagement.
    Methods: Using educational cultural hegemony as a theoretical framework and a critical constructivist approach, the research team conducted semi-structured interviews with sensitizing scenarios addressing three charged topics: gun control, reproductive healthcare coverage, and affirmative action. Following IRB approval, twenty medical students across all training years were interviewed. Transcripts were analyzed using Braun and Clarke's reflexive thematic analysis.
    Findings: We identified four themes: 'Constrained Voices' describes how power hierarchies influence student engagement with charged conversations. 'Burdened Voices' reveals how marginalized students bear a disproportionate burden when educator avoidance of discussions can reinforce dominant perspectives. 'Finding Voice' highlights how students use personal experience to center patient perspectives despite hierarchical constraints. In 'Guiding Voice', students describe the ideal educator as one who uses their experience and evidence-based knowledge to facilitate discussions.
    Conclusion: Power hierarchies constrain student engagement in charged discussions, with marginalized students bearing a disproportionate burden when educators avoid these topics. Despite these constraints, students assert agency through personal experience to center patient perspectives. Students seek educators who actively guide discussions using expertise and evidence, viewing neutrality as itself a stance. The findings underscore the need for faculty development addressing these dynamics.
    DOI:  https://doi.org/10.5334/pme.2253
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