bims-curels Biomed News
on Leigh syndrome
Issue of 2025–04–27
ten papers selected by
Cure Mito Foundation
  1. A rare mitochondrial disease with infantile severe metabolic disturbances that improved spontaneously.
  2. Pain Relief in Mitochondrial Disorders: Use of Spinal Cord Stimulation in a Patient With NARP Syndrome.
  3. Unlocking the Mysteries of Rare Disease Drug Development: A Beginner's Guide for Clinical Pharmacologists.
  4. Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.
  5. 280th ENMC International Workshop: The ERN EURO-NMD mitochondrial diseases working group; diagnostic criteria and outcome measures in primary mitochondrial myopathies. Hoofddorp, the Netherlands, 22-24 November 2024.
  6. Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.
  7. Mitochondrial DNA signals driving immune responses: Why, How, Where?
  8. Mitochondrial transfer drives immune evasion in tumor microenvironment.
  9. iPSC-derived and Patient-Derived Organoids: Applications and challenges in scalability and reproducibility as pre-clinical models.
  10. Reflections on "mitochondrial DNA abundance in blood is associated with Alzheimer's disease- and dementia-risk".
  1. Pediatr Int. 2025 Jan-Dec;67(1):67(1): e70052
    A rare mitochondrial disease with infantile severe metabolic disturbances that improved spontaneously.
    Mikiko Koizumi, Tae Ikeda, Tomokazu Kimizu, Yasushi Okazaki, Kei Murayama, Yuri Etani.
      
    Keywords:  mitochondrial disease; reversible infantile respiratory chain deficiency
    DOI:  https://doi.org/10.1111/ped.70052
  2. Pain Med Case Rep. 2025 Feb;9(1): 67-69
    Pain Relief in Mitochondrial Disorders: Use of Spinal Cord Stimulation in a Patient With NARP Syndrome.
    Augusta L Kiepper, Timothy Morgan, Christopher J Mallard.
       BACKGROUND: Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome is a mitochondrial disorder of the ATPase 6 gene. There is a wide variation of symptoms, but damage to the neuronal structures can result in chronic pain.
    CASE REPORT: A 31-year-old woman's chronic back and lower extremity pain related to NARP syndrome was successfully treated with dorsal column spinal cord stimulation (SCS).
    CONCLUSIONS: SCS can be used as a means of pain management in patients with genetic etiologies. This case provides an example of treating symptoms related to genetic defects with simulation improving quality of life.
    Keywords:   Case report ; NARP syndrome ; causalgia ; chronic pain ; mitochondrial disease ; neuromodulation ; spinal cord stimulation
  3. Clin Transl Sci. 2025 Apr;18(4): e70215
    Unlocking the Mysteries of Rare Disease Drug Development: A Beginner's Guide for Clinical Pharmacologists.
    Mariam A Ahmed, Bilal AbuAsal, Jeffrey S Barrett, Karim Azer, Yuen Yi Hon, Salwa Albusaysi, Elizabeth Shang, Meng Wang, Maria Burian, Noha Rayad.
      Clinical pharmacologists face unique challenges when developing drugs for rare diseases. These conditions are characterized by small patient populations, diverse disease progression patterns, and a limited understanding of underlying pathophysiology. This tutorial serves as a comprehensive guide, offering practical insights and strategies to navigate its complexities. In this tutorial, we outline global regulatory incentives and resources available to support rare disease research, describe some considerations for designing a clinical development plan for rare diseases, and we highlight the role of biomarkers, real-world data, and modeling and simulations to navigate rare disease challenges. By leveraging these tools and understanding regulatory pathways, clinical pharmacologists can significantly contribute to advancing therapeutic options for rare diseases.
    DOI:  https://doi.org/10.1111/cts.70215
  4. Mitochondrion. 2025 Apr 18. pii: S1567-7249(25)00039-X. [Epub ahead of print] 102042
    Mitochondrial transplantation: Triumphs, challenges, and impacts on nuclear genome remodelling.
    Elly H Shin, Quinn Le, Rachel Barboza, Amanda Morin, Shiva M Singh, Christina A Castellani.
      Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial transplantation; Nuclear epigenome; Nuclear transcriptome
    DOI:  https://doi.org/10.1016/j.mito.2025.102042
  5. Neuromuscul Disord. 2025 Mar 22. pii: S0960-8966(25)00067-7. [Epub ahead of print]50 105340
    280th ENMC International Workshop: The ERN EURO-NMD mitochondrial diseases working group; diagnostic criteria and outcome measures in primary mitochondrial myopathies. Hoofddorp, the Netherlands, 22-24 November 2024.
    280th ENMC workshop study group
      The 280th ENMC International Workshop, held in Hoofddorp, The Netherlands, November 22-24, 2024, focused on primary mitochondrial myopathies (PMM). The workshop aimed to update diagnostic criteria, outcome measures, and explore new digital health technologies (DHTs) in the context of clinical trial design and conduct for PMM. Key points discussed included: (i) PMM definition and phenotypes; PMM are genetically determined mitochondrial disorders with prominent skeletal muscle involvement with two major phenotypes: mitochondrial myopathy (MiMy) either with or without chronic progressive external ophthalmoplegia (PEO); (ii) diagnostic criteria, with emphasis on the importance of genetic testing and muscle biopsy for accurate diagnosis; (iii) outcome measures: consensus on clinical scales, functional tests, performance measures, and patient-reported outcome measures (PROMs) for both adults and children; (iv) digital health technologies, with exploration of wearable and non-wearable technologies for gait analysis, physical activity monitoring, and other assessments; (v) potential and limitations of biomarkers for PMM diagnosis and monitoring. The workshop concluded with a strong consensus on the updated definition of PMM, its phenotypes, and the recommended outcome measures for clinical studies. Further research is needed to validate digital health technologies and biomarkers for PMM.
    Keywords:  Biomarkers; Clinical trials; Diagnostic criteria; Outcome measures; Primary mitochondrial myopathy
    DOI:  https://doi.org/10.1016/j.nmd.2025.105340
  6. Front Pharmacol. 2025 ;16 1507493
    Interpreting the clinical significance of multiple large-scale mitochondrial DNA deletions (MLSMD) in skeletal muscle tissue in the diagnostic evaluation of primary mitochondrial disease.
    Jing Wang, James T Peterson, Joaquim Diego D Santos, Ada J S Chan, Maria Alejandra Diaz-Miranda, Imon Rahaman, Jean Flickinger, Amy Goldstein, Emily Bogush, Elizabeth M McCormick, Colleen C Muraresku, Vernon E Anderson, Matthew C Dulik, Douglas C Wallace, Rui Xiao, Marni J Falk, Angela N Viaene, Zarazuela Zolkipli-Cunningham.
       Background and Objectives: Improved detection sensitivity from combined Long-Range PCR (LR-PCR), Next-Generation Sequencing (NGS), and droplet digital PCR (ddPCR) to identify multiple large-scale mtDNA deletions (MLSMD) and quantify deletion heteroplasmy have introduced clinical interpretation challenges. We sought to evaluate clinical, biochemical, and histopathological phenotypes of a large clinical cohort harboring MLSMD in muscle to better understand their significance across a range of clinical phenotypes.
    Methods: A single-site retrospective study was performed of 212 diagnostic muscle biopsies obtained from patients referred for Primary Mitochondrial Disease (PMD) evaluation with muscle mitochondrial (mt)DNA sequencing performed at our institution, including electronic medical record (EMR) review of symptoms, biochemical results, and Mitochondrial Myopathy Composite Assessment Tool (MM-COAST) scores.
    Results: MLSMD were identified in 50 of 212 (24%) diagnostic tissue biopsies, and were universally present. in subjects ≥50 years (n = 18/18). In 45 of 50 (90%) subjects with MLSMD, no definitive genetic etiology was identified, despite clinical whole exome sequencing (WES) and/or whole genome sequencing (WGS). MLSMD heteroplasmy levels quantified by ddPCR ranged from 0% to 33%, exceeding 10% heteroplasmy in 5/45 (11%). Subjects with MLSMD (n = 45) were more likely to demonstrate mitochondrial abnormalities on histopathology, upregulation (≥150% of control mean) of one or more electron transport chain (ETC) complex enzyme activities, and reduced citrate synthase indicative of mitochondrial depletion (<60% of control mean) relative to subjects without MLSMD (n = 155). As clinical phenotypes varied across the MLSMD cohort, Bernier diagnostic criteria major/minor symptoms were used to discriminate 13 of 45 subjects with "suspected" PMD having unrevealing WES/WGS results and 32 of 45 subjects scored as "less likely" to have PMD. Relative to the "less likely" cohort, a significantly higher frequency of biochemical and muscle histopathological abnormalities (ragged red and COX negative fibers) were observed in the "suspected" cohort, further supporting a higher index of suspicion for PMD, p < 0.05.
    Discussion: MLSMD in skeletal muscle tissue were a common molecular finding (24%) in our cohort and consistently present in subjects ≥50 years. Among those with genetically undiagnosed MLSMD (n = 45), the "suspected" PMD subset (n = 13/45) represent a promising cohort for novel gene discoveries.
    Keywords:  electron transport chain (ETC) enzymatic activity; mitochondrial DNA (mtDNA); multiple large-scale mitochondrial DNA deletions (MLSMD); primary mitochondrial disease (PMD); ragged blue fibers (RBF); ragged red fibers (RRF)
    DOI:  https://doi.org/10.3389/fphar.2025.1507493
  7. Cell Commun Signal. 2025 Apr 22. 23(1): 192
    Mitochondrial DNA signals driving immune responses: Why, How, Where?
    Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.
      There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
    Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1186/s12964-025-02042-0
  8. Trends Cancer. 2025 Apr 22. pii: S2405-8033(25)00094-9. [Epub ahead of print]
    Mitochondrial transfer drives immune evasion in tumor microenvironment.
    Qiang Cai, Xiaojun Cai, Quazi T H Shubhra.
      Tumors subvert T cell metabolism through diverse mechanisms. Ikeda et al. reveal mitochondrial transfer as a tumor-driven immune evasion strategy, where cancer cells deliver dysfunctional mitochondria to T cells, impairing metabolism and inducing exhaustion. These findings highlight mitochondrial dynamics as a promising therapeutic target to improve immunotherapy outcomes.
    Keywords:  T cell exhaustion; cancer immunotherapy; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.002
  9. Curr Res Toxicol. 2024 ;7 100197
    iPSC-derived and Patient-Derived Organoids: Applications and challenges in scalability and reproducibility as pre-clinical models.
    Elisa Heinzelmann, Francesco Piraino, Mariana Costa, Aline Roch, Maxim Norkin, Virginie Garnier, Krisztian Homicsko, Nathalie Brandenberg.
      Recent advancements in stem cell technology have led to the development of organoids - three-dimensional (3D) cell cultures that closely mimic the structural and functional characteristics of human organs. These organoids represent a significant improvement over traditional two-dimensional (2D) cell cultures by preserving native tissue architecture and cellular interactions critical for physiological relevance. This review provides a comprehensive comparison between two main types of organoids: induced Pluripotent Stem Cell (iPSC)-derived and Adult Stem Cell (ASC)-derived (also known as Patient-Derived Organoids, PDOs). iPSC-derived organoids, derived from reprogrammed cells, exhibit remarkable plasticity, and can model a wide range of tissues and developmental stages. They are particularly valuable for studying early human development, genetic disorders, and complex diseases. However, challenges such as prolonged differentiation protocols and variability in maturation levels remain significant hurdles. In contrast, ASC-derived organoids, generated directly from patient tissues, faithfully recapitulate tissue-specific characteristics and disease phenotypes. This fidelity makes them indispensable for personalized medicine applications, including drug screening, disease modeling, and understanding individualized treatment responses. The review highlights the unique advantages and limitations of each organoid type, emphasizing their roles in advancing biomedical research and drug discovery. It addresses key challenges in organoid technology, such as scalability, reproducibility, and the need for standardized culture protocols. Furthermore, it explores recent innovations in scaffold-guided organoid engineering and the integration of organoids with advanced technologies like artificial intelligence and high-throughput screening. The integration of organoids with cutting-edge technologies holds promise for enhancing their utility in modeling complex human diseases and accelerating drug discovery and development. By providing more physiologically relevant models of human organs, organoid technology is poised to revolutionize biomedical research, offering new insights into disease mechanisms and personalized therapeutic strategies.
    Keywords:  3D cell culture; Induced Pluripotent Stem Cells (iPSCs); Micro Physiological Systems (MPS); Organoids; Patient-Derived Organoids (PDOs); Pre-clinical models
    DOI:  https://doi.org/10.1016/j.crtox.2024.100197
  10. Mol Psychiatry. 2025 Apr 24.
    Reflections on "mitochondrial DNA abundance in blood is associated with Alzheimer's disease- and dementia-risk".
    Huan Wang, Tianyi Ning, Ziyin Cui, Zedong Cheng.
      
    DOI:  https://doi.org/10.1038/s41380-025-02958-6
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒27 at 0:55.