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Lookup NU author(s): Dr Tiago Bernardino Gomes, Jordan Childs, Dr Valeria Di Leo, Dr Charlotte Warren, Professor Gavin HudsonORCiD, Emeritus Professor Doug Turnbull, Dr Conor LawlessORCiD, Dr Amy VincentORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. Myopathy is a prevalent and disabling feature of mitochondrial disease, in which skeletal muscle accumulates fibres with mitochondrial dysfunction in a variable mosaic pattern. This intra-individual spatial heterogeneity, a key consideration in longitudinal assessments, remains largely uncharacterised, hindering mechanistic studies and clinical trials by obscuring or confounding findings. We quantified this variability in m.3243 A > G-related myopathy, a leading cause of adult mitochondrial disease. Post-mortem biopsies from quadriceps femoris and tibialis anterior muscles of four patients were analysed for single-fibre deficiency in oxidative phosphorylation (OXPHOS) complex I and IV, while homogenate mitochondrial DNA (mtDNA) copy number and m.3243 A > G heteroplasmy were respectively determined by quantitative PCR and pyrosequencing. Bootstrapped combinatorial analyses established thresholds for minimum meaningful change above the 97.5th percentile, while accounting for anatomical biopsy distancing. Spatial variability in the proportion of OXPHOS-deficient fibres increased with distancing; within the same muscle, this threshold was 13.8% for NDUFB8 and 9.8% for MT-CO1. Variability in mtDNA copy number modestly increased with distance, while m.3243 A > G heteroplasmy remained largely stable, with within-muscle thresholds of 1,136 copies per nucleus and 8.2%, respectively. These findings provide assay-specific thresholds and offer mechanistic and translational insights for trial design, patient monitoring, and reliable detection of disease progression or therapeutic response.
Author(s): Bernardino Gomes TM, Childs JB, Di Leo V, Warren C, Hudson G, Turnbull DM, Lawless C, Vincent AE
Publication type: Article
Publication status: Published
Journal: Scientific Reports
Year: 2026
Volume: 16
Print publication date: 23/01/2026
Online publication date: 19/12/2025
Acceptance date: 16/12/2025
Date deposited: 09/02/2026
ISSN (electronic): 2045-2322
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41598-025-33106-3
DOI: 10.1038/s41598-025-33106-3
Data Access Statement: The data that support the findings of this study are available upon reasonable request and if in accordance with the respective research ethics boards policies.
PubMed id: 41419999
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