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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\u00a0A\u2009&gt;\u2009G-related myopathy, a leading cause of adult mitochondrial disease. Post-mortem biopsies from\n                    <jats:italic>quadriceps femoris<\/jats:italic>\n                    and\n                    <jats:italic>tibialis anterior<\/jats:italic>\n                    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\u00a0A\u2009&gt;\u2009G 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\u00a0A\u2009&gt;\u2009G 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-33106-3","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:06:01Z","timestamp":1766124361000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantifying variability of mitochondrial markers in m3243A\u2009&gt;\u2009G myopathy"],"prefix":"10.1038","volume":"16","author":[{"given":"Tiago M.","family":"Bernardino Gomes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan B.","family":"Childs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Di Leo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Warren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin","family":"Hudson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doug M.","family":"Turnbull","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor","family":"Lawless","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy E.","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"33106_CR1","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1001\/archneur.63.12.1701","volume":"63","author":"TD Jeppesen","year":"2006","unstructured":"Jeppesen, T. 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