{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:55:36Z","timestamp":1792130136858,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Kearns\u2013Sayre syndrome (KSS) is characterized by single large\u2010scale mitochondrial DNA deletions and by severe early\u2010onset clinical manifestations with neurological involvement. Reliable disease models, as well as validated biomarkers or effective treatments, are lacking. We aimed to determine whether patient\u2010derived fibroblasts represent a suitable cellular model for translational research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a cross\u2010sectional multicenter study, fibroblasts from 12 patients with KSS, and 10 age\u2010 and sex\u2010matched controls were analyzed to comprehensively characterize their genetic and transcriptomic profiles, mitochondrial functional signature, and secretion of soluble signaling molecules (lactate and growth differentiation factor\u201015).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fibroblasts derived from patients with KSS harbored single large\u2010scale mitochondrial DNA deletions in 75% of cases and showed significant mitochondrial DNA depletion. Transcriptomic profiling identified 71 differentially expressed genes and multiple significantly enriched pathways. Despite mitochondrial respiratory chain enzymatic activities being preserved, ubiquinol\u2010cytochrome c reductase core protein 2 complex III and MTCO1 complex IV protein expression was significantly decreased, and mitochondrial respiration was markedly impaired. Total adenosine triphosphate production rate was conserved, likely due to a metabolic shift toward glycolysis. Patient fibroblasts showed abnormal mitochondrial network organization and morphology, significant altered expression of fusion and fission proteins, a tendency to increase mitochondrial reactive oxygen species, and notably dysregulated antioxidant defenses. Mitochondrial content did not affect the functional signature. Lactate and growth differentiation factor\u201015 secretion were significantly increased, and demonstrated high sensitivity and specificity scores in distinguishing KSS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Patient\u2010derived fibroblasts show a reproducible mitochondrial phenotype in KSS, supporting their use as a translational model for mechanistic studies, biomarker discovery, and therapeutic screening. ANN NEUROL 2026<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78351","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:30:46Z","timestamp":1789648246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patient\u2010Derived Fibroblasts as a Clinically Relevant Model of Kearns\u2013Sayre Syndrome"],"prefix":"10.1002","author":[{"given":"Laura","family":"Valls\u2010Roca","sequence":"first","affiliation":[{"name":"Inherited Metabolic Diseases and Muscle Disorders Research Group, CELLEX Biomedical Research \u2013 Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Sciences \u2013 Universitat de Barcelona (UB), Internal Medicine Department \u2013 Hospital Cl\u00ednic de Barcelona  Barcelona Spain"},{"name":"CIBERER\u2014Spanish Biomedical Research Centre in Rare Diseases  Madrid 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