Laura Valls-Roca, Adrià Vilaseca-Capel, Judith Cantó-Santos, Ester Tobías, Félix Andújar-Sánchez, Laia Farré-Tarrats, Frederic Tort, Carles Rentero, Carlos Enrich, Virginia López, Juan R Tejedor, Anna Esteve-Codina, Cristina Núñez de Arenas, Pedro J Moreno-Lozano, José C Milisenda, Mar O'Callaghan, Teresa García-Silva, Montserrat Morales-Conejo, Mario F Fraga, Rafael Artuch, Miguel Á Martín, José M Cuezva, Ana Matas, Glòria Garrabou, Mariona Guitart-Mampel
Patient-derived 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.
OBJECTIVE: Kearns-Sayre syndrome (KSS) is characterized by single large-scale mitochondrial DNA deletions and by severe early-onset clinical manifestations with neurological involvement. Reliable disease models, as well as validated biomarkers or effective treatments, are lacking. We aimed to determine whether patient-derived fibroblasts represent a suitable cellular model for translational research.
METHODS: In a cross-sectional multicenter study, fibroblasts from 12 patients with KSS, and 10 age- and sex-matched 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-15).
RESULTS: Fibroblasts derived from patients with KSS harbored single large-scale 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-cytochrome 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-15 secretion were significantly increased, and demonstrated high sensitivity and specificity scores in distinguishing KSS.
INTERPRETATION: Patient-derived 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.