doi:10.1371/journal.pone.0148709engMontero, R.Yubero, D.Villarroya, J.Henares, D.Jou, C.Rodríguez, M.A.Ramos, F.Nascimento, A.Ortez, C.I.Campistol, J.Perez-Dueñas, B.O''Callaghan, M.Pineda, M.Garcia-Cazorla, A.Oferil, J.C.Montoya, J.Ruiz-Pesini, E.Emperador, S.Meznaric, M.Campderros, L.Kalko, S.G.Villarroya, F.Artuch, R.Jimenez-Mallebrera, C.GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunctionART-2016-94068Background: We previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction. Methods: We analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA. Results: Our results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3%(81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated levels of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated. Conclusions: Our data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochondrial dysfunction and that its levels correlate in vitro with FGF-21 levels.2016http://zaguan.unizar.es/record/4836310.1371/journal.pone.0148709http://zaguan.unizar.es/record/48363oai:zaguan.unizar.es:48363PloS one 11, 2 (2016), 0148709 [15 pp]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess