GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction

Montero, 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. (Universidad de Zaragoza) ; Ruiz-Pesini, E. (Universidad de Zaragoza) ; Emperador, S. ; Meznaric, M. ; Campderros, L. ; Kalko, S.G. ; Villarroya, F. ; Artuch, R. ; Jimenez-Mallebrera, C.

Resumen: Background: 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.

Idioma: Inglés

DOI: 10.1371/journal.pone.0148709

Año: 2016

Publicado en: PloS one 11, 2 (2016), 0148709 [15 pp]
ISSN: 1932-6203

Factor impacto JCR: 2.806 (2016)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 15 / 63 = 0.238 (2016) - Q1 - T1

Factor impacto SCIMAGO: 1.236 - Agricultural and Biological Sciences (miscellaneous) (Q1) - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)