PLoS ONE (Jan 2016)

GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction.

  • Raquel Montero,
  • Delia Yubero,
  • Joan Villarroya,
  • Desiree Henares,
  • Cristina Jou,
  • Maria Angeles Rodríguez,
  • Federico Ramos,
  • Andrés Nascimento,
  • Carlos Ignacio Ortez,
  • Jaume Campistol,
  • Belen Perez-Dueñas,
  • Mar O'Callaghan,
  • Mercedes Pineda,
  • Angeles Garcia-Cazorla,
  • Jaume Colomer Oferil,
  • Julio Montoya,
  • Eduardo Ruiz-Pesini,
  • Sonia Emperador,
  • Marija Meznaric,
  • Laura Campderros,
  • Susana G Kalko,
  • Francesc Villarroya,
  • Rafael Artuch,
  • Cecilia Jimenez-Mallebrera

DOI
https://doi.org/10.1371/journal.pone.0148709
Journal volume & issue
Vol. 11, no. 2
p. e0148709

Abstract

Read online

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.