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

PLoS One. 2016 Feb 11;11(2):e0148709. doi: 10.1371/journal.pone.0148709. eCollection 2016.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Biomarkers / blood*
  • Case-Control Studies
  • Cell Line
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Fibroblast Growth Factors / blood*
  • Growth Differentiation Factor 15 / blood*
  • Humans
  • Infant
  • Male
  • Mice
  • Mitochondrial Diseases / blood*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Myoblasts / metabolism
  • Neuromuscular Diseases / blood
  • RNA, Messenger / metabolism
  • ROC Curve
  • Reproducibility of Results
  • Sensitivity and Specificity


  • Biomarkers
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • RNA, Messenger
  • fibroblast growth factor 21
  • Fibroblast Growth Factors

Grants and funding

This work was funded by the "Plan Nacional de I+D+I and Instituto de Salud Carlos III- Subdirección General de Evaluación y Fomento de la Investigación Sanitaria", projects PI10/00177 (CJM), PI13/00837 (MAR, CJ, AN, JC, CJM), PI14/00028 (RA), PI14/00005 (SE, JM) and the European Regional Development Fund (FEDER). MAR is sponsored by the Hospital Sant Joan de Déu Reserch Grants. CJM is funded by the Instituto de Salud Carlos III grant CP09/00011. JM is funded by Departamento de Ciencia, Tecnología y Universidad del Gobierno de Aragón (Grupos Consolidados B33). JV, LC and FV are funded by grants from the “Ministerio de Economia y Competitividad, MINECO” (SAF2014-55725-R) and “Generalitat de Catalunya” (2014SGR-141).