Growth Differentiation Factor 15 Is a Novel Diagnostic Biomarker of Mitochondrial Diseases

Abstract

The present study aimed to investigate whether serum growth differentiation factor 15 concentration is a valuable and reliable diagnostic biomarker of mitochondrial diseases. We examined consecutive patients with mitochondrial diseases, in comparison with patients with non-mitochondrial disease neuromuscular disorders and healthy controls. The serum concentrations of growth differentiation factor 15 were measured by ELISA, and compared with those of FGF21, lactate, and creatine kinase. We also evaluated the correlations between growth differentiation factor 15 concentrations and the Newcastle Mitochondrial Disease Adult Scale, numbers of ragged-red fibers, and COX-negative fibers in the biopsied muscles. The median serum growth differentiation factor 15 concentration was significantly elevated in 42 patients with mitochondrial diseases, compared with 20 patients with non-mitochondrial disease neuromuscular disorders and 50 healthy controls. The area under the curve of growth differentiation factor 15 for the diagnosis of muscle-manifesting mitochondrial diseases was 0.999, in comparison with those area under the curves of the other biomarkers including fibroblast growth factor 21 (0.935, p < 0.01), lactate (0.845 for p < 0.001), and creatine kinase (0.575, p < 0.001). Growth differentiation factor 15 was significantly correlated with mitochondrial disease severity and the proportion of ragged-red fibers identified in the biopsied muscles. Circulating growth differentiation factor 15 measurement is a superior biomarker with high sensitivity and specificity, which can be used as a non-invasive test to screen for primary mitochondrial diseases and dysmetabolic myopathy with associated mitochondrial dysfunction in susceptible individuals.

Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer–Cardiovascular Cohort

“…Evidence suggests that GDF-15 is a potential biomarker for ageing and age-related cognitive decline [37, 38]. An elevated concentration of circulating GDF-15 could reflect mitochondrial dysfunction, which is a hallmark of ageing, and which contributes to the pathogenesis of various age-related disorders [38, 39]. In addition, oxidative stress, inflammation, protein glycation, cellular senescence and hormonal deregulation may develop with age [40].…”

Metformin is the key factor in elevated plasma growth differentiation factor‐15 levels in type 2 diabetes: A nested, case–control study

“…One possible explanation for the association of GDF‐15 with metformin treatment, and also with HbA1c, could be that this growth factor is also a powerful marker of presence and severity of mitochondrial disorders and/or hypoxia . In fact, both metformin and hyperglycaemia are known to interfere with mitochondrial bioenergetics.…”

Deoxynucleoside Therapy for Thymidine Kinase 2–Deficient Myopathy

“…32 Since then, elevated GDF-15 levels have been confirmed to have high sensitivity (67.8-97.9%) and specificity (87.7-96.2%) for mitochondrial diseases, indicating potential utility as a first-line diagnostic test for these diverse disorders. [33][34][35] Although it has been proposed as a potential biomarker for therapeutic efficacy in mitochondrial diseases, 36 this is the first report to link GDF-15 levels with clinical improvements in a clinical trial for a mitochondrial disorder. Our data demonstrate that in patients with TK2 deficiency, baseline circulating GDF-15 levels were elevated before deoxynucleoside therapy and decreased significantly with treatment in patients.…”

“…A cytokine member of the transforming growth factor β family, GDF‐15, is induced and secreted by muscle cells in response to mitochondrial damage, and has been identified as a biomarker for mitochondrial diseases via an unbiased global gene expression screening of muscle from patients with TK2 deficiency . Since then, elevated GDF‐15 levels have been confirmed to have high sensitivity (67.8–97.9%) and specificity (87.7–96.2%) for mitochondrial diseases, indicating potential utility as a first‐line diagnostic test for these diverse disorders . Although it has been proposed as a potential biomarker for therapeutic efficacy in mitochondrial diseases, this is the first report to link GDF‐15 levels with clinical improvements in a clinical trial for a mitochondrial disorder.…”