Mitochondrial metabolism related markers GDF-15, FGF-21, and HIF-1a are elevated in pediatric migraine attacks

Objective: The purpose of this study was to investigate the serum levels of mitochon-drial metabolism/reactive oxygen species (ROS)- related peptides (hypoxia induc-ible factor- 1a [HIF- 1a], fibroblast growth factor -21 [FGF- 21], growth differentiation factor -15 [GDF- 15]) and key migraine- related neuropeptides (calcitonin gene- related peptide [CGRP], pituitary adenylate cyclase- activating peptide -38 [PACAP- 38], sub-stance P [SP], and vasoactive intestinal peptide [VIP]) during migraine attacks and to evaluate their diagnostic value in pediatric migraine.Background: There is increasing evidence for the important role of impairment in oxidative mitochondrial metabolism in the pathophysiology of migraine. Potential biomarkers that may reflect the relationship between migraine and mitochondrial dysfunction are unclear.Methods: A total of 68 female pediatric migraine patients without aura and 20 fe -male healthy controls aged 8- 18 years, admitted to the hospital, were enrolled in this cross- sectional study. Serum concentrations of these molecules were determined by enzyme- linked immunosorbent assays, and clinical features and their possible diag-nostic value were analyzed.Results: Serum levels of HIF- 1a (252.4 +/- 51.9 [mean +/- standard deviation]) pg/mL), GDF- 15 (233.7 +/- 24.7 pg/mL), FGF- 21 (96.1 +/- 13.1 pg/mL), CGRP (44.5 +/- 11.3), and PACAP- 38 (504.7 +/- 128.9) were significantly higher in migraine patients compared to healthy controls (199.8 +/- 26.8, 192.8 +/- 20.7, 79.3 +/- 4.1, 34.1 +/- 3.5 and 361.2 +/- 86.3 pg/ mL, respectively). The serum levels of these peptides were also higher in patients with chronic migraine than in patients with episodic migraine, and higher in the ictal period than in the interictal period. A positive correlation was found between attack frequency and both HIF- 1a and FGF- 21 levels in migraine patients. Serum levels of VIP and SP were not different between the migraine patients and healthy controls.Conclusion: Migraine attacks are accompanied by elevated HIF- 1a, FGF- 21, GDF- 15, CGRP, and PACAP- 38 in medication -naive pediatric patients with migraine. Elevated circulating mitochondrial metabolism/ROS-related peptides suggest a mitochondrial stress in pediatric migraine attacks and may have potential diagnostic value in monitoring disease progression and treatment response in children. Novel approaches intervening with mitochondrial metabolism need to be investigated.