Abnormal Mitochondrial Dynamics And Impaired Mitochondrial Biogenesis In Trigeminal Ganglion Neurons In A Rat Model Of Migraine

Background:Accumulating evidence has demonstrated a possible role of mitochondrial dysfunction in migraine pathophysiology.Migraine sufferers exhibit impaired metabolic capacity,with an increased formation of reactive oxygen species(ROS).Nevertheless,the dynamic mechanisms of mitochondrial quality control in migraine pathogenesis remain unclear.Mitochondrial dynamics and mitochondrial biogenesis are key processes regulating mitochondrial homeostasis.Objective:The aim of this study was to explore the alterations of mitochondrial regulatory networks including mitochondrial dynamics and mitochondrial biogenesis in trigeminal ganglion(TG)neurons in a rat model of migraine.Methods:Adult male Sprague-Dawley rats were randomly divided into 4 groups:control group,inflammatory soup(IS)3 d group,IS 5 d group and IS 7 d group.Following repeated dural stimulation with inflammatory soup,the baseline periorbital mechanical thresholds were determined by von Frey monofilaments.Transmission electron microscopy was used to evaluate the morphology of mitochondria in TG neurons.The levels of mitochondrial fission protein dynamin-related protein 1(Drpl)and mitochondrial fusion protein Mitofusinl(Mfhl)in TG neurons were detected using Western blot analysis.The level of mitochondrial DNA(mtDNA)copy number was determined by Quantitative real-time PCR.The expression levels of key regulators responsible for mitochondrial biogenesis in TG neurons were further investigated by PCR analysis and Western blot analysis.Results:(1)The baseline periorbital mechanical threshold was significantly decreased following repeated dural inflammatory stimulation,suggesting the establishment of mechanical allodynia.(2)Mitochondria in TG neurons exhibited small and fragmented morphology after repeated dural stimulation for 7 days.Closer analysis revealed altered ultrastructure characterized by few remaining cristae and appearance of vacuoles(3)Compared with control group,Drp1 was significantly increased in IS 5 d and IS 7 d group while Mfnl was significantly reduced in TG neurons in IS 7 d group.(4)Compared with control group,mitochondrial DNA copy number in TG neurons was reduced significantly in IS 7 d group.(5)Compared with control group,the mRNA levels and protein levels of regulatory factors related to mitochondrial biogenesis including peroxisome proliferator-activated receptor-gamma coactivator-la(PGC-1?)and its downstream regulators were significantly downregulated in IS 5 d and IS 7 d group.Conclusions:These findings suggest that the mitochondrial dynamic regulatory networks including mitochondrial dynamics and mitochondrial biogenesis are maladjusted in TG neurons in a rat model of migraine,which possibly represent a novel mechanism for mitochondrial dysfunction in migraine headache.