Hierarchical Studies in TRAP2 Mice Demonstrate that Neuronal Activation and Mitochondrial Networks Integration Constitute the Key Mechanism Underlying Painful Syncope

Approximately 40% of the global population experiences at least one syncope episode during their lifetime. However, the neurobiological mechanisms underlying these effects remain unclear. In this study, facial administration of formalin in mice was used to induce painful syncope. Whole-brain atlas analysis of 116,283 c-Fos⁺ neurons in 856 brain regions revealed 11 key brain regions associated with painful syncope. Subsequent analysis of approximately 300,000 mitochondrial networks revealed that their morphology in the locus coeruleus (LC), nucleus tractus solitarius (NTS), gigantocellular reticular nucleus (GR), lateral reticular nucleus (LRN), and parabrachial nucleus, spinal trigeminal nucleus pars caudalis (SPVC) underwent significant changes during syncope. Furthermore, downregulation of the mitochondrial dynamin-related protein 1 (DRP1) in the NTS could mediate the exacerbation of weakly lying on the ground in painful syncope. Our findings reveal that abnormal neuronal activity and mitochondrial network remodeling may serve as key mechanisms underlying painful syncope.