Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons

Abstract

Neuronal stress-adaptation combines multiple molecular responses. We have previously reported that thorax trauma induces a transient loss of hippocampal excitatory synapses mediated by the local release of the stress-related hormone corticotropin-releasing hormone (CRH). Since a physiological synaptic activity relies also on mitochondrial functionality, we investigated the direct involvement of mitochondria in the (mal)-adaptive changes induced by the activation of neuronal CRH receptors 1 (CRHR1). We observed, in vivo and in vitro, a significant shift of mitochondrial dynamics towards fission, which correlated with increased swollen mitochondria and aberrant cristae. These morphological changes, which are associated with increased NF-kB activity and nitric oxide concentrations, correlated with a pronounced reduction of mitochondrial activity. However, ATP availability was unaltered, suggesting that neurons maintain a physiological energy metabolism to preserve them from apoptosis under CRH exposure. Our findings demonstrate that stress-induced CRHR1 activation leads to strong, but reversible, modifications of mitochondrial dynamics and morphology. These alterations are accompanied by bioenergetic defects and the reduction of neuronal activity, which are linked to increased intracellular oxidative stress, and to the activation of the NF-kB/c-Abl/DRP1 axis.

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

“…Several studies have linked DRP1-mediated mitochondrial fission to activation of NF-κB, thus linking increased DRP1 expression with an enhanced inflammatory response to various stimuli in multiple cell types [ 50 , 51 , 52 ]. There is, however, a lack in understanding of the role DRP1 plays in inflammation initiated by airway epithelial cells in response to allergen.…”

DRP1-Mediated Mitochondrial Fission Regulates the Lung Epithelial Response to Allergen

“…Several studies have linked DRP1-mediated mitochondrial ssion to activation of NF-κB, thus linking increased DRP1 expression with an enhanced in ammatory response to various stimuli in multiple cell types (50)(51)(52). There is, however, a lack in understanding of the role DRP1 plays in in ammation initiated by airway epithelial cells in response to allergen.…”

Propofol via Antioxidant Property Attenuated Hypoxia-Mediated Mitochondrial Dynamic Imbalance and Malfunction in Primary Rat Hippocampal Neurons

“…In addition, we reported in hippocampal neurons hypoxia-induced Drp1 expression was due to hypoxia-sensitive transcription factor HIF-1 α ( Figure 6(a) ), which was consistent with previous publications carried out in fibroblasts [ 30 ], cardiac cells [ 22 ], and vascular smooth muscle cells [ 34 ]. Although other transcription factors such as Smad2/3 [ 35 ], NF- κ B [ 36 ], and calcium-related transcription factors [ 37 ] have been reported to correlate with Drp1 expression, we demonstrated that HIF-1 α inhibitors could almost completely inhibit hypoxia-induced Drp1 expression ( Figure 6(b) ), and thus, suggesting the pivotal role of HIF-1 α .…”

“…Although other transcription factors such as Smad2/3 [35], NF-κB [36], and calcium-related transcription factors [37] have been reported to correlate with Drp1 expression, we demonstrated that HIF-1α inhibitors could almost completely inhibit hypoxia-induced Drp1 expression (Figure 6 Figure 7: Hypoxia-and propofol-modulated phosphorylation of Drp1 and mitochondrial dynamics was mediated via ERK and PKA pathway. The upper panel was a representative experiment, and the lower panel was the summary of densitometric data from 5 separate experiments.…”