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.
Highlights
Neurons rely on mitochondria for the preservation of the membrane potential, energy supply (ATP), Ca2+ homeostasis, metabolite production, and reactive oxygen species (ROS) regulation[1,2,3]
corticotropin-releasing hormone (CRH) alters mitochondrial network and morphology Since CRH triggers a dramatic loss of synapses[32], which require high amount of energy (ATP)[48], we investigated the effect of CRH release on neuronal mitochondria by analysing their morphology in mice 5 days after trauma (5 thorax trauma (TxT)) (Fig. 2A)
Cortical neurons deprived of glucose and oxygen display increased fission linked to reduced OPA1 levels, which eventually leads to neuronal death[58]; notably, mitochondrial activation of caspase-3 signaling triggers neuronal apoptosis, and controls neuronal plasticity[59]
Summary
Neurons rely on mitochondria for the preservation of the membrane potential, energy supply (ATP), Ca2+ homeostasis, metabolite production, and ROS regulation[1,2,3]. Mitochondria are distributed throughout the entire neuron and they are extremely dynamic organelles, whose shape and distribution are mainly governed by two processes: fusion and fission[4,5]. A group of dynaminrelated GTPases maintains the balance between these two processes, critical for the function of these organelles[5]. To the mitochondrial outer membrane upon phosphorylation[7]. OPA1 mediate the fusion of the outer and inner membrane, respectively[8,9]. Mitochondrial defects alter neuronal plasticity, metabolism, and survival in several pathological conditions[15,16,17,18], Official journal of the Cell Death Differentiation Association
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