Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Abstract

Aim Chronic stress exacerbates the symptoms of most pain disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). Abnormalities in urothelial cells (UTC) occur in this debilitating bladder condition. The sequence of events that might link stress (presumably through increased sympathetic nervous system‐SNS activity) to urothelial dysfunction are unknown. Since autonomic dysregulation, mitochondrial dysfunction, and oxidative stress all occur in chronic pain, we investigated whether chronic psychological stress initiated a cascade linking these three dysfunctions. Methods Adult female Wistar Kyoto rats were exposed to 10 days of water avoidance stress (WAS). Bladders were then harvested for Western blot and single cell imaging in UTC cultures. Results UTC from WAS rats exhibited depolarized mitochondria membrane potential (Ψm ∼30% more depolarized compared to control), activated AMPK and altered UT mitochondria bioenergetics. Expression of the fusion protein mitofusion‐2 (MFN‐2) was upregulated in the mucosa, suggesting mitochondrial structural changes consistent with altered cellular metabolism. Intracellular calcium levels were elevated in cultured WAS UTC, consistent with impaired cellular function. Stimulation of cultured UTC with alpha‐adrenergic (α‐AR) receptor agonists increased reactive oxidative species (ROS) production, suggesting a direct action of SNS activity on UTC. Treatment of rats with guanethidine to block SNS activity prevented most of WAS‐induced changes. Conclusions Chronic stress results in persistent sympathetically mediated effects that alter UTC mitochondrial function. This may impact the urothelial barrier and signaling, which contributes to bladder dysfunction and pain. This is the first demonstration, to our knowledge, of a potential autonomic mechanism directly linking stress to mitochondrial dysfunction.

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

“…In addition, this WAS‐induced bladder hypersensitivity was exacerbated by early life stress, 139 which could mimic the potential relationship between childhood relational affect dysregulation and the development of IC/BPS without Hunner lesions in humans 140 . Interestingly, a recent study reported the potential link between WAS‐induced chronic stress and urothelial dysfunction, which was mediated by autonomic mechanisms and mitochondrial malfunction 137,141 . Taken together, these models might facilitate the development of novel therapies and future research on the pathogenesis of IC/BPS without Hunner lesions.…”

Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

“…All these compounds increase primarily the cytosolic Ca 2+ concentration, followed by mitochondrial ROS formation and eventually followed by apoptosis and cell death. But also psychosocial stress results in the increase of cytosolic Ca 2+ concentration, as shown in isolated cardiomyocytes [85], in platelets [86], hippocampal-derived HT22 cells [87], urothelial cells [88], and cardiomyocytes [89]. The neurotoxic effect of glutamate in neurons via the N-methyl-D-aspartat-receptor was related to an increase of cytosolic Ca 2+ and the formation of ROS [90,91].…”

Regulation of cytochrome c oxidase contributes to health and optimal life

“…Various stress signals were shown to increase cytosolic calcium concentrations in cells including high glutamate[ 94 ] or glucose[ 95 ]. In addition, psychosocial stress was shown to increase cytosolic calcium, as shown in cardiomyocytes[ 96 ], platelets[ 97 ], hippocampal-derived HT22 cells[ 98 ], urothelial cells[ 99 ], and cardiomyocytes[ 100 ]. Under resting conditions the cytosolic calcium concentration is low (about 0.1 micromolar), and a cAMP-dependent PKA rephosphorylates CytOx, accompanied by dimerization and switching on the allosteric ATP-inhibition of CytOx.…”