Feedback Control of Adrenal Steroidogenesis via H2O2-Dependent, Reversible Inactivation of Peroxiredoxin III in Mitochondria

Abstract

Certain members of the peroxiredoxin (Prx) family undergo inactivation through hyperoxidation of the catalytic cysteine to sulfinic acid during catalysis and are reactivated by sulfiredoxin; however, the physiological significance of this reversible regulatory process is unclear. We now show that PrxIII in mouse adrenal cortex is inactivated by H(2)O(2) produced by cytochrome P450 enzymes during corticosterone production stimulated by adrenocorticotropic hormone. Inactivation of PrxIII triggers a sequence of events including accumulation of H(2)O(2), activation of p38 mitogen-activated protein kinase, suppression of steroidogenic acute regulatory protein synthesis, and inhibition of steroidogenesis. Interestingly, levels of inactivated PrxIII, activated p38, and sulfiredoxin display circadian oscillations. Steroidogenic tissue-specific ablation of sulfiredoxin in mice resulted in the persistent accumulation of inactive PrxIII and suppression of the adrenal circadian rhythm of corticosterone production. The coupling of CYP11B1 activity to PrxIII inactivation provides a feedback regulatory mechanism for steroidogenesis that functions independently of the hypothalamic-pituitary-adrenal axis.

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

“…Freshly obtained mouse airway epithelial cells from Arg2 KO mice (n = 10) had lower mitochondrial membrane potential as compared with WT (n = 10, P = 0.04) ( Figure 6, E and F) and less ROS production (P = 0.02) ( Figure 6, G and H). Mitochondrial redox was also assessed by cysteine oxidation of the mitochondrial-localized peroxiredoxin 3 (PRX3), a 2-Cys PRX family member that scavenges mitochondrial H 2 O 2 (47,48). In oxidative conditions, the PRX3 sulfenic intermediate (Cys51-SOH) is overoxidized to cysteine sulfinic acid (Cys51-SO 2 H) or cysteine sulfonic acid (Cys51-SO 3 H).…”

Anti-inflammatory and ECM gene expression modulations of β-eudesmol via NF-κB signaling pathway in normal human dermal fibroblasts

“…As an indicator for toxicity reaction inducing apoptotic and oxidative stress, GSH level change has been estimated (Esposito et al 2000;Zhang et al 2010;Kil et al …”

“…To identify effects of β-eudesmol to extinct intracellular H 2 O 2 and hinder OH − radical formation, we used a GSH measurement analysis method. As an indicator of toxicity reaction which induces apoptotic effect and oxidative stress, changing of GSH level has been estimated (Esposito et al 2000; Zhang et al 2010; Kil et al 2012). It was identified that GSH level increased in accordance with an increase in concentration of β-eudesmol.…”

Enzymatic control of cysteinyl thiol switches in proteins

“…A crucial aspect for future studies on Prx-dependent redox regulation will be the identification of similar complementary patterns in Prx substrates and (potential) signal transducers. The physiological relevance of such interactions cannot be overemphasized considering that Prx are at the center of a plethora of redox-regulated processes and have excellent hydroperoxide sensor properties as outlined below (Delaunay et al, 2002;Jang et al, 2004;Brigelius-Flohé and Flohé, 2011;Edgar et al, 2012;Jarvis et al, 2012;Kil et al, 2012;Cho et al, 2014).…”