Oxidative stress and adrenocortical insufficiency

Abstract

Maintenance of redox balance is essential for normal cellular functions. Any perturbation in this balance due to increased reactive oxygen species (ROS) leads to oxidative stress and may lead to cell dysfunction/damage/death. Mitochondria are responsible for the majority of cellular ROS production secondary to electron leakage as a consequence of respiration. Furthermore, electron leakage by the cytochrome P450 enzymes may render steroidogenic tissues acutely vulnerable to redox imbalance. The adrenal cortex, in particular, is well supplied with both enzymatic (glutathione peroxidases and peroxiredoxins) and non-enzymatic (vitamins A, C and E) antioxidants to cope with this increased production of ROS due to steroidogenesis. Nonetheless oxidative stress is implicated in several potentially lethal adrenal disorders including X-linked adrenoleukodystrophy, triple A syndrome and most recently familial glucocorticoid deficiency. The finding of mutations in antioxidant defence genes in the latter two conditions highlights how disturbances in redox homeostasis may have an effect on adrenal steroidogenesis.

Keywords: adrenal insufficiency; oxidative stress; reactive oxygen species; steroidogenesis.

Figure 1

Detoxification of mitochondrial superoxide species produced during electron leakage from the mitochondrial electron transport chain. The superoxide radical O₂ · ⁻, produced from electrons (e⁻) leaked at complexes I and III of the mitochondrial electron transport chain, can be protonated to form H₂O₂, this process of dismutation is catalysed by MnSOD. Mitochondrial H₂O₂ is detoxified by the thioredoxin and GSH systems, which require high concentrations of nicotinamide adenine dinucleotide phosphate (reduced NADPH) provided by NNT. The flow of electron transfer from NADPH to PRDX3 and GPX, through the various components of the thioredoxin and GSH systems, is shown in the figure. GSR, glutathione reductase; GSH, reduced glutathione; TXNRD2, thioredoxin reductase 2; TXN2, thioredoxin 2; GLRX2, glutaredoxin 2; NNT, nicotinamide nucleotide transhydrogenase; PRDX3, peroxiredoxin 3; GPX, glutathione peroxidase; MnSOD, manganese superoxide dismutase.

Figure 2

Reactive oxygen species (ROS) production during steroidogenesis. The import of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) is activated by STAR and mediated by the translocator protein (TSPO)-associated multi-component complex. This is followed by cholesterol side-chain cleavage to pregnenolone by P450scc (CYP11A1). The other steps in the steroidogenic pathway are catalysed by cytochrome P450 isoforms in the endoplasmic reticulum (ER). The final step in cortisol synthesis is catalysed by P450c11β (CYP11B1) in the mitochondria, converting 11-deoxycortisol to cortisol. Electron leakage during this process results in ROS production.

Figure 3

Maintenance of reduced peroxiredoxin 3 (PRDX3-SH) by thioredoxin 2 (TXN2) and sulfiredoxin (SRX). PRDX3, in its reduced form, detoxifies H₂O₂ in the mitochondria. This process induces the formation of disulphide PRDX3 which in turn is reduced back to PRDX3-SH by TXN2. With excessive H₂O₂ PRDX3 is hyperoxidised to an inactive sulfinic form (PRDX3-SO₂ ⁻) and this hyperoxidisation is reversed by SRX.