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

SummaryCertain 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 H2O2 produced by cytochrome P450 enzymes during corticosterone production stimulated by adrenocorticotropic hormone. Inactivation of PrxIII triggers a sequence of events including accumulation of H2O2, 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.

Graphical AbstractFigure optionsDownload high-quality image (272 K)Download as PowerPoint slideHighlights
► H2O2 produced by cytochrome p450 during steroidogenesis reversibly inactivates PrxIII
► PrxIII inactivation in mitochondria causes further accumulation of H2O2 and p38 activation
► Activated p38 suppresses StAR production and inhibits adrenal steroidogenesis
► The H2O2-p38-StAR pathway is critical for circadian variation of steroidogenesis