Feedback control of adrenal steroidogenesis via H2O2-dependent, reversible inactivation of peroxiredoxin III in mitochondria.
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.
Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea. iskil@ewha.ac.kr
In Sup
IS
Kil
Se Kyoung
SK
Lee
Keun Woo
KW
Ryu
Hyun Ae
HA
Woo
Meng-Chun
MC
Hu
Soo Han
SH
Bae
Sue Goo
SG
Rhee
D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003345:Corticosterone / Q000096:biosynthesis; D025461:Feedback, Physiological; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D061105:Peroxiredoxin III / Q000378:metabolism* / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol; D006861:Hydrogen Peroxide; D061105:Peroxiredoxin III; D013252:Steroid 11-beta-Hydroxylase; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D003345:Corticosterone