Mitochondrial H2O2 signaling is controlled by the concerted action of peroxiredoxin III and sulfiredoxin: Linking mitochondrial function to circadian rhythm

Abstract

Mitochondria produce hydrogen peroxide (H₂O₂) during energy metabolism in most mammalian cells as well as during the oxidation of cholesterol associated with the synthesis of steroid hormones in steroidogenic cells. Some of the H₂O₂ produced in mitochondria is released into the cytosol, where it serves as a key regulator of various signaling pathways. Given that mitochondria are equipped with several H₂O₂-eliminating enzymes, however, it had not been clear how mitochondrial H₂O₂ can escape destruction by these enzymes for such release. Peroxiredoxin III (PrxIII) is the most abundant and efficient H₂O₂-eliminating enzyme in mitochondria of most cell types. We found that PrxIII undergoes reversible inactivation through hyperoxidation of its catalytic cysteine residue to cysteine sulfinic acid, and that release of mitochondrial H₂O₂ likely occurs as a result of such PrxIII inactivation. The hyperoxidized form of PrxIII (PrxIII-SO₂H) is reduced and reactivated by sulfiredoxin (Srx). We also found that the amounts of PrxIII-SO₂H and Srx undergo antiphasic circadian oscillation in mitochondria of the adrenal gland, heart, and brown adipose tissue of mice maintained under normal conditions. Cytosolic Srx was found to be imported into mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is likely promoted by H₂O₂ released from mitochondria. The imported Srx was found to be degraded by Lon protease in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of Srx underlie Srx oscillation and consequent PrxIII-SO₂H oscillation in mitochondria. The rhythmic change in the amount of PrxIII-SO₂H suggests that mitochondrial release of H₂O₂ is also likely a circadian event that conveys temporal information on steroidogenesis in the adrenal gland and on energy metabolism in heart and brown adipose tissue to cytosolic signaling pathways.

Keywords: Circadian rhythm; Cysteine sulfinic acid; Hydrogen peroxide; Mitochondria; Peroxidase; Peroxiredoxin; Sulfiredoxin.