Animals ; Circadian Rhythm* ; HeLa Cells ; Heat-Shock Proteins/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/enzymology* ; Organ Specificity ; Oxidation-Reduction ; Oxidoreductases Acting on Sulfur Group Donors/metabolism* ; Peroxiredoxin III/metabolism ; Protease La/metabolism ; Protein Transport ; Proteolysis ; Sulfur Dioxide/metabolism ; Tacrolimus Binding Proteins/metabolism
Abstract
Hydrogen peroxide (H2O2) released from mitochondria regulates various cell signaling pathways. Given that H2O2-eliminating enzymes such as peroxiredoxin III (PrxIII) are abundant in mitochondria, however, it has remained unknown how such release can occur. Active PrxIII-SH undergoes reversible inactivation via hyperoxidation to PrxIII-SO2, which is then reduced by sulfiredoxin. We now show that the amounts of PrxIII-SO2 and sulfiredoxin undergo antiphasic circadian oscillation in the mitochondria of specific tissues of mice maintained under normal conditions. Cytosolic sulfiredoxin was found to be imported into the mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is promoted by H2O2 released from mitochondria. The imported sulfiredoxin is degraded by Lon in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of sulfiredoxin provide the basis for sulfiredoxin oscillation and consequent PrxIII-SO2 oscillation in mitochondria and likely result in an oscillatory H2O2 release.