title: Mitochondrial H2O2signaling 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 H2O2produced 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 H2O2can 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 H2O2likely 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 H2O2released 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 H2O2is 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.
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Electronic address: rheesg@yuhs.ac.
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.affiliation: Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: In Sup
authors.initials: IS
authors.lastname: Kil
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism* / Q000502:physiology; D061105:Peroxiredoxin III / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D006861:Hydrogen Peroxide; D061105:Peroxiredoxin III; D050862:Oxidoreductases Acting on Sulfur Group Donors
keywords: Circadian rhythm; Cysteine sulfinic acid; Hydrogen peroxide; Mitochondria; Peroxidase; Peroxiredoxin; Sulfiredoxin