Circadian Oscillation of Sulfiredoxin in the Mitochondria

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.

Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells

“…We interpret the lower hydrogen peroxide in mitochondria upon hypoxia as prior mitochondrial release of H 2 O 2 into the cytosol, but it might as well reflect reduced mitochondrial production of H 2 O 2 under hypoxic conditions. A mitochondrial release of H 2 O 2 might also explain the increased nocturnal levels of Prx ox found after treatment with short term hypoxia, knowing that the release of mitochondrial H 2 O 2 into the cytosol is controlled by PrxIII, [44, 45], the abundance of which constitutes a large portion of the peroxiredoxin isoform pool [46]. In order to test the actual impact of altered cellular H 2 O 2 signaling on circadian time keeping we inhibited catalase, a major light-driven antioxidant enzyme regulating intracellular H 2 O 2 levels [47], with Amitrol and found that inhibition of the enzyme led to a lengthened period of the period1 gene oscillation in the zebrafish per1 luciferase reporter cell line DAP49 [48] (Fig.…”

Keeping Oxidative Metabolism on Time: Mitochondria as an Autonomous Redox Pacemaker Animated by H2O2 and Peroxiredoxin

“…Given the known signaling role of H 2 O 2 , such a cyclic release of H 2 O 2 should alter in a timely fashion not only transcriptional clock regulators, many of which (such as REV-ERBb and the PER2:CRY1 heterodimer complex) are thiol-redox sensitive, but also the multitude of thiol-redox regulatory factors, as nuclear receptors, kinases, phosphatases, and transcription factors that are also or not involved in circadian regulation. In this regard, Kil et al (2015) show that activation of the p38 MAPK in the AG and BAT oscillates with a phase and period identical to that of PrxIII-SO 2 , which also indicates the oscillatory release of H 2 O 2 into the cytosol.…”

“…If indeed this is the case, the presence of the PrxIII/Srx clockwork in AG, heart, and BAT, and not in the liver, might indicate a fundamental difference between the signals of food intake and physiological activity with regards to their integration by systemic clockwork mechanisms. Many other great questions are raised by the study of Kil et al (2015), such as the possible regulation of the PrxIII/Srx clockwork by PrxIII acetylation and phosphorylation, which are known to change its sensitivity to sulfinylation.…”

“…As to the purpose of the energy-costly alternate sulfinylation cycle, an attribute exclusive to eukaryotic 2-Cys Prxs, Karplus and coworkers suggested that it is an evolutionary gain of function allowing H 2 O 2 signaling (Wood et al, 2003). This hypothesis is now fully supported by the paper of Kil et al (2015). of H 2 O 2 .…”

“…Rhee and colleagues now propose an Srx-dependent mechanism for the rhythmic sulfinylation of mitochondrial PrxIII (Kil et al, 2015) (Figure 2). As PrxIII is predicted to contribute to the degradation of 90% of mitochondrially produced H 2 O 2 , its inactivation by hyperoxidation, which reflects an important scavenging workload, eventually leads to an overflow of H 2 O 2 in the cytosol that triggers the slow import of Srx and the resetting of PrxIII scavenging capacity.…”