Keeping Oxidative Metabolism on Time: Mitochondria as an Autonomous Redox Pacemaker Animated by H2O2 and Peroxiredoxin  Michel B. Toledano, Agnès Delaunay-Moisan  Molecular Cell  Volume 59, Issue 4, Pages 517-519 (August 2015) DOI: 10.1016/j.molcel.2015.08.003 Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 1 The Two Enzymatic Cycles of 2-Cys Prxs 2-Cys Prx are head-to-tail homodimers, each with two catalytic cysteine (Cys) residues. In the peroxidatic cycle, the peroxidatic Cys (CP) reduces H2O2 and is in turn oxidized to a sulfenic acid (CP-SOH) (Fourquet et al., 2008). The CP-SOH then condenses with the resolving Cys (CR) of the other subunit into an intermolecular disulfide, reduced by thioredoxin. When levels of H2O2 are high, eukaryotic 2-Cys Prxs enter the sulfinylation cycle in which the CP-SOH, instead of condensing with CR, is hyperoxidized by H2O2 into a sulfinic acid (CP-SO2H), which interrupts the peroxidatic cycle. Sulfinylated Prx is reactivated by slow ATP-dependent reduction by Srx (Biteau et al., 2003). 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 H2O2 signaling (Wood et al., 2003). This hypothesis is now fully supported by the paper of Kil et al. (2015). Molecular Cell 2015 59, 517-519DOI: (10.1016/j.molcel.2015.08.003) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 2 Cyclic Reactivation of PrxIII upon Redox-Dependent Mitochondrial Import of Srx Sets the Redox Clockwork in Motion Of all mouse tissues except RBCs (see main text), a Prx in the sulfinylated form, identified as mitochondrial PrxIII, is only detected in the adrenal gland, brown adipose tissue (BAT), and heart. PrxIII-SO2 and mitochondrial Srx levels each oscillate with an antiphasic 24 hr period. Srx is cytosolic, and its import into and degradation within mitochondria are regulated during the 24 hr cycle. Srx is imported upon H2O2 released by mitochondria following PrxIII inactivation, guided by Hsp90 to the translocon to which it is transiently attached by a disulfide. In mitochondria, Srx is initially shielded from degradation by its tight interaction with PrxIII-SO2, until sulfinate reduction, which releases Srx from this interaction for Lon-dependent degradation. Srx import into and degradation within mitochondria are thus coupled to the accumulation and reduction of PrxIII-SO2, explaining the antiphasic 24 hr cycle of mitochondrial Srx and PrxIII-SO2 levels. In addition to stimulating Srx import, the periodic H2O2 release is expected to act on yet-to-be-defined cytosolic/nuclear redox targets. The Srx/PrxIII system thus uncouples mitochondrial H2O2 production and its cytosolic release, acting as a timely regulated rheostat to control cellular redox signaling. Molecular Cell 2015 59, 517-519DOI: (10.1016/j.molcel.2015.08.003) Copyright © 2015 Elsevier Inc. Terms and Conditions