Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

Abstract

Abstract:The molecular oxygen (O 2 ) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O 2 is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H 2 O 2 , are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H 2 O 2 elimination pathways are well characterized in mitochondria. However, less is known about how H 2 O 2 production is controlled. The present review examines the importance of mitochondrial H 2 O 2 in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H 2 O 2 can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H 2 O 2 production.

Deletion of the Glutaredoxin-2 Gene Protects Mice from Diet-Induced Weight Gain, Which Correlates with Increased Mitochondrial Respiration and Proton Leaks in Skeletal Muscle

“…Similar results have been collected with UCP2 (22). In addition, GRX2 is required to deactivate proton return through UCP3 through its S-glutathionylation (18). Elimination of GRX2 induces the chronic activation of leaks in muscle mitochondria and primary mouse myotubes, which could be inhibited by S-glutathionylation catalysts or further activated by deglutathionylation agents such as dithiothreitol (DTT) (28).…”

Physiological levels of formate activate mitochondrial superoxide/hydrogen peroxide release from mouse liver mitochondria

“…The results collected above suggest that sodium formate may augment /H 2 O 2 release from liver mitochondria oxidizing pyruvate by regulating either OGDH or PDH. OGDH and PDH are targeted for regulation by S‐glutathionylation which can modulate how much /H 2 O 2 is released from either enzyme complex . Using purified PDH and OGDH of porcine heart origin, we tested if sodium formate (0.03 m m ) affected /H 2 O 2 release by conjugating GSH to either enzyme complex.…”

Manganese Porphyrin-Based SOD Mimetics Produce Polysulfides from Hydrogen Sulfide

“…These include the thiyl radical (•SH), persufide (H 2 S 2 ), persulfide radical, i.e., "supersulfide" (S 2 • − ) and finally elemental sulfur (S 2 ); the latter may ultimately cyclize to S 8 [14]. Second, the downstream effectors activated by ROS, mainly cysteine sulfur on regulatory proteins, are essentially the same as those activated by RSS [15][16][17][18][19][20][21][22][23]. Third, not only are ROS and RSS chemically and biologically similar, but five of the most common methods used to measure ROS also detect RSS, with greater or equal sensitivity suggesting that even distinguishing between ROS and RSS in cells is challenging [24].…”