Battles with iron: manganese in oxidative stress protection

Abstract

The redox-active metal manganese plays a key role in cellular adaptation to oxidative stress. As a cofactor for manganese superoxide dismutase or through formation of non-proteinaceous manganese antioxidants, this metal can combat oxidative damage without deleterious side effects of Fenton chemistry. In either case, the antioxidant properties of manganese are vulnerable to iron. Cellular pools of iron can outcompete manganese for binding to manganese superoxide dismutase, and through Fenton chemistry, iron may counteract the benefits of non-proteinaceous manganese antioxidants. In this minireview, we highlight ways in which cells maximize the efficacy of manganese as an antioxidant in the midst of pro-oxidant iron.

FIGURE 1.

Models for metal selectivity of bacterial Mn-SOD and Fe-SOD enzymes. A, model of a Gram-negative E. coli cell showing Mn-SOD dimers in blue and Fe-SOD dimers in red. Under normal aerobic conditions, Mn-SOD molecules accumulate as mixed pools of all iron-, all manganese-, or iron- and manganese-containing dimers. Fe-SOD molecules are shown to accumulate only in the iron-bound state. Manganese (green) is far less abundant in E. coli than iron (pink). Depending on speciation, iron may exist in two states, only one of which is bioavailable (pink circles) to the SOD. B, shown is the Sec-driven export of the unfolded Mn-SOD polypeptide into the periplasmic space, where the enzyme may acquire its manganese without interference from iron. C, shown is the TAT-driven export of iron-bound and mature Fe-SOD into the periplasmic space. In this model, the Fe-SOD acquires its metal in the cytosol.

FIGURE 2.

Impact of the mitochondrial Fe-S pathway on manganese activation of Sod2. A, for eukaryotic Sod2, manganese is inserted into newly synthesized Sod2 polypeptides that are freshly imported into mitochondria. The Sod2 polypeptide is cotranslationally imported into mitochondria, and insertion of the manganese is coupled to Sod2 translocation across the mitochondrial inner membrane. Shown in red is a putative manganese transporter that may lie in close proximity to the site of Sod2 entry into mitochondria. Under normal conditions, much of the bioavailable iron is shielded from reacting with Sod2 by sequestration in the Fe-S pathway. Here, iron is used to assemble Fe-S scaffolds onto Isu, which are then transferred to Fe-S proteins. B, when the Fe-S pathway is blocked (indicated by red X on Isu), the iron for Fe-S clusters is diverted to Sod2. Iron binding to Sod2 precludes manganese binding, and the enzyme is inactive.

FIGURE 3.

Nutrient- and stress-signaling pathways regulate the manganese-antioxidant in yeast cells. The activity of the S. cerevisiae Rim15 kinase is controlled by a host of environmental signals, including stress, glucose, phosphate, and nitrogen. These environmental signals are sensed and relayed to the Rim15 kinase through upstream response kinases, including Pho80 for phosphate and Sch9 for nitrogen. Rim15 in turn activates the Gis1 and Msn2/Msn4 transcription factors, which work in opposite fashion to control the activity of non-proteinaceous manganese-antioxidants, including manganese-phosphate and manganese complexes with carboxylates, as illustrated. These compounds can promote oxidative stress resistance by removing O₂^˙̄ in a SOD-like reaction.