Regulation of Manganese Antioxidants by Nutrient Sensing Pathways in Saccharomyces cerevisiae

Abstract

In aerobic organisms, protection from oxidative damage involves the combined action of enzymatic and nonproteinaceous cellular factors that collectively remove harmful reactive oxygen species. One class of nonproteinaceous antioxidants includes small molecule complexes of manganese (Mn) that can scavenge superoxide anion radicals and provide a backup for superoxide dismutase enzymes. Such Mn antioxidants have been identified in diverse organisms; however, nothing regarding their physiology in the context of cellular adaptation to stress was known. Using a molecular genetic approach in Bakers' yeast, Saccharomyces cerevisiae, we report that the Mn antioxidants can fall under control of the same pathways used for nutrient sensing and stress responses. Specifically, a serine/threonine PASkinase, Rim15p, that is known to integrate phosphate, nitrogen, and carbon sensing, can also control Mn antioxidant activity in yeast. Rim15p is negatively regulated by the phosphate-sensing kinase complex Pho80p/Pho85p and by the nitrogen-sensing Akt/S6 kinase homolog, Sch9p. We observed that loss of either of these upstream kinase sensors dramatically inhibited the potency of Mn as an antioxidant. Downstream of Rim15p are transcription factors Gis1p and the redundant Msn2/Msn4p pair that typically respond to nutrient and stress signals. Both transcription factors were found to modulate the potency of the Mn antioxidant but in opposing fashions: loss of Gis1p was seen to enhance Mn antioxidant activity whereas loss of Msn2/4p greatly suppressed it. Our observed roles for nutrient and stress response kinases and transcription factors in regulating the Mn antioxidant underscore its physiological importance in aerobic fitness.

Battles with Iron: Manganese in Oxidative Stress Protection

“…Seminal studies by Archibald and Fridovich (39,59) identified the manganese-antioxidant as a superoxide-scavenging activity in extracts of L. plantarum that was dialyzable and heat-and protease-resistant but susceptible to metal chelation by EDTA. Similar findings have since been reported for cell-free lysates of E. coli (41), D. radiodurans (60), Bacillus subtilis (42), and the bakers' yeast S. cerevisiae (43,61). The hexaquo Mn 2ϩ cation is a weak scavenger of superoxide, but when liganded to small molecules such as orthophosphate or carboxylates (e.g.…”

“…SOD, peroxidases, and catalases) are regulated during oxidative stress (71). In our recent studies with S. cerevisiae, we provided evidence to the contrary: like their enzymatic counterparts, the formation of non-proteinaceous manganeseantioxidants is tightly regulated according to cellular need (61). In particular, we found that conserved nutrient-sensing and nutrient-signaling pathways control the efficacy of intracellular manganese as a non-SOD antioxidant (61).…”

“…We observed that this intricate signaling system for responding to stress and nutrients also regulates manganeseantioxidant activity in S. cerevisiae. Specifically, the manganese-antioxidant was promoted under conditions in which Msn2 and Msn4 were activated and was repressed through activation of Gis1 (61). Msn2, Msn4, and Gis1 modulate the activity of manganese-antioxidants without changing the levels of intracellular manganese and are proposed to control the assembly of manganese complexes that remove superoxide (61).…”

The relationship among serum levels of manganese superoxide dismutase and mtDNA 8-hydroxy-2'-deoxyguanosine, and dietary antioxidants intake in Type 2 Diabetes

“…Manganese (Mn) is an important antioxidant that scavenges free radicals and is secondary to biochemical functions, behaving as a backup free radical scavenger that is similar to MnSOD, especially in regard to oxidative stress (Reddi & Culotta, 2011).…”

“…Although there is a lack of data on the mechanism by which Mn participates in the cellular adaptation to oxidative stress (Reddi & Culotta, 2011), research has shown that the antioxidant activity is regulated by nutrient-sensing pathways.…”