Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation

Abstract

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging.Nutrient availability relative to both carbohydrates and amino acids (AAs), 2 in the mammalian diet, has potentially critical impacts on metabolic flux and ultimately the generation of ATP and its equivalents. With constantly changing constituents associated with the mammalian diet, organisms have adapted metabolic strategies to efficiently accommodate changes in the availability of critical nutrients. Extensive studies have addressed the importance of glucose excess (1) and deprivation (2) as well as AA availability on metabolic and nuclear events (3). For example, the levels of branch chain AA regulate intracellular signaling through the central regulator, mammalian target of rapamycin (mTOR), culminating in downstream impacts on overall protein synthesis (4 -6). Analogously, maintenance of tryptophan levels in fibroblast medium is critical to the regulation of the matrix-degrading enzymes, collagenase and stromelysin, by 8). On the other hand, tryptophan degradation mediates the inhibitory effects of interferon-␥-dependent increases in cellular indoleamine 2,3-dioxygenase mRNA (8, 9). Most relevant to the present study, deprivation of essential AA has been demonstrated to evoke responses at both the transcriptional and post-transcriptional levels for genes such as asparagine synthetase (ASNS), CCAAT/enhancerbinding protein homologous protein, cationic AA transporter (Cat-1), sodium-coupled neutral AA transporter system A (SNAT2), and insulin-like growth factor-binding protein-1 (IGFBP-1) (3). Fernandez et al. (10) have also demonstrated the existence of an internal ribosome entry site within the 5Ј-untranslated region of the cat-1 gene that controls translation of this transport protein under conditions of AA depletion.Tissue and cellular adaptation to nutrient availability also affects carbon and nitrogen utilization th...

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“…In Ehrich ascites tumor cells, glutaminase knockdown led to enhanced phosphorylation, DNA binding, and transcriptional activity of Sp1 (Segura et al , 2005). In HepG2 hepatoma cells, glutamine was required for the induction of manganese superoxide dismutase (MnSOD) expression that accompanied the depletion of essential amino acids (Aiken et al , 2008). Glutamine's involvement in MnSOD expression was blocked by inhibiting the TCA cycle, ERK1/2 or mTOR, suggesting that an integration between mitochondrial glutamine metabolism and signal transduction facilitates the effect.…”

Human duodenal proteome modulations by glutamine and antioxidants

“…MnSOD catalyses the dismutation of superoxide radicals to hydrogen peroxide, which are subsequently neutralized by catalase or glutathione peroxidase and protects the redox sensitive cellular machinery from ROS‐induced damage 61. MnSOD gene expression was reported to be dependent on amino acid availability in HepG2 cells 62. The decrease of MnSOD expression in the absence of essential amino acids can be prevented by Gln through ERK and mTOR kinases pathways 62.…”

“…MnSOD gene expression was reported to be dependent on amino acid availability in HepG2 cells 62. The decrease of MnSOD expression in the absence of essential amino acids can be prevented by Gln through ERK and mTOR kinases pathways 62. MnSOD is constitutively expressed in small intestine epithelium and was found to be upregulated in biopsies from IBD and colorectal cancer patients 10, 11, 63.…”

Amino Acid Deprivation Decreases Intracellular Levels of Reactive Oxygen Species in Hepatic Stellate Cells

“…This effect is caused mainly by the absence of the essential amino acid methionine, a precursor of metabolites involved in the antioxidant defense like homocysteine and S-Adenosylmethionine [17]. Another example of a potential role for amino acid deprivation in the regulation of intracellular oxidative status is the recently reported induction of Mn-SOD in histidine-deprived human hepatoma cells, an effect that requires MEK/ERK and mTOR activities and the presence of the amino acid glutamine [30].…”