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ABSTRACT The ubiquitously distributed ammonia-oxidizing archaea generate energy from ammonia and build cell mass from inorganic carbon sources, thereby contributing to both the global nitrogen and carbon cycles. However, little is known about the regulation of their predicted core carbon metabolism. A thermodynamic model for Nitrososphaera viennensis was developed to estimate the consumption of inorganic carbon in relation to ammonia consumed for energy and was tested experimentally by growing cells in carbon-limited and excess conditions. A combined proteomic and metabolomic approach to the experimental conditions revealed distinct metabolic adaptation depending on the amount of carbon supplied, either in a catalase or pyruvate background as a reactive oxygen species scavenger. Integration of protein and metabolite dynamics revealed a cellular strategy under carbon limitation to maintain a pool of amino acids and an upregulation of proteins necessary for translation initiation to stay primed for protein synthesis. The combination of modeling and functional genomics fills gaps in the understanding of the central metabolism and its regulation in a chemolithoautotrophic, ammonia-oxidizing archaeon, even in the absence of available genetic tools. IMPORTANCE Little is known about the regulation of carbon metabolism within ammonia-oxidizing archaea (AOA), a widespread clade that plays a critical role in the global nitrogen cycle while also fixing inorganic carbon. To address this missing knowledge, the soil AOA Nitrososphaera viennensis was subjected to various levels of inorganic carbon and analyzed via a systems biology approach to better understand how its core metabolism is regulated. The results demonstrate a strong dependence on the carbon fixation cycle and highlight key connection points between the core metabolic pathways. The analysis additionally revealed tight control on translational processes and elucidated unique cellular responses when the organism was exposed to either exogenous catalase or pyruvate to relieve oxidative stress from reactive oxygen species. The presented data highlight metabolic responses of N. viennensis and provide a better understanding of how the organism, and likely other AOA, respond to various environmental conditions. Show less

Metabolic reprogramming is one of the hallmarks of cancer. Nrf2 pathway is one of the critical signaling cascades involved in cell defense and survival against oxidative stress. The significance of Nrf2 in cancer metabolism begins to be recognized. In this minireview, we focus on the Nrf2-mediated cancer metabolic reprogramming and intend to highlight the role of Nrf2 in the regulation of malignant transformation, cancer proliferation, and the development of treatment resistance via metabolic adaptations. We hope for the development of noninvasive biomarkers and novel therapeutic approaches for cancer based on Nrf2-directed cancer metabolic reprogramming in the near future. Show less

The HCT116 cell line, which has a pseudo-diploid karotype, is a popular model in the fields of cancer cell biology, intestinal immunity, and inflammation. In the current study, we describe two batches of diverged HCT116 cells, which we designate as HCT116NIH and HCT116UCL. Using both gel electrophoresis and HPLC, we show that HCT116UCL cells contain 6-fold higher levels of InsP8 than HCT116NIH cells. This observation is significant because InsP8 is one of a group of molecules collectively known as ‘inositol pyrophosphates’ (PP-InsPs)—highly ‘energetic’ and conserved regulators of cellular and organismal metabolism. Variability in the cellular levels of InsP8 within divergent HCT116 cell lines could have impacted the phenotypic data obtained in previous studies. This difference in InsP8 levels is more remarkable for being specific; levels of other inositol phosphates, and notably InsP6 and 5-InsP7, are very similar in both HCT116NIH and HCT116UCL lines. We also developed a new HPLC procedure to record 1-InsP7 levels directly (for the first time in any mammalian cell line); 1-InsP7 comprised <2% of total InsP7 in HCT116NIH and HCT116UCL lines. The elevated levels of InsP8 in the HCT116UCL lines were not due to an increase in expression of the PP-InsP kinases (IP6Ks and PPIP5Ks), nor to a decrease in the capacity to dephosphorylate InsP8. We discuss how the divergent PP-InsP profiles of the newly-designated HCT116NIH and HCT116UCL lines should be considered an important research opportunity: future studies using these two lines may uncover new features that regulate InsP8 turnover, and may also yield new directions for studying InsP8 function. Show less