RESUMO
Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine1. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation2,3, but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin-null flies (Sesn-/-) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet. Knock-in flies expressing a leucine-binding-deficient Sestrin mutant (SesnL431E) have reduced, leucine-insensitive mTORC1 activity. Notably, we find that flies can discriminate between food with or without leucine, and preferentially feed and lay progeny on leucine-containing food. This preference depends on Sestrin and its capacity to bind leucine. Leucine regulates mTORC1 activity in glial cells, and knockdown of Sesn in these cells reduces the ability of flies to detect leucine-free food. Thus, nutrient sensing by mTORC1 is necessary for flies not only to adapt to, but also to detect, a diet deficient in an essential nutrient.
Assuntos
Adaptação Fisiológica , Dieta , Proteínas de Drosophila , Drosophila melanogaster , Leucina , Sestrinas , Adaptação Fisiológica/genética , Ração Animal , Animais , Autofagia , Dieta/veterinária , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Preferências Alimentares , Leucina/deficiência , Leucina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Neuroglia/metabolismo , Sestrinas/deficiência , Sestrinas/genética , Sestrinas/metabolismo , Transdução de SinaisRESUMO
Malignant cells remodel their metabolism to meet the demands of uncontrolled cell proliferation. These demands lead to differential requirements in energy, biosynthetic precursors, and signaling intermediates. Both genetic programs arising from oncogenic events and transcriptional programs and epigenomic events are important in providing the necessary metabolic network activity. Accumulating evidence has established that environmental factors play a major role in shaping cancer cell metabolism. For metabolism, diet and nutrition are the major environmental aspects and have emerged as key components in determining cancer cell metabolism. In this review, we discuss these emerging concepts in cancer metabolism and how diet and nutrition influence cancer cell metabolism.
Assuntos
Dietoterapia/métodos , Neoplasias/dietoterapia , Neoplasias/metabolismo , Carcinogênese/metabolismo , Proliferação de Células/genética , Dieta/tendências , Dietoterapia/tendências , Metabolismo Energético/genética , Humanos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Neoplasias/genética , Terapia Nutricional/métodos , Transdução de Sinais/genéticaRESUMO
The small molecule erastin inhibits the cystine-glutamate antiporter, system xc-, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied. To this end, we investigated how erastin impacts global metabolism in cultured cells and compared this metabolic profile to that caused by the ferroptosis inducer RAS-selective lethal 3 or in vivo cysteine deprivation. Common among the metabolic profiles were alterations in nucleotide and central carbon metabolism. Supplementing nucleosides to cysteine-deprived cells rescued cell proliferation in certain contexts, showing that these alterations to nucleotide metabolism can affect cellular fitness. While inhibition of the glutathione peroxidase GPX4 caused a similar metabolic profile as cysteine deprivation, nucleoside treatment did not rescue cell viability or proliferation under RAS-selective lethal 3 treatment, suggesting that these metabolic changes have varying importance in different scenarios of ferroptosis. Together, our study shows how global metabolism is affected during ferroptosis and points to nucleotide metabolism as an important target of cysteine deprivation.
Assuntos
Cisteína , Ferroptose , Nucleotídeos , Piperazinas , Morte Celular , Cisteína/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos , Piperazinas/farmacologia , Nucleotídeos/metabolismoRESUMO
Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE. We found that KA-resistant cells lose the WE but continue to conduct glycolysis and surprisingly remain dependent on glucose as a carbon source and also on central carbon metabolism. Consequently, this altered state of glycolysis led to differential metabolic activity and requirements, including emergent activities in and dependences on fatty acid metabolism. These findings reveal that aerobic glycolysis is a process functionally distinct from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.
Assuntos
Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Glicólise , Oxigênio/metabolismo , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/antagonistas & inibidores , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/genética , Humanos , Células MCF-7 , Sesquiterpenos/farmacologiaRESUMO
Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that we developed for Drosophila melanogaster, we surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline.
RESUMO
Plant-based diets exclude or substantially limit the consumption of meat and animal products and are of growing interest to many due to their sustainability and health benefits (Eshel et al, 2016). Veganism is an extreme type of plant-based diet which excludes the consumption of all animal-derived foods such as meat, eggs, and dairy, as well as foods containing animal-derived ingredients. In adults, for example, certain observational studies have suggested lower body mass index, total cholesterol, LDL-cholesterol, decreased incidence and mortality from ischemic heart disease, and decreased incidence of cancer in vegans and vegetarians versus omnivores (Dinu et al, 2017). The mechanistic basis for these observations and their generality are unclear.
Assuntos
Dieta Vegetariana , Dieta , Animais , Humanos , Metabolômica , VegetarianosRESUMO
Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.
Assuntos
Glicólise , Piruvato Quinase , Animais , Glucose , Camundongos , Neoplasias , Isoformas de ProteínasRESUMO
Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism. We show that inhibition of PHGDH induces alterations in nucleotide metabolism independent of serine utilization. These changes are not attributable to defects in serine-derived nucleotide synthesis and redox maintenance, another key aspect of serine metabolism, but result from disruption of mass balance within central carbon metabolism. Mechanistically, this leads to simultaneous alterations in both the pentose phosphate pathway and the tri-carboxylic acid cycle, as we demonstrate based on a quantitative model. These findings define a mechanism whereby disruption of one metabolic pathway induces toxicity by simultaneously affecting the activity of multiple related pathways.