Metabolic regulation: fasting in the dark

It is natural to starve. Learning how animals cope by juggling their scarce metabolic resources should therefore allow us to pinpoint physiological switches relevant to diabetes and cardiovascular disease. One known environmental trigger to metabolic adaptation is darkness; new studies suggest its endocrine mediator is 5' AMP.     

Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis

Increased glutaminolysis is now recognized as a key feature of the metabolic profile of cancer cells, along with increased aerobic glycolysis (the Warburg effect). In this review, we discuss the roles of glutamine in contributing to the core metabolism of proliferating cells by supporting energy production and biosynthesis. We address how oncogenes and tumor suppressors regulate glutamine metabolism and how cells coordinate glucose and glutamine as nutrient sources. Finally, we highlight the novel therapeutic and imaging applications that are emerging as a result of our improved understanding of the role of glutamine metabolism in cancer.     

Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma

Cancer stem cells (CSCs) represent a subpopulation of tumor cells endowed with self-renewal capacity and are considered as an underlying cause of tumor recurrence and metastasis. The metabolic signatures of CSCs and the mechanisms involved in the regulation of their stem cell-like properties still remain elusive. We utilized nasopharyngeal carcinoma (NPC) CSCs as a model to dissect their metabolic signatures and found that CSCs underwent metabolic shift and mitochondrial resetting distinguished from their differentiated counterparts. In metabolic shift, CSCs showed a greater reliance on glycolysis for energy supply compared with the parental cells. In mitochondrial resetting, the quantity and function of mitochondria of CSCs were modulated by the biogenesis of the organelles, and the round-shaped mitochondria were distributed in a peri-nuclear manner similar to those seen in the stem cells. In addition, we blocked the glycolytic pathway, increased the ROS levels, and depolarized mitochondrial membranes of CSCs, respectively, and examined the effects of these metabolic factors on CSC properties. Intriguingly, the properties of CSCs were curbed when we redirected the quintessential metabolic reprogramming, which indicates that the plasticity of energy metabolism regulated the balance between acquisition and loss of the stemness status. Taken together, we suggest that metabolic reprogramming is critical for CSCs to sustain self-renewal, deter from differentiation and enhance the antioxidant defense mechanism. Characterization of metabolic reprogramming governing CSC properties is paramount to the design of novel therapeutic strategies through metabolic intervention of CSCs.     

Metabolic engineering in dark fermentative hydrogen production; theory and practice

Dark fermentation is an attractive option for hydrogen production since it could use already existing reactor technology and readily available substrates without requiring a direct input of solar energy. However, a number of improvements are required before the rates and yields of such a process approach those required for a practical process. Among the options for achieving the required advances, metabolic engineering offers some powerful tools for remodeling microbes to increase product production rates and molar yields. Here we review the current metabolic engineering tool box that is available, discuss the current status of engineering efforts as applied to dark hydrogen production, and suggest areas for future improvements.     

Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma

Cancer stem cells (CSCs) represent a subpopulation of tumor cells endowed with self-renewal capacity and are considered as an underlying cause of tumor recurrence and metastasis. The metabolic signatures of CSCs and the mechanisms involved in the regulation of their stem cell-like properties still remain elusive. We utilized nasopharyngeal carcinoma (NPC) CSCs as a model to dissect their metabolic signatures and found that CSCs underwent metabolic shift and mitochondrial resetting distinguished from their differentiated counterparts. In metabolic shift, CSCs showed a greater reliance on glycolysis for energy supply compared with the parental cells. In mitochondrial resetting, the quantity and function of mitochondria of CSCs were modulated by the biogenesis of the organelles, and the round-shaped mitochondria were distributed in a peri-nuclear manner similar to those seen in the stem cells. In addition, we blocked the glycolytic pathway, increased the ROS levels, and depolarized mitochondrial membranes of CSCs, respectively, and examined the effects of these metabolic factors on CSC properties. Intriguingly, the properties of CSCs were curbed when we redirected the quintessential metabolic reprogramming, which indicates that the plasticity of energy metabolism regulated the balance between acquisition and loss of the stemness status. Taken together, we suggest that metabolic reprogramming is critical for CSCs to sustain self-renewal, deter from differentiation and enhance the antioxidant defense mechanism. Characterization of metabolic reprogramming governing CSC properties is paramount to the design of novel therapeutic strategies through metabolic intervention of CSCs.     

Metabolic reprogramming enables hepatocarcinoma cells to efficiently adapt and survive to a nutrient-restricted microenvironment

Hepatocellular carcinoma (HCC) is a metabolically heterogeneous cancer and the use of glucose by HCC cells could impact their tumorigenicity. Dt81Hepa1-6 cells display enhanced tumorigenicity compared to parental Hepa1-6 cells. This increased tumorigenicity could be explained by a metabolic adaptation to more restrictive microenvironments. When cultured at high glucose concentrations, Dt81Hepa1-6 displayed an increased ability to uptake glucose (P<0.001), increased expression of 9 glycolytic genes, greater GTP and ATP (P<0.001), increased expression of 7 fatty acid synthesis-related genes (P<0.01) and higher levels of Acetyl-CoA, Citrate and Malonyl-CoA (P<0.05). Under glucose-restricted conditions, Dt81Hepa1-6 used their stored fatty acids with increased expression of fatty acid oxidation-related genes (P<0.01), decreased triglyceride content (P<0.05) and higher levels of GTP and ATP (P<0.01) leading to improved proliferation (P<0.05). Inhibition of lactate dehydrogenase and aerobic glycolysis with sodium oxamate led to decreased expression of glycolytic genes, reduced lactate, GTP and ATP levels (P<0.01), increased cell doubling time (P<0.001) and reduced fatty acid synthesis. When combined with cisplatin, this inhibition led to lower cell viability and proliferation (P<0.05). This metabolic-induced tumorigenicity was also reflected in human Huh7 cells by a higher glucose uptake and proliferative capacity compared to HepG2 cells (P<0.05). In HCC patients, increased tumoral expression of Glut-1, Hexokinase II and Lactate dehydrogenase correlated with poor survival (P = 2.47E^?5, P = 0.016 and P = 6.58E^?5). In conclusion, HCC tumorigenicity can stem from a metabolic plasticity allowing them to thrive in a broader range of glucose concentrations. In HCC, combining glycolytic inhibitors with conventional chemotherapy could lead to improved treatment efficacy.     

Nuclear actin in transcriptional reprogramming by oocytes

Comment on: Miyamoto K, et al. Genes Dev 2011; 25:946-58.     

Metabolic reprogramming in response to cold stress is like real estate,it's all about location

This article comments on: Subcellular reprogramming of metabolism during cold acclimation in Arabidopsis thaliana     

Cohesin's role in pluripotency and reprogramming

Cohesin is required for ES cell self-renewal and iPS-mediated reprogramming of somatic cells. This may indicate a special role for cohesin in the regulation of pluripotency genes, perhaps by mediating long-range chromosomal interactions between gene regulatory elements. However, cohesin is also essential for genome integrity, and its depletion from cycling cells induces DNA damage responses. Hence, the failure of cohesin-depleted cells to establish or maintain pluripotency gene expression could be explained by a loss of long-range interactions or by DNA damage responses that undermine pluripotency gene expression. In recent work we began to disentangle these possibilities by analyzing reprogramming in the absence of cell division. These experiments showed that cohesin was not specifically required for reprogramming, and that the expression of most pluripotency genes was maintained when ES cells were acutely depleted of cohesin. Here we take this analysis to its logical conclusion by demonstrating that deliberately inflicted DNA damage - and the DNA damage that results from proliferation in the absence of cohesin - can directly interfere with pluripotency and reprogramming. The role of cohesin in pluripotency and reprogramming may therefore be best explained by essential cohesin functions in the cell cycle.     

Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses

Double-stranded RNA (dsRNA) longer than 30 bp is a key activator of the innate immune response against viral infections. It is widely assumed that the generation of dsRNA during genome replication is a trait shared by all viruses. However, to our knowledge, no study exists in which the production of dsRNA by different viruses is systematically investigated. Here, we investigated the presence and localization of dsRNA in cells infected with a range of viruses, employing a dsRNA-specific antibody for immunofluorescence analysis. Our data revealed that, as predicted, significant amounts of dsRNA can be detected for viruses with a genome consisting of positive-strand RNA, dsRNA, or DNA. Surprisingly, however, no dsRNA signals were detected for negative-strand RNA viruses. Thus, dsRNA is indeed a general feature of most virus groups, but negative-strand RNA viruses appear to be an exception to that rule.     

细胞融合致体细胞重编程机制研究进展

已分化的体细胞能够通过重编程转化回多能干细胞,在细胞移植、疾病细胞模型的制备以及药物筛选等领域具有重要意义。通过干细胞和体细胞的细胞融合,可使体细胞重编程。细胞融合致体细胞重编程速度快、效率高,是一种研究重编程机制的重要手段。对细胞融合致体细胞重编程的机制作一综述。     

Getting to the core of repeat expansions by cell reprogramming

In this issue of Cell Stem Cell, Ku et?al. (2010) demonstrate that iPSCS derived from Friedreich's ataxia patients exhibit expansion of the causative (GAA)(n) repeat, consistent with the repeat instability observed during intergenerational transmissions in humans. Furthermore, the epigenetic signature of the disease remains intact in Friedreich's ataxia iPSCs.