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Cell Metabolism

Clara Bien Peek, Daniel C Levine, Jonathan Cedernaes, Akihiko Taguchi, Yumiko Kobayashi, Stacy J Tsai, Nicolle A Bonar, Maureen R McNulty, Kathryn Moynihan Ramsey, Joseph Bass
Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1(-/-) myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia...
October 19, 2016: Cell Metabolism
Yaarit Adamovich, Benjamin Ladeuix, Marina Golik, Maarten P Koeners, Gad Asher
The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1α-dependent manner...
October 19, 2016: Cell Metabolism
Yaling Wu, Dingbin Tang, Na Liu, Wei Xiong, Huanwei Huang, Yang Li, Zhixiong Ma, Haijiao Zhao, Peihao Chen, Xiangbing Qi, Eric Erquan Zhang
Circadian regulation is critically important in maintaining metabolic and physiological homeostasis. However, little is known about the possible influence of the clock on physiological abnormalities occurring under pathological conditions. Here, we report the discovery that hypoxia, a condition that causes catastrophic bodily damage, is gated by the circadian clock in vivo. Hypoxia signals conversely regulate the clock by slowing the circadian cycle and dampening the amplitude of oscillations in a dose-dependent manner...
October 14, 2016: Cell Metabolism
Mathias Wenes, Min Shang, Mario Di Matteo, Jermaine Goveia, Rosa Martín-Pérez, Jens Serneels, Hans Prenen, Bart Ghesquière, Peter Carmeliet, Massimiliano Mazzone
Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases...
October 13, 2016: Cell Metabolism
Xiaojing Liu, Iris L Romero, Lacey M Litchfield, Ernst Lengyel, Jason W Locasale
Repurposing metformin for cancer therapy is attractive due to its safety profile, epidemiological evidence, and encouraging data from human clinical trials. Although it is known to systemically affect glucose metabolism in liver, muscle, gut, and other tissues, the molecular determinants that predict a patient response in cancer remain unknown. Here, we carry out an integrative metabolomics analysis of metformin action in ovarian cancer. Metformin accumulated in patient biopsies, and pathways involving nucleotide metabolism, redox, and energy status, all related to mitochondrial metabolism, were affected in treated tumors...
October 12, 2016: Cell Metabolism
Dan Y Gui, Lucas B Sullivan, Alba Luengo, Aaron M Hosios, Lauren N Bush, Nadege Gitego, Shawn M Davidson, Elizaveta Freinkman, Craig J Thomas, Matthew G Vander Heiden
Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis...
October 12, 2016: Cell Metabolism
Sergio Guerrero-Castillo, Fabian Baertling, Daniel Kownatzki, Hans J Wessels, Susanne Arnold, Ulrich Brandt, Leo Nijtmans
Mitochondrial complex I is the largest integral membrane enzyme of the respiratory chain and consists of 44 different subunits encoded in the mitochondrial and nuclear genome. Its biosynthesis is a highly complicated and multifaceted process involving at least 14 additional assembly factors. How these subunits assemble into a functional complex I and where the assembly factors come into play is largely unknown. Here, we applied a dynamic complexome profiling approach to elucidate the assembly of human mitochondrial complex I and its further incorporation into respiratory chain supercomplexes...
September 30, 2016: Cell Metabolism
Kevin Man, Vassily I Kutyavin, Ajay Chawla
Evolution of metazoans resulted in the specialization of cellular and tissue function. This was accomplished by division of labor, which allowed tissue parenchymal cells to prioritize their core functions while ancillary functions were delegated to tissue accessory cells, such as immune, stromal, and endothelial cells. In metabolic organs, the accessory cells communicate with their clients, the tissue parenchymal cells, to optimize cellular processes, allowing organisms to adapt to changes in their environment...
September 21, 2016: Cell Metabolism
Jason D Arroyo, Alexis A Jourdain, Sarah E Calvo, Carmine A Ballarano, John G Doench, David E Root, Vamsi K Mootha
Oxidative phosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOS can arise from mutations in either mitochondrial or nuclear genomes and comprise the largest collection of inborn errors of metabolism. At present we lack a complete catalog of human genes and pathways essential for OXPHOS. Here we introduce a genome-wide CRISPR "death screen" that actively selects dying cells to reveal human genes required for OXPHOS, inspired by the classic observation that human cells deficient in OXPHOS survive in glucose but die in galactose...
September 9, 2016: Cell Metabolism
Gregory S Ducker, Joshua D Rabinowitz
One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense. Both within eukaryotic cells and across organs, 1C metabolic reactions are compartmentalized. Here we review the fundamentals of mammalian 1C metabolism, including the pathways active in different compartments, cell types, and biological states. Emphasis is given to recent discoveries enabled by modern genetics, analytical chemistry, and isotope tracing...
September 8, 2016: Cell Metabolism
Almut Brand, Katrin Singer, Gudrun E Koehl, Marlene Kolitzus, Gabriele Schoenhammer, Annette Thiel, Carina Matos, Christina Bruss, Sebastian Klobuch, Katrin Peter, Michael Kastenberger, Christian Bogdan, Ulrike Schleicher, Andreas Mackensen, Evelyn Ullrich, Stefan Fichtner-Feigl, Rebecca Kesselring, Matthias Mack, Uwe Ritter, Maximilian Schmid, Christian Blank, Katja Dettmer, Peter J Oefner, Petra Hoffmann, Stefan Walenta, Edward K Geissler, Jacques Pouyssegur, Andreas Villunger, André Steven, Barbara Seliger, Stephan Schreml, Sebastian Haferkamp, Elisabeth Kohl, Sigrid Karrer, Mark Berneburg, Wolfgang Herr, Wolfgang Mueller-Klieser, Kathrin Renner, Marina Kreutz
Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates...
September 7, 2016: Cell Metabolism
Nisebita Sahu, Darlene Dela Cruz, Min Gao, Wendy Sandoval, Peter M Haverty, Jinfeng Liu, Jean-Philippe Stephan, Benjamin Haley, Marie Classon, Georgia Hatzivassiliou, Jeff Settleman
The role of essential amino acids in metabolic reprogramming of cancer cells is now well established, whereas the role of non-essential amino acids (NEAAs) in malignancy remains less clear. Here, we have identified an important role for the NEAA proline in the tumorigenic potential of a subset of cancer cells. By profiling a large panel of cancer cell lines, we observed that proline consumption and expression of proline biosynthesis enzymes were well correlated with clonogenic and tumorigenic potential. Moreover, proline starvation or inhibition of proline biosynthesis enzymes impaired clonogenic/tumorigenic potential...
September 3, 2016: Cell Metabolism
Gregory S Ducker, Li Chen, Raphael J Morscher, Jonathan M Ghergurovich, Mark Esposito, Xin Teng, Yibin Kang, Joshua D Rabinowitz
No abstract text is available yet for this article.
October 11, 2016: Cell Metabolism
Yue J Wang, Maria L Golson, Jonathan Schug, Daniel Traum, Chengyang Liu, Kumar Vivek, Craig Dorrell, Ali Naji, Alvin C Powers, Kyong-Mi Chang, Markus Grompe, Klaus H Kaestner
The human endocrine pancreas consists of multiple cell types and plays a critical role in glucose homeostasis. Here, we apply mass cytometry technology to measure all major islet hormones, proliferative markers, and readouts of signaling pathways involved in proliferation at single-cell resolution. Using this innovative technology, we simultaneously examined baseline proliferation levels of all endocrine cell types from birth through adulthood, as well as in response to the mitogen harmine. High-dimensional analysis of our marker protein expression revealed three major clusters of beta cells within individuals...
October 11, 2016: Cell Metabolism
Evandro Fei Fang, Henok Kassahun, Deborah L Croteau, Morten Scheibye-Knudsen, Krisztina Marosi, Huiming Lu, Raghavendra A Shamanna, Sumana Kalyanasundaram, Ravi Chand Bollineni, Mark A Wilson, Wendy B Iser, Bradley N Wollman, Marya Morevati, Jun Li, Jesse S Kerr, Qiping Lu, Tyler B Waltz, Jane Tian, David A Sinclair, Mark P Mattson, Hilde Nilsen, Vilhelm A Bohr
Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD(+), and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD(+) reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models...
October 11, 2016: Cell Metabolism
Maxime Janin, Manel Esteller
Mutations to the Krebs cycle enzyme fumarate hydratase in cancer cells leads to an accumulation of the oncometabolite fumarate. Sciacovelli et al. (2016) demonstrate an epigenetically dependent epithelial-to-mesenchymal transition mediated by modulation of the miR-200 cluster and TET demethylation in response to fumarate accumulation.
October 11, 2016: Cell Metabolism
Leonard Guarente
In this issue, Fang et al. (2016) show that both the DNA repair defect and mitochondrial dysfunction in ATM(-/-) cells or mice are mitigated by the anti-aging compound nicotinamide riboside or a SIRT1 activator. This broad suppression by activating the NAD(+)/SIRT1 axis may generally apply to diseases and aging maladies.
October 11, 2016: Cell Metabolism
José Antonio Enríquez, Fátima Sánchez-Cabo, Jesús Vázquez
Two independent investigations based on the power of yeast genetics, but using radically different discovery-driven approaches, have solved a long-pursued goal: the understanding of the early steps in CoQ biosynthesis, which may help diagnose CoQ deficiencies of unknown origin (Payet et al., 2016; Stefely et al., 2016).
October 11, 2016: Cell Metabolism
Rashmi B Prasad, Leif Groop
RNA sequencing of human pancreatic islets has provided important insights into the islet transcriptome but little information on the specific cells. In this issue, Segerstolpe et al. (2016) and Xin et al. (2016b) report on the transcriptome of single pancreatic cells from non-diabetic and type 2 diabetic donors.
October 11, 2016: Cell Metabolism
Chen-Song Zhang, Mengqi Li, Teng Ma, Yue Zong, Jiwen Cui, Jin-Wei Feng, Yu-Qing Wu, Shu-Yong Lin, Sheng-Cai Lin
No abstract text is available yet for this article.
October 11, 2016: Cell Metabolism
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