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Cell Metabolism

Sung Min Son, So Jung Park, Huikyong Lee, Farah Siddiqi, Jong Eun Lee, Fiona M Menzies, David C Rubinsztein
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and metabolism. Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Here we describe that the Leu metabolite acetyl-coenzyme A (AcCoA) positively regulates mTORC1 activity by EP300-mediated acetylation of the mTORC1 regulator, Raptor, at K1097. Leu metabolism and consequent mTORC1 activity are regulated by intermediary enzymes. As AcCoA is a Leu metabolite, this process directly correlates with Leu abundance, and does not require Leu sensing via intermediary proteins, as has been described previously...
August 30, 2018: Cell Metabolism
Sara Ricciardi, Nicola Manfrini, Roberta Alfieri, Piera Calamita, Maria Cristina Crosti, Gallo Simone, Rolf Müller, Massimiliano Pagani, Sergio Abrignani, Stefano Biffo
Naive T cells respond to T cell receptor (TCR) activation by leaving quiescence, remodeling metabolism, initiating expansion, and differentiating toward effector T cells. The molecular mechanisms coordinating the naive to effector transition are central to the functioning of the immune system, but remain elusive. Here, we discover that T cells fulfill this transitional process through translational control. Naive cells accumulate untranslated mRNAs encoding for glycolysis and fatty acid synthesis factors and possess translational machinery poised for immediate protein synthesis...
August 29, 2018: Cell Metabolism
Marion Curtis, Hilary A Kenny, Bradley Ashcroft, Abir Mukherjee, Alyssa Johnson, Yilin Zhang, Ynes Helou, Raquel Batlle, Xiaojing Liu, Nuria Gutierrez, Xia Gao, S Diane Yamada, Ricardo Lastra, Anthony Montag, Nagib Ahsan, Jason W Locasale, Arthur R Salomon, Angel R Nebreda, Ernst Lengyel
Successful metastasis requires the co-evolution of stromal and cancer cells. We used stable isotope labeling of amino acids in cell culture coupled with quantitative, label-free phosphoproteomics to study the bidirectional signaling in ovarian cancer cells and human-derived, cancer-associated fibroblasts (CAFs) after co-culture. In cancer cells, the interaction with CAFs supported glycogenolysis under normoxic conditions and induced phosphorylation and activation of phosphoglucomutase 1, an enzyme involved in glycogen metabolism...
August 28, 2018: Cell Metabolism
Sarah J Mitchell, Michel Bernier, Julie A Mattison, Miguel A Aon, Tamzin A Kaiser, R Michael Anson, Yuji Ikeno, Rozalyn M Anderson, Donald K Ingram, Rafael de Cabo
The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens...
August 24, 2018: Cell Metabolism
Salvatore Fabbiano, Nicolas Suárez-Zamorano, Claire Chevalier, Vladimir Lazarević, Silas Kieser, Dorothée Rigo, Stefano Leo, Christelle Veyrat-Durebex, Nadia Gaïa, Marcello Maresca, Doron Merkler, Mercedes Gomez de Agüero, Andrew Macpherson, Jacques Schrenzel, Mirko Trajkovski
Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals...
August 24, 2018: Cell Metabolism
Meagan J McManus, Martin Picard, Hsiao-Wen Chen, Hans J De Haas, Prasanth Potluri, Jeremy Leipzig, Atif Towheed, Alessia Angelin, Partho Sengupta, Ryan M Morrow, Brett A Kauffman, Marc Vermulst, Jagat Narula, Douglas C Wallace
Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4-/- null mutation with a homoplasmic mtDNA ND6P25L or COIV421A variant...
August 23, 2018: Cell Metabolism
Maria Apicella, Elisa Giannoni, Stephany Fiore, Karin Johanna Ferrari, Daniel Fernández-Pérez, Claudio Isella, Carlotta Granchi, Filippo Minutolo, Antonino Sottile, Paolo Maria Comoglio, Enzo Medico, Filippo Pietrantonio, Marco Volante, Diego Pasini, Paola Chiarugi, Silvia Giordano, Simona Corso
The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner...
August 23, 2018: Cell Metabolism
Zhongfu Ying, Ge Xiang, Lingjun Zheng, Haite Tang, Lifan Duan, Xiaobing Lin, Qiuge Zhao, Keshi Chen, Yi Wu, Guangsuo Xing, Yiwang Lv, Linpeng Li, Liang Yang, Feixiang Bao, Qi Long, Yanshuang Zhou, Xueying He, Yaofeng Wang, Minghui Gao, Duanqing Pei, Wai-Yee Chan, Xingguo Liu
Reprogramming of somatic cells to induced pluripotent stem cells reconfigures chromatin modifications. Whether and how this process is regulated by signals originating in the mitochondria remain unknown. Here we show that the mitochondrial permeability transition pore (mPTP), a key regulator of mitochondrial homeostasis, undergoes short-term opening during the early phase of reprogramming and that this transient activation enhances reprogramming. In mouse embryonic fibroblasts, greater mPTP opening correlates with higher reprogramming efficiency...
August 23, 2018: Cell Metabolism
Kiran Kurmi, Sadae Hitosugi, Jia Yu, Felix Boakye-Agyeman, Elizabeth K Wiese, Thomas R Larson, Qing Dai, Yuichi J Machida, Zhenkun Lou, Liewei Wang, Judy C Boughey, Scott H Kaufmann, Matthew P Goetz, Larry M Karnitz, Taro Hitosugi
How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2+ breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. Inhibition of the phosphocreatine energy shuttle by MtCK1 knockdown or with the creatine analog cyclocreatine decreases proliferation of trastuzumab-sensitive and -resistant HER2+ cell lines in culture and in xenografts...
August 23, 2018: Cell Metabolism
Sue Tsai, Xavier Clemente-Casares, Angela C Zhou, Helena Lei, Jennifer J Ahn, Yi Tao Chan, Okmi Choi, Helen Luck, Minna Woo, Shannon E Dunn, Edgar G Engleman, Tania H Watts, Shawn Winer, Daniel A Winer
T cells represent a critical effector of cell-mediated immunity. Activated T cells engage in metabolic reprogramming during effector differentiation to accommodate dynamic changes in energy demands. Here, we show that the hormone, insulin, and downstream signaling through its insulin receptor shape adaptive immune function through modulating T cell metabolism. T cells lacking insulin receptor expression (LckCre+ Insrfl/fl ) show reduced antigen-specific proliferation and compromised production of pro-inflammatory cytokines...
August 22, 2018: Cell Metabolism
Kevin D Courtney, Divya Bezwada, Tomoyuki Mashimo, Kumar Pichumani, Vamsidhara Vemireddy, Alexander M Funk, Jennifer Wimberly, Sarah S McNeil, Payal Kapur, Yair Lotan, Vitaly Margulis, Jeffrey A Cadeddu, Ivan Pedrosa, Ralph J DeBerardinis, Craig R Malloy, Robert M Bachoo, Elizabeth A Maher
Clear cell renal cell carcinoma (ccRCC) is the most common form of human kidney cancer. Histological and molecular analyses suggest that ccRCCs have significantly altered metabolism. Recent human studies of lung cancer and intracranial malignancies demonstrated an unexpected preservation of carbohydrate oxidation in the tricarboxylic acid (TCA) cycle. To test the capacity of ccRCC to oxidize substrates in the TCA cycle, we infused 13 C-labeled fuels in ccRCC patients and compared labeling patterns in tumors and adjacent kidney...
August 21, 2018: Cell Metabolism
Ulrike Bruning, Francisco Morales-Rodriguez, Joanna Kalucka, Jermaine Goveia, Federico Taverna, Karla C S Queiroz, Charlotte Dubois, Anna Rita Cantelmo, Rongyuan Chen, Stefan Loroch, Evy Timmerman, Vanessa Caixeta, Katarzyna Bloch, Lena-Christin Conradi, Lucas Treps, An Staes, Kris Gevaert, Andrew Tee, Mieke Dewerchin, Clay F Semenkovich, Francis Impens, Birgit Schilling, Eric Verdin, Johannes V Swinnen, Jordan L Meier, Rhushikesh A Kulkarni, Albert Sickmann, Bart Ghesquière, Luc Schoonjans, Xuri Li, Massimiliano Mazzone, Peter Carmeliet
The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD ) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218)...
August 21, 2018: Cell Metabolism
Joanna Kalucka, Laura Bierhansl, Nadine Vasconcelos Conchinha, Rindert Missiaen, Ilaria Elia, Ulrike Brüning, Samantha Scheinok, Lucas Treps, Anna Rita Cantelmo, Charlotte Dubois, Pauline de Zeeuw, Jermaine Goveia, Annalisa Zecchin, Federico Taverna, Francisco Morales-Rodriguez, Aleksandra Brajic, Lena-Christin Conradi, Sandra Schoors, Ulrike Harjes, Kim Vriens, Gregor-Alexander Pilz, Rongyuan Chen, Richard Cubbon, Bernard Thienpont, Bert Cruys, Brian W Wong, Bart Ghesquière, Mieke Dewerchin, Katrien De Bock, Xavier Sagaert, Sebastian Jessberger, Elizabeth A V Jones, Bernard Gallez, Diether Lambrechts, Massimiliano Mazzone, Guy Eelen, Xuri Li, Sarah-Maria Fendt, Peter Carmeliet
Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration...
August 20, 2018: Cell Metabolism
Giuseppe D'Agostino, David Lyons, Claudia Cristiano, Miriam Lettieri, Cristian Olarte-Sanchez, Luke K Burke, Megan Greenwald-Yarnell, Celine Cansell, Barbora Doslikova, Teodora Georgescu, Pablo Blanco Martinez de Morentin, Martin G Myers, Justin J Rochford, Lora K Heisler
To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2C R) improve obesity. Here we probed the functional significance of 5-HT2C Rs specifically within the brainstem nucleus of the solitary tract (5-HT2C RNTS ) in feeding behavior. Selective activation of 5-HT2C RNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2C R agonist obesity medication lorcaserin...
August 20, 2018: Cell Metabolism
Amandine Chaix, Terry Lin, Hiep D Le, Max W Chang, Satchidananda Panda
Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the idea that a molecular clock is necessary for metabolic homeostasis. However, these mice often lack a normal feeding-fasting cycle. We tested whether time-restricted feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2 and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic defects...
August 17, 2018: Cell Metabolism
H Furkan Alkan, Katharina E Walter, Alba Luengo, Corina T Madreiter-Sokolowski, Sarah Stryeck, Allison N Lau, Wael Al-Zoughbi, Caroline A Lewis, Craig J Thomas, Gerald Hoefler, Wolfgang F Graier, Tobias Madl, Matthew G Vander Heiden, Juliane G Bogner-Strauss
Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839...
August 14, 2018: Cell Metabolism
Carly S Cox, Sharen E McKay, Marissa A Holmbeck, Brooke E Christian, Andrew C Scortea, Annie J Tsay, Laura E Newman, Gerald S Shadel
Transient mitochondrial stress can promote beneficial physiological responses and longevity, termed "mitohormesis." To interrogate mitohormetic pathways in mammals, we generated mice in which mitochondrial superoxide dismutase 2 (SOD2) can be knocked down in an inducible and reversible manner (iSOD2-KD mice). Depleting SOD2 only during embryonic development did not cause post-natal lethality, allowing us to probe adaptive responses to mitochondrial oxidant stress in adult mice. Liver from adapted mice had increased mitochondrial biogenesis and antioxidant gene expression and fewer reactive oxygen species...
August 13, 2018: Cell Metabolism
Rubén Cereijo, Aleix Gavaldà-Navarro, Montserrat Cairó, Tania Quesada-López, Joan Villarroya, Samantha Morón-Ros, David Sánchez-Infantes, Marion Peyrou, Roser Iglesias, Teresa Mampel, Jean-Valery Turatsinze, Décio L Eizirik, Marta Giralt, Francesc Villarroya
The beneficial effects of brown adipose tissue (BAT) are attributed to its capacity to oxidize metabolites and produce heat, but recent data suggest that secretory properties of BAT may also be involved. Here, we identify the chemokine CXCL14 (C-X-C motif chemokine ligand-14) as a novel regulatory factor secreted by BAT in response to thermogenic activation. We found that the CXCL14 released by brown adipocytes recruited alternatively activated (M2) macrophages. Cxcl14-null mice exposed to cold showed impaired BAT activity and low recruitment of macrophages, mainly of the M2 phenotype, into BAT...
August 10, 2018: Cell Metabolism
Sukru Anil Dogan, Raffaele Cerutti, Cristiane Benincá, Gloria Brea-Calvo, Howard Trevor Jacobs, Massimo Zeviani, Marten Szibor, Carlo Viscomi
Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O2 . They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses...
August 9, 2018: Cell Metabolism
Mylène Tajan, Andreas K Hock, Julianna Blagih, Neil A Robertson, Christiaan F Labuschagne, Flore Kruiswijk, Timothy J Humpton, Peter D Adams, Karen H Vousden
Numerous mechanisms to support cells under conditions of transient nutrient starvation have been described. Several functions of the tumor-suppressor protein p53 can contribute to the adaptation of cells to metabolic stress and help cancer cell survival under nutrient-limiting conditions. We show here that p53 promotes the expression of SLC1A3, an aspartate/glutamate transporter that allows the utilization of aspartate to support cells in the absence of extracellular glutamine. Under glutamine deprivation, SLC1A3 expression maintains electron transport chain and tricarboxylic acid cycle activity, promoting de novo glutamate, glutamine, and nucleotide synthesis to rescue cell viability...
August 8, 2018: Cell Metabolism
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