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Walter A Baseler, Luke C Davies, Laura Quigley, Lisa A Ridnour, Jonathan M Weiss, S Perwez Hussain, David A Wink, Daniel W McVicar
Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, "alternatively activated" macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments...
September 16, 2016: Redox Biology
Ekta Lachmandas, Macarena Beigier-Bompadre, Shih-Chin Cheng, Vinod Kumar, Arjan van Laarhoven, Xinhui Wang, Anne Ammerdorffer, Lily Boutens, Dirk de Jong, Thirumala-Devi Kanneganti, Mark S Gresnigt, Tom H M Ottenhoff, Leo A B Joosten, Rinke Stienstra, Cisca Wijmenga, Stefan H E Kauffman, Reinout van Crevel, Mihai G Netea
Cells in homeostasis metabolise glucose mainly through the tri-carboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), whilst activated cells switch their basal metabolism to aerobic glycolysis. In thus study, we examined whether metabolic reprogramming towards aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism towards aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs)...
September 14, 2016: European Journal of Immunology
Aaron Boudreau, Hans E Purkey, Anna Hitz, Kirk Robarge, David Peterson, Sharada Labadie, Mandy Kwong, Rebecca Hong, Min Gao, Christopher Del Nagro, Raju Pusapati, Shuguang Ma, Laurent Salphati, Jodie Pang, Aihe Zhou, Tommy Lai, Yingjie Li, Zhongguo Chen, Binqing Wei, Ivana Yen, Steve Sideris, Mark McCleland, Ron Firestein, Laura Corson, Alex Vanderbilt, Simon Williams, Anneleen Daemen, Marcia Belvin, Charles Eigenbrot, Peter K Jackson, Shiva Malek, Georgia Hatzivassiliou, Deepak Sampath, Marie Evangelista, Thomas O'Brien
Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin...
October 2016: Nature Chemical Biology
Jennifer L McQuade, Yn Vashisht Gopal
Mitochondrial oxidative phosphorylation (OxPhos) induces resistance to MAPK pathway inhibitors in melanoma. However, therapeutic targeting of mitochondria is challenging. In a recent study, we showed that inhibition of mTOR kinase activity resensitized resistant melanomas by indirectly inhibiting OxPhos via a novel mechanism. Here, we discuss the implications of these findings.
July 2015: Molecular & Cellular Oncology
Xintao Cao, Yan Qin
Mitochondria are semi-autonomous organelle possessing their own translation machinery to biosynthesize mitochondrial DNA (mtDNA)-encoded polypeptides, which are the core subunits of oxidative phosphorylation (OXPHOS) complexes. Mitochondrial translation elongation factor 4 (mtEF4) is a key quality control factor in mitochondrial translation (mt-translation) that regulates mitochondrial tRNA translocation and modulates cellular responses by influencing cytoplasmic translation (ct-translation). In addition to mtEF4, mt-translational activators, mitochondrial microRNAs (mitomiRs), and MITRAC have been reported recently as crucial mt-translation regulators...
April 19, 2016: Free Radical Biology & Medicine
Wasakorn Kittipongdaja, Xuesong Wu, Justine Garner, Xiping Liu, Steven M Komas, Sam T Hwang, Stefan M Schieke
The mTOR pathway is a master regulator of cellular growth and metabolism. The biosynthetic and energetic demand of rapidly proliferating cells such as cancer cells is met by metabolic adaptations such as an increased glycolytic rate known as the Warburg effect. Herein, we characterize the anti-tumor effect of rapamycin in a mouse model of T-cell lymphoma and examine the metabolic effects in vitro. The murine T-cell lymphoma line, MBL2, and human cutaneous T-cell lymphoma (CTCL) lines, HH and Hut78, were used in syngeneic or standard NSG mouse models to demonstrate a marked suppression of tumor growth by rapamycin accompanied by inhibition of mTORC1/2...
September 2015: Journal of Investigative Dermatology
Gabriela Bomfim Ferreira, An-Sofie Vanherwegen, Guy Eelen, Ana Carolina Fierro Gutiérrez, Leentje Van Lommel, Kathleen Marchal, Lieve Verlinden, Annemieke Verstuyf, Tatiane Nogueira, Maria Georgiadou, Frans Schuit, Décio L Eizirik, Conny Gysemans, Peter Carmeliet, Lut Overbergh, Chantal Mathieu
Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)2D3 upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)2D3, hypoxia did not change the tolerogenic function of 1,25(OH)2D3-treated DCs...
February 4, 2015: Cell Reports
Hélène Pelicano, Wan Zhang, Jinyun Liu, Naima Hammoudi, Jiale Dai, Rui-Hua Xu, Lajos Pusztai, Peng Huang
INTRODUCTION: Triple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. TNBC is not amenable to endocrine therapy and often exhibit resistance to current chemotherapeutic agents, therefore, further understanding of the biological properties of these cancer cells and development of effective therapeutic approaches are urgently needed. METHODS: We first investigated the metabolic alterations in TNBC cells in comparison with other subtypes of breast cancer cells using molecular and metabolic analyses...
2014: Breast Cancer Research: BCR
Olga V Leontieva, Mikhail V Blagosklonny
A groundbreaking publication by Sinclair and coworkers has illuminated the pseudo-hypoxic state in aging and its reversibility. Remarkably, these data also fit the mTOR-centered model of aging. Here we discuss that the mTOR pathway can cause cellular pseudo-hypoxic state, manifested by HIF-1 expression and lactate production under normoxia. We found that rapamycin decreased HIF-1 and lactate levels in proliferating and senescent cells in vitro. This reduction was independent from mitochondrial respiration: rapamycin decreased lactate production in normoxia, hypoxia, and in the presence of the OXPHOS inhibitor oligomycin...
2014: Cell Cycle
Sharon M Blättler, Francisco Verdeguer, Marc Liesa, John T Cunningham, Rutger O Vogel, Helen Chim, Huifei Liu, Klaas Romanino, Orian S Shirihai, Francisca Vazquez, Markus A Rüegg, Yang Shi, Pere Puigserver
The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature...
August 2012: Molecular and Cellular Biology
Elizabeth A Mazzio, Nawal Boukli, Nery Rivera, Karam F A Soliman
The Warburg effect describes a heightened propensity of tumor cells to produce lactic acid in the presence or absence of O(2) . A generally held notion is that the Warburg effect is related to energy. Using whole-genome, proteomic MALDI-TOF-MS and metabolite analysis, we investigated the Warburg effect in malignant neuroblastoma N2a cells. The findings show that the Warburg effect serves a functional role in regulating acidic pericellular pH (pHe), which is mediated by metabolic inversion or a fluctuating dominance between glycolytic-rate substrate level phosphorylation (SLP) and mitochondrial (mt) oxidative phosphorylation (OXPHOS) to control lactic acid production...
March 2012: Cancer Science
Xing-ding Zhang, Zheng-hong Qin, Jin Wang
The p53 tumor suppressor gene has recently been shown to mediate metabolic changes in cells under physiological and pathological conditions. It has been revealed that p53 regulates energy metabolism, oxidative stress, and amino acid metabolism through balancing glycolysis and oxidative phosphorylation (OXPHOS) as well as the autophagy pathway. p53 is activated by metabolic stress through AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) signaling pathways. p53 regulates OXPHOS through the transcriptional regulation of fructose-2,6-bisphosophatase, TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2) subunit of complex IV of the electron transport chain...
September 2010: Acta Pharmacologica Sinica
Petr Jezek, Lydie Plecitá-Hlavatá, Katarína Smolková, Rodrigue Rossignol
In this review we compare situations under which the major cellular role of mitochondria, oxidative phosphorylation (OXPHOS), is transiently suppressed. Two types of cellular bioenergetics exist, related to the predominance of glycolysis either disconnected or fully connected to OXPHOS: i) "glycolytic" phenotype, when the glycolytic end-product pyruvate is marginally used for OXPHOS; and, ii) OXPHOS phenotype with fully developed and active OXPHOS machinery consuming all pyruvate. A switch to glycolytic phenotype is typically orchestrated by gene reprogramming due to AMP-activated protein kinase, hypoxia-induced factor (HIF), NFkappaB, mTOR, and by oncogenes...
May 2010: International Journal of Biochemistry & Cell Biology
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