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  • 1
    Publication Date: 2016-03-31
    Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027295" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-03-17
    Description: The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1alpha, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1alpha(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1alpha(-/-) mice. Inducible tubular transgenic mice (iNephPGC1alpha) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1alpha coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1alpha deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product beta-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of beta-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1alpha-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1alpha-dependent stress resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tran, Mei T -- Zsengeller, Zsuzsanna K -- Berg, Anders H -- Khankin, Eliyahu V -- Bhasin, Manoj K -- Kim, Wondong -- Clish, Clary B -- Stillman, Isaac E -- Karumanchi, S Ananth -- Rhee, Eugene P -- Parikh, Samir M -- K08-DK090142/DK/NIDDK NIH HHS/ -- K08-DK101560/DK/NIDDK NIH HHS/ -- P30-DK079337/DK/NIDDK NIH HHS/ -- R01 DK095072/DK/NIDDK NIH HHS/ -- R01-DK095072/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 24;531(7595):528-32. doi: 10.1038/nature17184. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Clinical Chemistry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Bioinformatics and Systems Biology Core, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Nephrology and Endocrine Divisions, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02139, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982719" target="_blank"〉PubMed〈/a〉
    Keywords: 3-Hydroxybutyric Acid/metabolism ; Acute Kidney Injury/drug therapy/*metabolism ; Adipose Tissue/drug effects/metabolism ; Amino Acids/metabolism ; Animals ; Cytokines/metabolism ; Dinoprostone/biosynthesis/metabolism ; Humans ; Ischemia/drug therapy/metabolism ; Kidney/drug effects/*metabolism/physiology/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; NAD/*biosynthesis ; Niacinamide/deficiency/pharmacology/therapeutic use ; Nicotinamide Phosphoribosyltransferase/metabolism ; Oxidation-Reduction ; Signal Transduction/drug effects ; Stress, Physiological ; Transcription Factors/deficiency/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-05-26
    Description: Metabolic reprogramming has been proposed to be a hallmark of cancer, yet a systematic characterization of the metabolic pathways active in transformed cells is currently lacking. Using mass spectrometry, we measured the consumption and release (CORE) profiles of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated these data with a preexisting atlas of gene expression. This analysis identified glycine consumption and expression of the mitochondrial glycine biosynthetic pathway as strongly correlated with rates of proliferation across cancer cells. Antagonizing glycine uptake and its mitochondrial biosynthesis preferentially impaired rapidly proliferating cells. Moreover, higher expression of this pathway was associated with greater mortality in breast cancer patients. Increased reliance on glycine may represent a metabolic vulnerability for selectively targeting rapid cancer cell proliferation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526189/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526189/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jain, Mohit -- Nilsson, Roland -- Sharma, Sonia -- Madhusudhan, Nikhil -- Kitami, Toshimori -- Souza, Amanda L -- Kafri, Ran -- Kirschner, Marc W -- Clish, Clary B -- Mootha, Vamsi K -- K08 HL107451/HL/NHLBI NIH HHS/ -- K08HL107451/HL/NHLBI NIH HHS/ -- R01 DK081457/DK/NIDDK NIH HHS/ -- R01 GM026875/GM/NIGMS NIH HHS/ -- R01DK081457/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2012 May 25;336(6084):1040-4. doi: 10.1126/science.1218595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22628656" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/genetics/metabolism/pathology ; Cell Cycle ; Cell Line ; Cell Line, Tumor ; *Cell Proliferation ; Cell Transformation, Neoplastic ; Chromatography, Liquid ; Culture Media ; Gene Expression ; Gene Expression Profiling ; Glycine/biosynthesis/*metabolism ; Humans ; Metabolic Networks and Pathways/genetics ; Metabolome ; Mitochondria/enzymology/metabolism ; Neoplasms/genetics/*metabolism/*pathology ; Purines/biosynthesis ; Tandem Mass Spectrometry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-03-29
    Description: As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012432/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012432/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Birsoy, Kivanc -- Possemato, Richard -- Lorbeer, Franziska K -- Bayraktar, Erol C -- Thiru, Prathapan -- Yucel, Burcu -- Wang, Tim -- Chen, Walter W -- Clish, Clary B -- Sabatini, David M -- AI07389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- K99 CA168940/CA/NCI NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R00 CA168940/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 3;508(7494):108-12. doi: 10.1038/nature13110. Epub 2014 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [5]. ; Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670634" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Biguanides/*pharmacology ; Cell Culture Techniques/instrumentation/methods ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Culture Media/chemistry/*metabolism/*pharmacology ; DNA, Mitochondrial/genetics ; Electron Transport Complex I/deficiency/genetics/metabolism ; Glucose/*deficiency/metabolism/pharmacology ; Humans ; Hypoglycemic Agents/pharmacology ; Male ; Mice ; Mitochondria/genetics/metabolism ; Molecular Typing ; Mutation ; Neoplasm Transplantation ; Neoplasms/drug therapy/*metabolism/pathology ; Oxidative Phosphorylation/drug effects ; Phenformin/pharmacology ; RNA Interference ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-02-26
    Description: The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kryukov, Gregory V -- Wilson, Frederick H -- Ruth, Jason R -- Paulk, Joshiawa -- Tsherniak, Aviad -- Marlow, Sara E -- Vazquez, Francisca -- Weir, Barbara A -- Fitzgerald, Mark E -- Tanaka, Minoru -- Bielski, Craig M -- Scott, Justin M -- Dennis, Courtney -- Cowley, Glenn S -- Boehm, Jesse S -- Root, David E -- Golub, Todd R -- Clish, Clary B -- Bradner, James E -- Hahn, William C -- Garraway, Levi A -- KL2 TR001100/TR/NCATS NIH HHS/ -- U01 CA176058/CA/NCI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. levi_garraway@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912360" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Deoxyadenosines/metabolism/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Deletion ; Humans ; Isoquinolines/pharmacology ; Neoplasms/*drug therapy/enzymology ; Protein-Arginine N-Methyltransferases/antagonists & ; inhibitors/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; Pyrimidines/pharmacology ; Thionucleosides/metabolism/pharmacology ; Transcription Factors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2014-06-21
    Description: Tuberous sclerosis complex (TSC) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of hamartomas in various organs and neurological manifestations including epilepsy, intellectual disability and autism. TSC1/2 protein complex negatively regulates the mammalian target of rapamycin complex 1 (mTORC1) a master regulator of protein synthesis, cell growth and autophagy. Autophagy is a cellular quality-control process that sequesters cytosolic material in double membrane vesicles called autophagosomes and degrades it in autolysosomes. Previous studies in dividing cells have shown that mTORC1 blocks autophagy through inhibition of Unc-51-like-kinase1/2 (ULK1/2). Despite the fact that autophagy plays critical roles in neuronal homeostasis, little is known on the regulation of autophagy in neurons. Here we show that unlike in non-neuronal cells, Tsc2 -deficient neurons have increased autolysosome accumulation and autophagic flux despite mTORC1-dependent inhibition of ULK1. Our data demonstrate that loss of Tsc2 results in autophagic activity via AMPK-dependent activation of ULK1. Thus, in Tsc2 -knockdown neurons AMPK activation is the dominant regulator of autophagy. Notably, increased AMPK activity and autophagy activation are also found in the brains of Tsc1- conditional mouse models and in cortical tubers resected from TSC patients. Together, our findings indicate that neuronal Tsc1/2 complex activity is required for the coordinated regulation of autophagy by AMPK. By uncovering the autophagy dysfunction associated with Tsc2 loss in neurons, our work sheds light on a previously uncharacterized cellular mechanism that contributes to altered neuronal homeostasis in TSC disease.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2015-01-13
    Description: 5-Hydroxymethylcytosine (5-hmC) is an intermediate in active demethylation in metazoans, as well as a potentially stable epigenetic mark. Previous reports investigating 5-hydroxymethylcytosine in plants have reached conflicting conclusions. We systematically investigated whether 5-hmC is present in plant DNA using a range of methods. Using the model organism Arabidopsis thaliana , in addition to other plant species, we assayed the amount or distribution of 5-hydroxymethylcytosine by thin-layer chromatography, immunoprecipitation-chip, ELISA, enzymatic radiolabeling, and mass spectrometry. The failure to observe 5-hydroxymethylcytosine by thin-layer chromatography established an upper bound for the possible fraction of the nucleotide in plant DNA. Antibody-based methods suggested that there were low levels of 5-hmC in plant DNA, but these experiments were potentially confounded by cross-reactivity with the abundant base 5-methylcytosine. Enzymatic radiolabeling and mass spectrometry, the most sensitive methods for detection that we used, failed to detect 5-hydroxymethylcytosine in A. thaliana genomic DNA isolated from a number of different tissue types and genetic backgrounds. Taken together, our results led us to conclude that 5-hmC is not present in biologically relevant quantities within plant genomic DNA.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 8
    Publication Date: 2011-07-20
    Description: Tunicamycin (TM) inhibits eukaryotic asparagine-linked glycosylation, protein palmitoylation, ganglioside production, proteoglycan synthesis, 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, and cell wall biosynthesis in bacteria. Treatment of cells with TM elicits endoplasmic reticulum stress and activates the unfolded protein response. Although widely used in laboratory settings for many years, it is unknown how TM enters cells. Here, we identify in an unbiased genetic screen a transporter of the major facilitator superfamily, major facilitator domain containing 2A (MFSD2A), as a critical mediator of TM toxicity. Cells without MFSD2A are TM-resistant, whereas MFSD2A-overexpressing cells are hypersensitive. Hypersensitivity is associated with increased cellular TM uptake concomitant with an enhanced endoplasmic reticulum stress response. Furthermore, MFSD2A mutant analysis reveals an important function of the C terminus for correct intracellular localization and protein stability, and it identifies transmembrane helical amino acid residues essential for mediating TM sensitivity. Overall, our data uncover a critical role for MFSD2A by acting as a putative TM transporter at the plasma membrane.
    Keywords: Feature Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 9
    Publication Date: 2013-06-12
    Description: Mitochondrial metabolism, respiration, and ATP production necessitate ion transport across the inner mitochondrial membrane. Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1), one of the genes deleted in Wolf–Hirschhorn syndrome, encodes a putative mitochondrial Ca2+/H+ antiporter. Cellular Letm1 knockdown reduced Ca2+mito uptake, H+mito extrusion and impaired mitochondrial ATP generation capacity. Homozygous...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2012-02-22
    Description: Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation, and reactive oxygen species (ROS) scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1α is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1α activity. To test this model, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1α (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1α is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy (EM) demonstrated that PGC-1α is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1α is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1α nor mitochondrial biogenesis in skeletal muscle are required for the whole-body metabolic benefits of CR.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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