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  • 1
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    The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-05-16
    Description: Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that alpha-ketoglutarate (alpha-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit beta is identified as a novel binding protein of alpha-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that alpha-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by alpha-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by alpha-KG requires ATP synthase subunit beta and is dependent on target of rapamycin (TOR) downstream. Endogenous alpha-KG levels are increased on starvation and alpha-KG does not extend the lifespan of dietary-restricted animals, indicating that alpha-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263271/" 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/PMC4263271/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chin, Randall M -- Fu, Xudong -- Pai, Melody Y -- Vergnes, Laurent -- Hwang, Heejun -- Deng, Gang -- Diep, Simon -- Lomenick, Brett -- Meli, Vijaykumar S -- Monsalve, Gabriela C -- Hu, Eileen -- Whelan, Stephen A -- Wang, Jennifer X -- Jung, Gwanghyun -- Solis, Gregory M -- Fazlollahi, Farbod -- Kaweeteerawat, Chitrada -- Quach, Austin -- Nili, Mahta -- Krall, Abby S -- Godwin, Hilary A -- Chang, Helena R -- Faull, Kym F -- Guo, Feng -- Jiang, Meisheng -- Trauger, Sunia A -- Saghatelian, Alan -- Braas, Daniel -- Christofk, Heather R -- Clarke, Catherine F -- Teitell, Michael A -- Petrascheck, Michael -- Reue, Karen -- Jung, Michael E -- Frand, Alison R -- Huang, Jing -- DP2 OD008398/OD/NIH HHS/ -- P01 HL028481/HL/NHLBI NIH HHS/ -- P40 OD010440/OD/NIH HHS/ -- T32 CA009120/CA/NCI NIH HHS/ -- T32 GM007104/GM/NIGMS NIH HHS/ -- T32 GM007185/GM/NIGMS NIH HHS/ -- T32 GM008496/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):397-401. doi: 10.1038/nature13264. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA. ; Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. ; Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2] UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828042" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/*drug effects ; Cell Line ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Jurkat Cells ; Ketoglutaric Acids/*pharmacology ; Longevity/drug effects/genetics/*physiology ; Mice ; Mitochondrial Proton-Translocating ATPases/genetics/*metabolism ; Protein Binding ; TOR Serine-Threonine Kinases/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Brain tumour cells interconnect to a functional and resistant network (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-11-05
    Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Osswald, Matthias -- Jung, Erik -- Sahm, Felix -- Solecki, Gergely -- Venkataramani, Varun -- Blaes, Jonas -- Weil, Sophie -- Horstmann, Heinz -- Wiestler, Benedikt -- Syed, Mustafa -- Huang, Lulu -- Ratliff, Miriam -- Karimian Jazi, Kianush -- Kurz, Felix T -- Schmenger, Torsten -- Lemke, Dieter -- Gommel, Miriam -- Pauli, Martin -- Liao, Yunxiang -- Haring, Peter -- Pusch, Stefan -- Herl, Verena -- Steinhauser, Christian -- Krunic, Damir -- Jarahian, Mostafa -- Miletic, Hrvoje -- Berghoff, Anna S -- Griesbeck, Oliver -- Kalamakis, Georgios -- Garaschuk, Olga -- Preusser, Matthias -- Weiss, Samuel -- Liu, Haikun -- Heiland, Sabine -- Platten, Michael -- Huber, Peter E -- Kuner, Thomas -- von Deimling, Andreas -- Wick, Wolfgang -- Winkler, Frank -- England -- Nature. 2015 Dec 3;528(7580):93-8. doi: 10.1038/nature16071. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. ; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, INF 224, 69120 Heidelberg, Germany. ; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), INF 224, 69120 Heidelberg, Germany. ; Department of Functional Neuroanatomy, Institute of Anatomy and Cell Biology, Heidelberg University, INF 307, 69120 Heidelberg, Germany. ; Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universitat Munchen, 81675 Munich, Germany. ; Neurosurgery Clinic, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. ; Department of Neuroradiology, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. ; Department of Neurophysiology, Institute of Physiology, University of Wurzburg, 97070 Wurzburg, Germany. ; Department of Medical Physics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. ; Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. ; Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria. ; Tools For Bio-Imaging, Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany. ; Institute of Physiology II, Eberhard Karls University of Tubingen, 72074 Tubingen, Germany. ; Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, CNS Unit, Medical University of Vienna, 1090 Vienna, Austria. ; Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada. ; Department of Cell Biology and Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4Z6, Canada. ; Clark Smith Brain Tumor Research Centre, Southern Alberta Cancer Research Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada. ; Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany. ; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; CCU Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany. ; Department of Radiation Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536111" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytoma/metabolism/*pathology/radiotherapy ; Brain Neoplasms/metabolism/*pathology/radiotherapy ; Cell Communication/radiation effects ; Cell Death/radiation effects ; Cell Proliferation/radiation effects ; Cell Surface Extensions/metabolism/radiation effects ; Cell Survival/radiation effects ; Connexin 43/metabolism ; Disease Progression ; GAP-43 Protein/metabolism ; Gap Junctions/*metabolism/radiation effects ; Glioma/metabolism/pathology/radiotherapy ; Humans ; Male ; Mice ; Mice, Nude ; Neoplasm Invasiveness ; Radiation Tolerance/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
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