Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis.

Autor:	Hollinshead KER; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Munford H; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Eales KL; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Bardella C; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., Li C; Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China; Institute of Biomedical Sciences, Fudan University, #131 Dong'an Road, Shanghai 200040, China., Escribano-Gonzalez C; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Thakker A; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Nonnenmacher Y; Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany., Kluckova K; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Jeeves M; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Murren R; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Cuozzo F; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Ye D; Institute of Biomedical Sciences, Fudan University, #131 Dong'an Road, Shanghai 200040, China., Laurenti G; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Zhu W; Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China., Hiller K; Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany., Hodson DJ; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK., Hua W; Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China., Tomlinson IP; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Ludwig C; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Mao Y; Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China; Institute of Biomedical Sciences, Fudan University, #131 Dong'an Road, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200040, China; The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200040, China., Tennant DA; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: d.tennant@bham.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2018 Mar 20; Vol. 22 (12), pp. 3107-3114.
DOI:	10.1016/j.celrep.2018.02.084
Abstrakt:	Since the discovery of mutations in isocitrate dehydrogenase 1 (IDH1) in gliomas and other tumors, significant efforts have been made to gain a deeper understanding of the consequences of this oncogenic mutation. One aspect of the neomorphic function of the IDH1 R132H enzyme that has received less attention is the perturbation of cellular redox homeostasis. Here, we describe a biosynthetic pathway exhibited by cells expressing mutant IDH1. By virtue of a change in cellular redox homeostasis, IDH1-mutated cells synthesize excess glutamine-derived proline through enhanced activity of pyrroline 5-carboxylate reductase 1 (PYCR1), coupled to NADH oxidation. Enhanced proline biosynthesis partially uncouples the electron transport chain from tricarboxylic acid (TCA) cycle activity through the maintenance of a lower NADH/NAD + ratio and subsequent reduction in oxygen consumption. Thus, we have uncovered a mechanism by which tumor cell survival may be promoted in conditions associated with perturbed redox homeostasis, as occurs in IDH1-mutated glioma. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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