Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis
Kate E.R. Hollinshead,
Haydn Munford,
Katherine L. Eales,
Chiara Bardella,
Chunjie Li,
Cristina Escribano-Gonzalez,
Alpesh Thakker,
Yannic Nonnenmacher,
Katarina Kluckova,
Mark Jeeves,
Robert Murren,
Federica Cuozzo,
Dan Ye,
Giulio Laurenti,
Wei Zhu,
Karsten Hiller,
David J. Hodson,
Wei Hua,
Ian P. Tomlinson,
Christian Ludwig,
Ying Mao,
Daniel A. Tennant
Affiliations
Kate E.R. Hollinshead
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Haydn Munford
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Katherine L. Eales
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Chiara Bardella
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
Chunjie Li
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
Cristina Escribano-Gonzalez
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Alpesh Thakker
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Yannic Nonnenmacher
Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany
Katarina Kluckova
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Mark Jeeves
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Robert Murren
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Federica Cuozzo
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Dan Ye
Institute of Biomedical Sciences, Fudan University, #131 Dong’an Road, Shanghai 200040, China
Giulio Laurenti
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Wei Zhu
Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China
Karsten Hiller
Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany
David J. Hodson
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
Wei Hua
Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China
Ian P. Tomlinson
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Christian Ludwig
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Ying Mao
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
Daniel A. Tennant
Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Corresponding author
Summary: 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. : Hollinshead et al. demonstrate a role for PYCR1 in control of mitochondrial redox homeostasis. Expression of IDH1 R132H mutation leads to increased NADH-coupled proline biosynthesis, mediated by PYCR1. The resulting metabolic phenotype partially uncouples mitochondrial NADH oxidation from respiration, representing an oxygen-sparing metabolic phenotype. Keywords: glioma, IDH1, redox, metabolism, proline
