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

doi:10.1016/j.celrep.2018.02.084

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

Cell Rep. 2018 Mar 20;22(12):3107-3114. doi: 10.1016/j.celrep.2018.02.084.

Authors

Kate E R Hollinshead¹, Haydn Munford¹, Katherine L Eales¹, Chiara Bardella², Chunjie Li³, Cristina Escribano-Gonzalez¹, Alpesh Thakker¹, Yannic Nonnenmacher⁴, Katarina Kluckova¹, Mark Jeeves⁵, Robert Murren¹, Federica Cuozzo¹, Dan Ye⁶, Giulio Laurenti¹, Wei Zhu⁷, Karsten Hiller⁴, David J Hodson⁸, Wei Hua⁷, Ian P Tomlinson⁵, Christian Ludwig¹, Ying Mao⁹, Daniel A Tennant¹⁰

Affiliations

¹ Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
² 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.
³ 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.
⁴ Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
⁵ Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
⁶ Institute of Biomedical Sciences, Fudan University, #131 Dong'an Road, Shanghai 200040, China.
⁷ Department of Neurosurgery, Huashan Hospital, Fudan University, #12 Middle Wulumuqi Road, Shanghai 200040, China.
⁸ 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.
⁹ 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.
¹⁰ Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: d.tennant@bham.ac.uk.

Abstract

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.

Keywords: IDH1; glioma; metabolism; proline; redox.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Citric Acid Cycle
Gene Knockdown Techniques
Glutamine / metabolism
Homeostasis
Humans
Isocitrate Dehydrogenase / genetics*
Isocitrate Dehydrogenase / metabolism*
Mitochondria / enzymology
Mitochondria / genetics
Mitochondria / metabolism*
Mutation*
Oligodendroglioma
Oxidation-Reduction
Proline / biosynthesis*
Pyrroline Carboxylate Reductases / genetics
Pyrroline Carboxylate Reductases / metabolism*
delta-1-Pyrroline-5-Carboxylate Reductase

Substances

Glutamine
Proline
Isocitrate Dehydrogenase
IDH1 protein, human
Pyrroline Carboxylate Reductases

Abstract

Publication types

MeSH terms

Substances

Grants and funding