| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 22, Iss 12, Pp 3107-3114 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2018.02.084 |
| Popis: |
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 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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