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Abstract
Heritable renal cancer syndromes (RCS) are associated with numerous chromosomal alterations including inactivating mutations in von Hippel-Lindau (VHL) gene. Here we identify a novel aspect of the phenotype in VHL-deficient human renal cells. We call it reductive stress as it is characterised by increased NADH/NAD+ ratio that is associated with impaired cellular respiration, impaired CAC activity, upregulation of reductive carboxylation of glutamine and accumulation of lipid droplets in VHL-deficient cells. Reductive stress was mitigated by glucose depletion and supplementation with pyruvate or resazurin, a redox-reactive agent. This study demonstrates for the first time that reductive stress is a part of the phenotype associated with VHL-deficiency in renal cells and indicates that the reversal of reductive stress can augment respiratory activity and CAC activity, suggesting a strategy for altering the metabolic profile of VHL-deficient tumours.
Original language | English |
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Pages (from-to) | 1-12 |
Number of pages | 12 |
Journal | Free Radical Biology and Medicine |
Volume | 208 |
Early online date | 26 Jul 2023 |
Publication status | Published - 1 Nov 2023 |
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Dive into the research topics of 'VHL-deficiency leads to reductive stress in renal cells'. Together they form a unique fingerprint.Projects
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Pseudohypoxia-led identification of metabolic vulnerabilities in hypoxic tumours to improve patient outcomes
Tennant, D., Ludwig, C. & Spill, F.
1/02/18 → 31/01/24
Project: Research