Picture child's feet next to pens, pencils and paper

Open Access research that is helping to improve educational outcomes for children

Strathprints makes available scholarly Open Access content by researchers in the School of Education, including those researching educational and social practices in curricular subjects. Research in this area seeks to understand the complex influences that increase curricula capacity and engagement by studying how curriculum practices relate to cultural, intellectual and social practices in and out of schools and nurseries.

Research at the School of Education also spans a number of other areas, including inclusive pedagogy, philosophy of education, health and wellbeing within health-related aspects of education (e.g. physical education and sport pedagogy, autism and technology, counselling education, and pedagogies for mental and emotional health), languages education, and other areas.

Explore Open Access education research. Or explore all of Strathclyde's Open Access research...

Fumarate induces redox-dependent senescence by modifying glutathione metabolism

Zheng, Liang and Cardaci, Simone and Jerby, Livnat and Mackenzie, Elaine D. and Sciacovelli, Marco and Johnson, T. Isaac and Gaude, Edoardo and King, Ayala and Leach, Joshua D.G. and Edrada-Ebel, RuAngelie and Hedley, Ann and Morrice, Nicholas A. and Kalna, Galbriela and Blyth, Karen and Ruppin, Eytan and Frezza, Christian and Gottlieb, Eyal (2015) Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nature Communications, 6. ISSN 2041-1723

[img]
Preview
Text (Zheng-etal-NC2015-Fumarate-induces-redox-dependent-senescence)
Zheng_etal_NC2015_Fumarate_induces_redox_dependent_senescence.pdf
Final Published Version
License: Creative Commons Attribution 4.0 logo

Download (949kB) | Preview

Abstract

Mutations in the tricarboxylic acid (TCA) cycle enzyme ​fumarate hydratase (​FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of ​FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of ​fumarate caused by the inactivation of ​FH leads to oxidative stress that is mediated by the formation of ​succinicGSH, a covalent adduct between ​fumarate and ​glutathione. Chronic succination of ​GSH, caused by the loss of ​FH, or by exogenous ​fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of ​p21, a key mediator of senescence, in ​Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that ​fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.