Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury

Beach, T. E. et al. (2020) Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury. Redox Biology, 36, 101640. (doi: 10.1016/j.redox.2020.101640)

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Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by ‘tuned’ malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Pala, Ms Laura and Hartley, Professor Richard
Authors: Beach, T. E., Prag, H. A., Pala, L., Logan, A., Huang, M. M., Gruszczyk, A. V., Martin, J. L., Mahbubani, K., Hamed, M. O., Hosgood, S. A., Nicholson, M. A., James, A. M., Hartley, R. C., Murphy, M. P., and Saeb-Parsy, K.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Redox Biology
ISSN (Online):2213-2317
Published Online:12 July 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Redox Biology 36: 101640
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172617Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZChemistry