Academic Journal
Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury.
| Title: | Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury. |
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| Authors: | Beach TE; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., Prag HA; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK., Pala L; School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK., Logan A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK., Huang MM; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., Gruszczyk AV; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK., Martin JL; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., Mahbubani K; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., Hamed MO; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., Hosgood SA; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., Nicholson ML; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK., James AM; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK., Hartley RC; School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK. Electronic address: mpm@mrc-mbu.cam.ac.uk., Saeb-Parsy K; Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK. Electronic address: ks10014@cam.ac.uk. |
| Source: | Redox biology [Redox Biol] 2020 Sep; Vol. 36, pp. 101640. Date of Electronic Publication: 2020 Jul 12. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| MeSH Terms: | Prodrugs*/pharmacology , Reperfusion Injury*/drug therapy, Succinate Dehydrogenase/metabolism ; Animals ; Esters ; Humans ; Malonates ; Mice ; Swine |
| Abstract: | 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. (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.) |
| Grant Information: | MC_U105663142 United Kingdom MRC_ Medical Research Council; MC_UU_00015/3 United Kingdom MRC_ Medical Research Council; 110159/Z/15/Z United Kingdom WT_ Wellcome Trust; 110158/Z/15/Z United Kingdom WT_ Wellcome Trust |
| Contributed Indexing: | Keywords: Ischemia reperfusion injury; Kidney; Malonate; Mitochondria; Succinate; Succinate dehydrogenase |
| Substance Nomenclature: | 0 (Esters) 0 (Malonates) 0 (Prodrugs) EC 1.3.99.1 (Succinate Dehydrogenase) |
| Entry Date(s): | Date Created: 20200901 Date Completed: 20210618 Latest Revision: 20250530 |
| Update Code: | 20260407 |
| PubMed Central ID: | PMC7372157 |
| DOI: | 10.1016/j.redox.2020.101640 |
| PMID: | 32863205 |
| Database: | MEDLINE |
| ISSN: | 2213-2317 |
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| DOI: | 10.1016/j.redox.2020.101640 |