Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury
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 underli...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-09-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720308454 |
| _version_ | 1819175312283402240 |
|---|---|
| author | Timothy E. Beach Hiran A. Prag Laura Pala Angela Logan Margaret M. Huang Anja V. Gruszczyk Jack L. Martin Krishnaa Mahbubani Mazin O. Hamed Sarah A. Hosgood Michael L. Nicholson Andrew M. James Richard C. Hartley Michael P. Murphy Kourosh Saeb-Parsy |
| author_facet | Timothy E. Beach Hiran A. Prag Laura Pala Angela Logan Margaret M. Huang Anja V. Gruszczyk Jack L. Martin Krishnaa Mahbubani Mazin O. Hamed Sarah A. Hosgood Michael L. Nicholson Andrew M. James Richard C. Hartley Michael P. Murphy Kourosh Saeb-Parsy |
| author_sort | Timothy E. Beach |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T20:52:52Z |
| format | Article |
| id | doaj.art-038ddcdac34144049d5f8e694c7a30c8 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-22T20:52:52Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-038ddcdac34144049d5f8e694c7a30c82022-12-21T18:13:02ZengElsevierRedox Biology2213-23172020-09-0136101640Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injuryTimothy E. Beach0Hiran A. Prag1Laura Pala2Angela Logan3Margaret M. Huang4Anja V. Gruszczyk5Jack L. Martin6Krishnaa Mahbubani7Mazin O. Hamed8Sarah A. Hosgood9Michael L. Nicholson10Andrew M. James11Richard C. Hartley12Michael P. Murphy13Kourosh Saeb-Parsy14Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UKSchool of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UKDepartment of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UKDepartment of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKDepartment of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKDepartment of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKDepartment of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKDepartment of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UKSchool of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK; Corresponding author.Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2213231720308454Ischemia reperfusion injuryMalonateSuccinateMitochondriaKidneySuccinate dehydrogenase |
| spellingShingle | Timothy E. Beach Hiran A. Prag Laura Pala Angela Logan Margaret M. Huang Anja V. Gruszczyk Jack L. Martin Krishnaa Mahbubani Mazin O. Hamed Sarah A. Hosgood Michael L. Nicholson Andrew M. James Richard C. Hartley Michael P. Murphy Kourosh Saeb-Parsy Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury Redox Biology Ischemia reperfusion injury Malonate Succinate Mitochondria Kidney Succinate dehydrogenase |
| title | Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury |
| title_full | Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury |
| title_fullStr | Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury |
| title_full_unstemmed | Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury |
| title_short | Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury |
| title_sort | targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury |
| topic | Ischemia reperfusion injury Malonate Succinate Mitochondria Kidney Succinate dehydrogenase |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720308454 |
| work_keys_str_mv | AT timothyebeach targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT hiranaprag targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT laurapala targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT angelalogan targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT margaretmhuang targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT anjavgruszczyk targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT jacklmartin targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT krishnaamahbubani targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT mazinohamed targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT sarahahosgood targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT michaellnicholson targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT andrewmjames targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT richardchartley targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT michaelpmurphy targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury AT kouroshsaebparsy targetingsuccinatedehydrogenasewithmalonateesterprodrugsdecreasesrenalischemiareperfusioninjury |