Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Hiran A. Prag
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK
Laura Pala
School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK
Angela Logan
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK
Margaret M. Huang
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Anja V. Gruszczyk
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK
Jack L. Martin
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Krishnaa Mahbubani
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Mazin O. Hamed
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Sarah A. Hosgood
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Michael L. Nicholson
Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 0QQ, UK
Andrew M. James
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK
Richard C. Hartley
School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK
Michael P. Murphy
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK; Corresponding author.
Kourosh Saeb-Parsy
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.
