Fig. 1.

Mechanism of I/R injury and requirements for a malonate drug. a Timeline of clinically relevant therapeutic window in MI patients undergoing PPCI. b During ischemia, succinate accumulates. Upon reperfusion, succinate is rapidly oxidised by SDH allowing proton pumping from complex III and IV, maintaining the highly reduced CoQ pool and generating a large ∆p, thus driving electrons through complex I by RET. RET transfers electrons to oxygen, generating superoxide initiating the oxidative damage in I/R injury. c Malonate prodrugs could be administered during PPCI where they would enter cells, hydrolyse to release malonate and go on to inhibit SDH in mitochondria