Succinate metabolism: a new therapeutic target for myocardial reperfusion injury

Abstract

Myocardial ischemia/reperfusion (IR) injury is a major cause of death worldwide and remains a disease for which current clinical therapies are strikingly deficient. While the production of mitochondrial reactive oxygen species (ROS) is a critical driver of tissue damage upon reperfusion, the precise mechanisms underlying ROS production have remained elusive. More recently it has been demonstrated that a specific metabolic mechanism occurs during ischemia that underlies elevated ROS at reperfusion, suggesting a unifying model as to why so many different compounds have been found to be cardioprotective against IR injury. This review will discuss the role of the citric acid cycle intermediate succinate in IR pathology focussing on the mechanism by which this metabolite accumulates during ischemia and how it can drive ROS production at complex I via reverse electron transport (RET). We will then examine the potential for manipulating succinate accumulation and metabolism during IR injury in order to protect the heart against IR damage and discuss targets for novel therapeutics designed to reduce reperfusion injury in patients.