Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy

Abstract

Mitochondrial reactive oxygen species production has emerged as an important pathological mechanism in myocardial ischemia/reperfusion injury. Attempts at targeting reactive oxygen species by scavenging using antioxidants have, however, been clinically disappointing. This review will provide an overview of the current understanding of mitochondrial reactive oxygen species in ischemia/reperfusion injury. We will outline novel therapeutic approaches designed to directly target the mitochondrial respiratory chain and prevent excessive reactive oxygen species production and its associated pathology. This approach could lead to more effective interventions in an area where there is an urgent need for new treatments.

Keywords: antioxidants; mitochondria; oxygen; reactive oxygen species; reperfusion injury.

Figure 1. The mitochondrial electron transport chain

Electrons derived from the oxidation of NADH and FADH₂ enter the electron transport chain at complexes I (NADH ubiquinone oxidoreductase) and II (Succinate dehydrogenase). They are then funneled through the electron carriers, Coenzyme Q, and complex III (Ubiquinol cytochrome c oxidoreductase), until they reach complex IV (cytochrome c oxidase) where they are used to reduce molecular oxygen to water. This transfer of electrons is coupled to the extrusion of protons at complexes I, III, and IV generating an electrochemical gradient across the mitochondrial membrane. Protons in the intermembrane space are then used to drive the synthesis of ATP at complex V (ATP synthase). C indicates cytochrome c; and TCA, tricarboxylic acid. Dashed arrows indicate path of electrons.

Figure 2. Respiratory Complex I and II Yin-Yang during ischemia and reperfusion

Under normoxic conditions, both complex I (red) and complex II (blue) work in the forward direction (dashed gray line indicates direction of electron flow), taking electrons from NADH and succinate, respectively, and reducing ubiquinone (Q) to ubiquinol (QH₂). Electrons are eventually passed down the respiratory chain to O₂, and complex I pumps protons to generate a transmembrane ΔpH. During ischemia, QH₂ generated by complex I working forward, is oxidized by complex II working in reverse. In this Yin-Yang formation, fumarate acts as an electron acceptor, resulting in accumulation of succinate. This process allows complex I to continue pumping protons during ischemia. At reperfusion, the rapid consumption of accumulated succinate generates too much QH₂ for the reoxygenated terminal respiratory chain to handle (dotted line). Coupled with residual acidic pH from ischemia, this drives reverse electron transfer in complex I, resulting in the generation of significant amounts of reactive oxygen species (ROS).