Inhibiting succinate release worsens cardiac reperfusion injury by enhancing mitochondrial reactive oxygen species generation

Abstract

The metabolite succinate accumulates during cardiac ischemia. Within 5 min. of 22 reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by 23 mitochondrial complex II (Cx-II). The latter drives reactive oxygen species (ROS) generation and 24 subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. 25 Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically 26 beneficial in cardiac ischemia-reperfusion (IR) injury. It has been proposed that blocking 27 monocarboxylate transporter 1 (MCT-1) may be beneficial in IR, by preventing succinate release 28 and subsequent engagement of downstream inflammatory signaling pathways. In contrast, 29 herein we hypothesized that blocking MCT-1 would retain succinate in cells, exacerbating ROS 30 generation and IR injury.