Succinate is Broadly Tissue-Permeant and Uncouples Mitochondrial Respiration from ATP Synthesis
When tissues have limited access to O2 the mitochondrial respiratory apparatus can reduce fumarate to succinate as a surrogate for reducing O2 to H2O. The succinate can be released from the tissue into the systemic circulation, but its metabolic fate in the body is mostly unknown. Using a combination of ex vivo and in vivo strategies we investigated the fate of circulating succinate in mice. We find that succinate from the blood is imported and oxidized by most tissues. Remarkably, succinate from the circulation can stimulate metabolic activity in most tissues, regardless of their energy demands, by uncoupling mitochondrial respiration from ATP synthesis. A notable exception is the retina, where carbons from succinate are incorporated into gluconeogenic intermediates.