Succinate Can Shuttle Reducing Power from the Hypoxic Retina to the O₂-Rich Pigment Epithelium

When O₂ is plentiful, the mitochondrial electron transport chain uses it as a terminal electron acceptor. However, the mammalian retina thrives in a hypoxic niche in the eye. We find that mitochondria in retinas adapt to their hypoxic environment by reversing the succinate dehydrogenase reaction to use fumarate to accept electrons instead of O₂. Reverse succinate dehydrogenase activity produces succinate and is enhanced by hypoxia-induced downregulation of cytochrome oxidase. Retinas can export the succinate they produce to the neighboring O₂-rich retinal pigment epithelium-choroid complex. There, succinate enhances O₂ consumption by severalfold. Malate made from succinate in the pigment epithelium can then be imported into the retina, where it is converted to fumarate to again accept electrons in the reverse succinate dehydrogenase reaction. This malate-succinate shuttle can sustain these two tissues by transferring reducing power from an O₂-poor tissue (retina) to an O₂-rich one (retinal pigment epithelium-choroid).