Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium.

Abstract

When O2 is plentiful, the mitochondrial electron transport chain uses it as a terminal electron acceptor. However, the mammalian retina thrives within a hypoxic niche in the eye. We find that mitochondria in retinas adapt to their hypoxic environment by relying on the "reverse" succinate dehydrogenase reaction, where fumarate accepts electrons instead of O2. Reverse succinate dehydrogenase activity produces succinate and is enhanced by down-regulation of cytochrome oxidase subunits. Retinas can export the succinate to the neighboring retinal pigment epithelium/choroid complex. There, succinate stimulates O2 consumption several fold and enhances synthesis and release of malate. Malate released from the pigment epithelium can be imported into the retina, where it is converted to fumarate and again used to accept electrons in the reverse succinate dehydrogenase reaction. Our findings show how a 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).