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). [Display omitted] •Succinate is produced by reversal of succinate dehydrogenase in the retina•Hypoxia decreases complex IV expression to drive retinal succinate production•The retina exports succinate, which is oxidized by the RPE-choroid•The RPE-choroid exports malate, which fuels retinal succinate production Bisbach et al. describe a metabolite shuttle that can transfer electrons from a hypoxic tissue to an O2-rich one. In the retina, low O2 causes succinate dehydrogenase to operate in reverse, reducing fumarate to produce succinate. Retinas export this succinate, and the O2-rich RPE-choroid imports and oxidizes it.