Succinate metabolism uncouples retinal pigment epithelium mitochondria

Abstract

Succinate is a mitochondrial metabolite well known for its ability to stimulate respiration through succinate dehydrogenase. Data from multiple studies have implied that succinate localized to mitochondria and does not cross tissue boundaries. We tested this hypothesis by infusing 13C-labeled succinate into the bloodstream of awake, moving C57BL6/J mice through a jugular catheter. Following the infusion we probed intermediates of glycolytic and Krebs cycle metabolism to determine how different tissues utilize succinate. We found that retina and eyecup metabolism appeared unique in their handling of succinate. The retina appeared to be the least permeant to succinate, and succinate that was taken up was not well integrated into the Krebs cycle and was rather directed to become glycolytic intermediates. In the eyecup, 13C originating from succinate populated Krebs cycle intermediates particularly well. We also found that ex vivo, succinate stimulates mitochondrial uncoupling in eyecup tissue, which may be particularly relevant in the biology of the eye, as retina tissue secretes succinate.

Monocarboxylate Transporter 1 (MCT1) Mediates Succinate Export in the Retina

“…4 A). 1 , 27 Eyecup tissue is composed of sclera, choroidal endothelial cells, and RPE cells. MCT distribution on RPE cells is polarized, with MCT3 localized to the basal RPE surface and robust MCT1 expression on the apical processes.…”

“…However, because supplying retinas with as much as 100 mM succinate does not stimulate significant O 2 consumption, it is unlikely that the small amount of MCT1-mediated succinate import in retinas is biologically relevant. 27 …”

Monocarboxylate Transporter 1 (MCT1) mediates succinate export in the retina

“…However, since supplying retinas with as much as 100 mM succinate does not stimulate significant O2 consumption, it is unlikely that the small amount of MCT1-mediated succinate import in retinas is biologically relevant. 2 Considering that for a MCT at equilibrium [H + ]out, [monocarboxylate]out = [H + ]in,…”

“…Unlike retina tissue, eyecup explants do not export succinate and instead measurably deplete it from the incubation (Figure 3A). 1,2 Eyecup tissue is composed of sclera, choroidal endothelial cells, and RPE cells. MCT expression on RPE cells is polarized, with MCT3 localized to the basal RPE surface and robust MCT1 expression on the apical processes.…”

“…It is a valuable metabolic fuel, and evidence supports a model where succinate produced by fumarate respiration and exported from the retina is oxidized by the neighboring retinal pigment epithelium (RPE). 1,2 Succinate is also implicated in retinal pathology. In a model of O2-induced retinopathy, succinate accumulates in the retina and drives angiogenesis via SUCNR1 signaling on retinal ganglion cells.…”