Retinal energy metabolism: Photoreceptors switch between Cori, Cahill, and mini-Krebs cycles to uncouple glycolysis from mitochondrial respiration

The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilized 1H-NMR spectroscopy-based metabolomics, in situenzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: 1) the mini-Krebs-cycle, fueled by glutamine and branched-chain amino acids, generating N-acetylaspartate; 2) the alanine-generating Cahill-cycle; 3) the lactate-releasing Cori-cycle. Moreover, the metabolomic data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/496788v3_figa1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1ef3692org.highwire.dtl.DTLVardef@1e7e193org.highwire.dtl.DTLVardef@8aa6fborg.highwire.dtl.DTLVardef@d8c5bd_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Retinal photoreceptors employ both glucose and glutamate as fuels. While rod photoreceptors rely strongly on oxidative phosphorylation and the N-acetylaspartate producing mini-Krebs-cycle, cone photoreceptors rely on the lactate-producing Cori cycle and the oxidative, alanine producing Cahill cycle. C_FIG HighlightsO_LIThe retina utilizes a complex energy switchboard consisting of the Krebs cycle, mini-Krebs cycle, Cahill cycle, and Cori cycle. C_LIO_LIMini-Krebs cycle runs more efficiently than full Krebs cycle. C_LIO_LIAlanine transaminase decouples glycolysis from the Krebs cycle. C_LIO_LILactate, alanine, and N-acetylaspartate are distinctive energetic pathway signatures. C_LI