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 remains poorly understood. Here, we manipulated retinal energy metabolism under entirely controlled conditions and utilised 1H-NMR metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experiments resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. Notably, rod photoreceptors relied strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were highly dependent on glycolysis but insensitive to electron transport chain decoupling. Moreover, photoreceptors uncouple glycolytic and Krebs-cycle metabolism via three different pathways: 1) the mini-Krebs cycle, fuelled by glutamine and branched chain amino acids, generating N-acetylaspartate; 2) the alanine-generating Cahill cycle; 3) the lactate-releasing Cori cycle. These findings forward the understanding of retinal physiology and pathology, and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases. ![Figure][1] Retinal photoreceptors employ both glucose and anaplerotic substrates as fuels. While rod photoreceptors rely strongly on oxidative phosporylation and the N-acetylaspartate producing mini Krebs-cycle, cone photoreceptors rely much more on the lacate-producing Cori-cycle and the oxidative, alanine-producing Cahill-cycle. ### Competing Interest Statement The authors have declared no competing interest. * 1,9-DDF : 1,9 dideoxyforskolin AA : amino acids AAT : aspartate amino transferase ADP : adenosine diphosphate ALT : alanine transaminase ATP : adenosine triphosphate BCAA : branched chain amino acid COX : cytochrome oxidase GAC : glutaminase C GCs : ganglion cells GLUT : glucose transporter GS : glutamine synthase GTP : guanosine triphosphate GABA : gamma amino butyric acid GPC : sn-glycero-3-phosphate FCCP : carbonyl cyanide- p -trifluoromethoxyphenylhydrazone GSSG : glutathione disulfide INL : inner nuclear layer MGC : Müller glial cells NAA : N-acetylaspartate NAD+ : nicotinamide adenine dinucleotide ONL : outer nuclear layer O-PE : O-phosphoethanolamine OXPHOS : oxidative phosphorylation PARP : poly(ADP)ribose polymerase PCK : pyruvate carboxy kinase PKM : pyruvate kinase M PNA : peanut agglutinin RP : retinitis pigmentosa RPE : retinal pigment epithelium RPE65 : retinal pigment epithelium-specific 65 kDa protein SUCLG1 : succinate-CoA ligase-1 TUNEL : terminal UDP nick-end labelling UDP : uracil diphosphate [1]: pending:yes