RT Journal Article
SR Electronic
T1 Retinal energy metabolism: Photoreceptors switch between Cori, Cahill, and mini-Krebs cycles to uncouple glycolysis from mitochondrial respiration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.20.496788
DO 10.1101/2022.06.20.496788
A1 Yiyi Chen
A1 Laimdota Zizmare
A1 Victor Calbiague
A1 Shirley Yu
A1 Friedrich W. Herberg
A1 Oliver Schmachtenberg
A1 François Paquet-Durand
A1 Christoph Trautwein
YR 2022
UL http://biorxiv.org/content/early/2022/06/21/2022.06.20.496788.abstract
AB 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.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 StatementThe authors have declared no competing interest.1,9-DDF1,9 dideoxyforskolinAAamino acidsAATaspartate amino transferaseADPadenosine diphosphateALTalanine transaminaseATPadenosine triphosphateBCAAbranched chain amino acidCOXcytochrome oxidaseGACglutaminase CGCsganglion cellsGLUTglucose transporterGSglutamine synthaseGTPguanosine triphosphateGABAgamma amino butyric acidGPCsn-glycero-3-phosphateFCCPcarbonyl cyanide-p-trifluoromethoxyphenylhydrazoneGSSGglutathione disulfideINLinner nuclear layerMGCMüller glial cellsNAAN-acetylaspartateNAD+nicotinamide adenine dinucleotideONLouter nuclear layerO-PEO-phosphoethanolamineOXPHOSoxidative phosphorylationPARPpoly(ADP)ribose polymerasePCKpyruvate carboxy kinasePKMpyruvate kinase MPNApeanut agglutininRPretinitis pigmentosaRPEretinal pigment epitheliumRPE65retinal pigment epithelium-specific 65 kDa proteinSUCLG1succinate-CoA ligase-1TUNELterminal UDP nick-end labellingUDPuracil diphosphate