Retinal metabolism: Evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle

Abstract

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.

Imaging of lactate metabolism in retinal Müller cells with a FRET nanosensor

“…Thus, MCs could convert lactate into pyruvate through LDH-B to fuel mitochondria and produce ATP through oxidative phosphorylation. However, MCs lack the enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDH-A) required for lactate production (Chen et al, 2022;Chinchore et al, 2017;Lindsay et al, 2014;Rajala et al, 2018). It is possible that the expression of pyruvate kinase M1 (PKM1) and LDH-B are sufficient to sustain lactate synthesis in MCs and release it through MCT1 and MCT4 when metabolically required.…”

Extracellular lactate as an alternative energy source for retinal bipolar cells

“…1b, c). Notably, under all conditions, the number of TUNEL-positive cells in the ONL was much higher: SR = 19.9 ± 6.9%, n = 6, p < 0.0001, AR-C = 16.6 ± 5.2%, n = 6, p = 0.0007, Shikonin = 14.5 ± 5.9%, n = 6, p = 0.0018, reflecting the sensitivity of photoreceptors to metabolic disruptions 6 .…”

“…However, a demonstration of this transporter´s function and its role in inner retinal physiology was missing. In vascular retinas, inner retinal cells can obtain metabolites from alternative sources 5 , and previous studies have demonstrated the ability of the neuroretina to be metabolically flexible to meet its energy demands 6 . Although that study focused on the outer retina, some important enzymes involved in different metabolic pathways were expressed in the INL, supporting a similar metabolic flexibility for the inner retina.…”

“…The constant turnover of the photopigment in the outer segments (OS) and the large ATP consumption required to keep the ion pumps working to maintain the dark current in the inner segment (IS) of photoreceptors are among the main reasons why the retina is the most energy-demanding neural tissue [1][2][3][4] . Photoreceptors receive glucose, oxygen, and other metabolites from the choroidal vasculature 5 through the retinal pigment epithelium ((RPE; 6 ). However, the inner retina may either be vascular or avascular.…”