Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye

Abstract

Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.

Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen

“…As a secondary mode of validation, we employed 2-NBDG, a fluorescent glucose analog that is used to monitor glucose uptake from living cells and tissues. Oral gavage of 2-NBDG is used to assess glucose absorption from the intestine to extraintestinal sites in whole animals and co-administration with d-glucose, greatly diminishes uptake indicative of competitive uptake (Kanow et al, 2017) (Figure S4E). After oral gavage, infected mice fed dietary iron exhibited reduced absorption of 2-NBDG into the bloodstream within the first 15 minutes post-gavage compared to infected mice fed control chow and uninfected mice (Figure S4F,G).…”

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

“…High mTORC1 activity supports aerobic glycolysis (47) and suppresses ketogenesis (48), which may serve as an off signal after the cells have used free fatty acids derived from POS as metabolic substrates. When mTORC1 activity returns to basal level, utilization of glucose through glycolysis will be reduced, and the RPE can export glucose to support photoreceptor function (49). Thus, the rhythmic activation and inactivation of mTORC1 in response to phagocytosis is likely essential for metabolic coupling between the RPE and photoreceptor neurons.…”

Neurons rely on glucose rather than astrocytic lactate during stimulation

“…Even neglecting the likely distortion of metabolism that occurs in prolonged cell culture, as well as the critical dependence on small details of the culture conditions (Sünwoldt, Bosche, Meisel, & Mergenthaler, 2017), these studies on separate neurons and astrocytes support the feasibility of an ANLS; however, they cannot demonstrate the actual direction of transport of lactate between neurons and astrocytes when they are in normal contact in the brain. Incidentally, an opposite proposal of a neuronto-astrocyte lactate shuttle has been made (Hurley, Lindsay, & Du, 2015;Mangia, Simpson, Vannucci, & Carruthers, 2009); this situation is well-documented in retina, where the radial glia (Müller cells) cannot perform glycolysis normally and rely on photoreceptor-produced lactate (Kanow et al, 2017;Lindsay et al, 2014). 3 Few researchers would claim that the energy-rich lactate produced by aerobic glycolysis is a "waste product" (i.e.…”