Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

Evolving architecture of the retinal vasculature during development

Two vascular networks supply the mature retina, the inner retinal vasculature and the choroid. The inner retinal vasculature provides nutrients and oxygen to the inner two-thirds of the retina and forms three distinct vascular layers originating from branches of the central retinal artery. Murine inner retinal vascular development begins after birth, making it useful for preclinical studies of preterm retinal vascular development. The superficial vasculature forms first and emerges from the

Neuronal energy requirements to sustain retinal function

The metabolic demands of neurons that determine the vascular network that supplies oxygen and nutrients are intrinsically linked to neuronal structure and function. The primary energetic demands include light sensing via phototransduction and maintenance of electrical gradients, production of the molecules and structures (such as renewable outer segments) that allow vision and managing the oxidative stress arising from these processes.

Pathways to energy production in the retina

How the retina meets its energy demands is not fully understood. There are two primary pathways that cells can use to generate ATP, glycolysis and oxidative phosphorylation (OXPHOS). Work over the past century has highlighted the need of the retina to have both a very high glycolytic and oxidative capacity. The following sections will review the relative contributions of these energy-producing pathways in the retina, as well as discuss the substrate utilization and ability of the retina to use

Oxygen consumption and oxidative phosphorylation

Oxygen consumption reflects the activity of the electron transport chain and the production of ATP by the mitochondria. The retina is one of the most oxidative tissues in the body, consuming more oxygen than the brain (Ames Iii, 1992) and has the equivalent expression of oxygen-carrying proteins as skeletal muscle (Schmidt et al., 2003). The outer retina, which consists mainly of photoreceptors with some Müller glial feet, is estimated to account for more than 60% of the oxygen consumption of

Lipid metabolism in the retina

Although the prevailing dogma has been that glucose is the only fuel substrate of the neural retina, as noted above, pioneering work by Cohen and Noell in the 1960s, implied that this was not the case. They reported that almost 65% of the CO₂ produced from the TCA cycle by retinas is not derived from glucose (Cohen and Noell, 1960). These results imply that the oxidation of non-carbohydrate carbons is used to meet the retinal ATP demand. In the retina, one might rationalize that the use of both

Lipids versus glucose as fuel: the Randle cycle and fatty acid receptors

Adapting fuel utilization to match nutrient availability might improve metabolic efficiency in the retina as in other tissues. Hormones, such as insulin and glucagon, help to control the relative abundance of fuel substrate in circulation but different mechanisms are needed at the cellular level to determine which substrates are used. Randle and colleagues first proposed a mechanism for fuel selection by tissue, independent of hormonal control (Fig. 5a and b). Tissues that use lipids to produce

Retinal lipid composition

As we do not yet know what lipids are used as fuel in the retina we will review lipid composition and lipid metabolism in the retina.

Retinal cell-specific metabolism

In vivo or ex vivo measurements of retinal metabolism is the sum of the activity of multiple cell types. These cells have distinct metabolic activities and potentially compartmentalized and opposing metabolic reactions. In this review, we will focus on the metabolism of cells of the outer retina, namely photoreceptors, Müller glia, and RPE.

Neuroglial mitochondria: nutrient and oxygen sensors that drive angiogenesis

Elaborate mechanisms preserve the critical homeostasis between the vascular supply of nutrients and oxygen, and the neuronal energy demands fuelled by mitochondria, the cell's powerhouse. Major mitochondrial energy pathways including the TCA cycle, fatty acid β-oxidation, and oxidative phosphorylation require nutrients and oxygen to produce energy. Glucose, amino acids and fatty acids fuel the Krebs cycle by generating acetyl-CoA. Nutrient deficiency may, therefore, decrease acetyl-CoA

Pathological angiogenesis in disease as a marker of retinal energy failure

Vessels supplying oxygen and nutrients to neurons, continually adapt to neuronal energy requirements. Vascular remodeling is, therefore, an early sign of changes in retinal neuron metabolism, possibly driven by energy needs. Hence, diseases involving mitochondria may present a unique vascular signature.

Mitochondrial ocular diseases are categorized as either primary or secondary. Primary retinal disorders result from direct impairment of mitochondrial functions by mutations in either

Primary mitochondropathies and ocular diseases

Neuro-ophthalmic mitochondrial disorders can be broadly divided into four groups: (1) bilateral optic neuropathies; (2) pigmentary retinopathies that affect the inner and outer retina respectively; (3) ophthalmoplegia with ptosis; and (4) retrochiasmal visual loss (Fig. 6a). The extra-retinal ocular manifestations and are reviewed elsewhere (Biousse and Newman, 2003, Newman, 2012).

Secondary mitochondropathies and ocular diseases

Acquired (or secondary) mitochondrial dysfunction is likely involved in the development of diabetic retinopathy, and age-related macular degeneration (AMD). AMD is primarily caused by aging changes, which include aging mitochondria, while fuel shifts induced by hyperglycemia and dyslipidemia contribute to DR. Both diseases are associated with secondary energetic dysfunction of photoreceptors and vessels. Retinal degenerative disease, such as retinitis pigmentosa, often also present signs of

Kinetics of photoreceptor degeneration and mitochondrial adaptation

Our mechanistic understanding of photoreceptor and neuronal decay due to bioenergetic failure and excess RONS would predict progressive damage accumulation, and accelerating cell death with aging (Clarke et al., 2000) (Fig. 9a). This conflicts with all investigated examples of inherited photoreceptor loss, where cell death kinetics is almost constant, and declines slightly in later stages of the disease (stretched exponential kinetics; Fig. 9b) (Clarke et al., 2000). Exponential decay of

Conclusion and perspectives

Vascular remodeling is intimately coupled to retinal energy metabolism. Surges in neuronal energy demands are met with vascular proliferation. Conversely, neuronal atrophy and lower retinal metabolic requirements result in vascular pruning. Vascular remodeling is, therefore, an early sign of neuronal metabolic changes. Classic evidence describes the importance of glucose as a primary retinal fuel, sustaining energy production and the biosynthesis of building blocks for growth through aerobic

Acknowledgements

This work was supported by: JSJ: Burroughs Wellcome Fund Career Award for Medical Scientists, Fondation Fighting Blindness, Natural Sciences and Engineering Research Council of Canada (NSERC) 06743, Fonds de Recherche du Québec – Santé (FRQS), Canadian Child Health Clinician Scientist Program, and CIHR New Investigator Award. LEHS: NIH EY024864, EY017017, P01 HD18655, BCH IDDRC, 1U54HD090255, Lowy Medical Research Institute, European Commission FP7 project 305485 PREVENT-ROP.