Retinal energetics: its critical role in retinal physiology and pathology

Keywords::

• adenosine triphosphate
• metabolism
• oxygen
• oxygen consumption
• retina
• retinal energetics
• retinal vascular disease

Many forms of visual impairment stem from a defect of the retina. Age-related macular degeneration is the leading cause of blindness in the Western world and its prevalence is set to rise owing to the increase in the older population [1]. Diabetic retinopathy remains the leading cause of preventable blindness in working adults [2]. Effective treatment of these visual impairments is limited because we lack detailed knowledge of the dysfunction underlying these disorders [3–6]. In recent years, significant progress has been made in the understanding of the signaling pathways and possible pathogenic factors involved in specific retinal diseases [7]. As a consequence of the advent of new technologies, ranging from those of molecular biology to theoretical computations, we have accumulated an impressive amount of information that has made it possible to pursue a host of previously unanswerable questions. However, it is clear that much remains to be done. Although multidisciplinary approaches are necessary, some common features for all retinal disorders may be more critical for linking multiple hypotheses. Retinal energetics could be a fundamentally important area, but this field has received relatively little attention.

Why is retinal energetics particularly important?

It is well known that all living cells must have metabolic activity capable of converting the food into chemical components. These chemical components can be used by cells for cell growth and energy utilization. All biochemical reactions involve energy exchange. There is a large amount of internal free energy in cells. The key energy-containing molecules within the cell are nucleotide triphosphates, such as ATP. Roughly 10⁹ molecules of ATP are present in a typical cell at any instant. In many cells, all this ATP may be used up and replaced every 1–2 min [8]. ATP is produced by a series of chemical reactions and finally synthesized by oxidative phosphorylation in mitochondria and glycolysis in the cytosol.

It is argued that the energetics in the retina are more vulnerable than in most other tissues. The retina is a thin sheet of brain-like tissue protracted into the eye to provide neural processing for photoreceptor signals. The miracle of vision begins when our photoreceptors absorb light from surrounding objects. Vision is the dominant sense in humans and other primates, with nearly 30% of our cortical surface representing information that is predominantly visual [9]. It is also estimated that 90% of our sense signals are from visual input. The role of the photoreceptor does not end with photon capture. It must also convert the energy of the absorbed photon into an electrochemical signal to be relayed to the visual cortex of the brain. The process of visual transduction involves a G-protein-mediated second messenger system that ultimately controls membrane potential and neurotransmitter release. Furthermore, unlike other sense organs, the retina is not only sensing, but also processing signals before sending to the brain. There is a huge amount of information transformed from retina defined by the photons impinging on the retina at any given moment to brain organizing spatiotemporal patterns into a coherent visual world.

A large amount of energy is required to perform the normal functions of the brain and retina. The high energy demand is mainly produced through the chemical process of oxidative phosphorylation in the mitochondria to produce adequate quantities of ATP. It is estimated that approximately 20% of the total oxygen consumption in the human body is consumed by the brain which constitutes only approximately 2% of bodyweight [10] and oxygen consumption per tissue weight in the retina is higher than that in the brain [11]. Arguably, the retina is one of highest energy demand tissues in the body. As a consequence of its unusual energy requirements, retinal cells are exquisitely sensitive to disturbances in the supply of their energy sources (oxygen and other substrates).

Delicate balance between high energy demands & limited blood supply

The retina performs the vital task of transducing and encoding the visual input for later processing by the visual centers of the brain. The retina has the conflicting constraints of a high metabolic requirement, yet the transparency of the retina cannot be compromised by an overly rich vascular network on the inner retinal side. Therefore, only a limited blood supply can be provided by the retinal circulation. In addition, the photoreceptor layer itself is totally avascular, and the oxygen supply is predominantly dependent on diffusion from the choroid. This results in a very delicate balance between the available oxygen supply and the consumption of oxygen within the retina. Such a delicate balance can only be achieved by precise regulatory mechanisms to match local blood flow with tissue demands in order to maintain retinal homeostasis. Disruption of these mechanisms can have severe consequences in the retina. This means that the retina is particularly vulnerable to a wide range of vascular diseases. In the Western world, 75% of blindness and visual loss is attributable to retinal diseases with a vascular component [12]. Such diseases include diabetic and hypertensive retinopathy, glaucoma, age-related macular degeneration, central and branch arterial occlusion and venous occlusion. The underlying pathogeneses of these diseases remains poorly understood. Thus, we are not currently in a position to provide satisfactory procedures for early diagnosis and treatment. As the oxidative metabolism is essential for supplying retinal energy and supporting function, retinal oxygenation and oxygen consumption provide important information that can be used to evaluate retinal energetics in healthy and diseased retinas.

What we know & what we do not know about retinal energetics?

Using oxygen sensitive microelectrode techniques, we can precisely measure the oxygen tension across each cellular layer of the retina. Detailed information of oxygen tensions in each retinal layer have been obtained from vascular and avascular retinas and the changes induced by perturbations of physiological conditions and diseased states have been investigated [13]. Intraretinal oxygen distribution is remarkably nonuniform and contains important information regarding oxygen tension, oxygen supply from different circulations, oxygen diffusion and solubility properties, and oxygen consumption rates in specific retinal layers. In some intraretinal regions, oxygen levels are very low even under physiological conditions [14,15]. It is fundamentally important to address how retinal cells and their compartments share the limited energy available responding to very active function under varying physiological and pathological conditions.

It is relatively easy to identify the high oxygen consumption region of the inner segments of the photoreceptors in the outer retina because the outer retina is an avascular region in which oxygen consumption can be determined using the mathematical models based on Fick’s law of diffusion [16,17]. By contrast, the inner retina typically has vascular beds making it more difficult to determine the oxygen consumption here. It has been demonstrated that the oxidative metabolism of the inner retina in species with avascular inner retinas such as guinea pigs, or partially avascular inner retinas such as the rabbit, is very different to that in vascularized retinas such in rats and monkeys [15,16,18–20]. We performed a series of experiments involving changes in physiological conditions and/or occlusion of the retinal circulation to investigate oxygen consumption in the inner retinal layers [13–16,21,22]. It was demonstrated that two distinct regions of the inner retina, the inner and outer plexiform layers, have high oxygen consumption rates. There are abundant synapses located in the inner and outer plexiform layers. Interestingly, although the three distinct high oxygen consuming regions across the entire retina are rich in mitochondria, there are significant differences in the oxidative metabolism between the inner segments of the photoreceptors and the plexiform layers. For example, the oxygen consumption in the inner segments can be significantly changed by dark and light adaptation as well as some diseased situations such as retinal degeneration or laser-induced lesions, but it is not affected by increased oxygen availability [16,20,21,23,24]. However, the oxygen consumption in the plexiform layers is not affected by dark and light adaptation, or by loss of outer retinal input due to retinal degeneration as well as some diseased situations such as retinal degeneration, but it is increased dramatically in the presence of increased oxygen availability [13,14,25,26].

It is well known that oxygen is the only molecule serving as the primary biological oxidant [27] and is essential for the survival of cells. Understanding the retinal oxidative metabolism and retinal energetics could be critical for retinal physiology and pathology. Developing more effective therapeutic intervention strategies requires improved basic knowledge to understand many fundamentally important questions. The following questions are examples for which we seek answers in our future work. We know that there is significant heterogeneity of intraretinal oxygen tension, but we still do not know what minimum requirement (critical oxygen tension) is needed for each cell layer or how to restore the cellular environment in pathological conditions? Retinal oxygen consumption is dominated by three distinct layers, but why is the inner segment metabolic behavior so different compared with that in inner and outer plexiform layers? There are remarkable species differences of inner retinal oxygen consumption; can we switch off some enzymes in vascular retina to avoid hypoxic damage in the presence of inner retinal ischemia? Light and dark (steady state) can significantly change photoreceptor oxidative metabolism, but not that of the inner retina; will dynamic light stimulation induce changes in photoreceptors and inner retinal oxygen requirements? What are the energetics differences between cones and rods? What is the relationship between oxygen tension and consumption with altered photocurrents and signaling processes in the inner retina? In addition to retinal oxidative metabolism, does retinal glycolytic metabolism and other pathways participate in retinal metabolism in some retinal cells and components? How does retinal metabolism interact with neuronal function, blood supply and glial cells? It is also important to understand the differences in mitochondrial function in the inner segments and plexiform layers as well as to characterize cellular metabolism of retinal neurons in normal and pathological conditions.

How is the delicate balance between high energy demands & limited blood supply achieved?

Since oxygen cannot be ‘stored’ in tissue, a constant and adequate supply must be guaranteed in order to preserve function. Oxygen supply to the retina is arguably more vulnerable to vascular deficiencies than in any other organ. It is very important to know how to achieve the delicate balance between high energy demands and limited blood supply. We have previously reported detailed measurements of intraretinal oxygen distribution in the monkey retina [15]. In the parafoveal region we often observed oxygen peaks in the inner retina that reflected the presence and activity of foveal capillaries. The parafoveal region, like most retinal regions except the foveola, is supplied by two circulations, the retinal and choroidal circulations. The choroid is highly vascularized and lies immediately behind the retina. The choroid has a very high blood flow and little regulatory capacity [28] despite the presence of autonomic innervation [29,30]. The relatively sparse retinal circulation exhibits a well-developed regulatory capacity [31], which must be locally controlled as there is no apparent autonomic innervation [32]. The choroid has high oxygen tension and is the dominant oxygen supply for the outer retina as evidenced by the steep oxygen gradients in the outermost retina. Oxygen tensions ranged from 2 to 8 mmHg at the inner surface of the retina and retinal ganglion cell layer in the monkey. However, there were multiple peaks (reaching up to ∼40 mmHg) in the inner retina, mostly located between the inner and outer plexiform layers. These peaks occurred with variable timing and amplitudes, indicating that the blood supply is very actively regulated to meet the local metabolic demands. The lowest oxygen tension appears to be in inner segments of the photoreceptors before the steep gradients up to the peak in the choroid. It seems likely that these opposing requirements of minimal interference with the light path and provision of sustenance to the highly metabolizing retinal tissue have led to the development of a system that is delicately, if not precariously, balanced.

Consumption of free energy is fundamental to life [33]. Cell function and survival are dependent on the consumption of free energy. It seems likely that the high energy demands and limited supply in the retina may require rapid redirection of energy sources when local energy demand changes. ATP is the dominant source of cellular energy, so the control mechanism of dynamic processes of ATP production, distribution and utilization could be particularly critical for retinal cells [34–36]. It is very important to encourage substantial research efforts in this field to improve our knowledge. Active intracellular redistribution of energy could involve mitochondria, dynamic organelles in cells and various signaling pathways. The control of mitochondrial motility by signaling mechanisms and the significance of rapid changes in motility remains elusive. Bearing in mind that intracellular mitochondria redistribution can vary between different cells and species. Numerous studies have demonstrated the marked heterogeneity of oxygen metabolism across the retina, even in different components of the same cell.

Significance & future directions

The retina is a unique organ performing incredible work with such a limited energy supply. It is predictable that research into retinal energetics will grow significantly. Lack of sufficient oxygen for retinal neurons may be a major pathogenic factor that has been proposed as a linking hypothesis for many ocular diseases such as macular diseases and glaucoma. We have succeeded in identifying three major sites of oxygen consumption in the vascularized retina. A very different pattern of oxygen metabolism has been shown to exist in species with avascular retinas. Regulation of oxygen delivery and consumption in the retina has also been demonstrated, but the specific mechanisms involved remain a mystery. The importance of understanding mechanisms controlling oxygen supply and consumption in the retina is indisputable. The diverse nature of the findings that we report from three species of common laboratory animals serves to illustrate that there is much work left to be done if the important features of oxygen supply and metabolism in the retina are to be understood. Determining the specific mechanisms responsible for the regulation of oxygen delivery and consumption may be a logical starting point. However, creative approaches from multiple disciplines are required to explore this important field. Finding out how such mechanisms are affected in retinal disease would then be the next logical step.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.