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Most teleost fishes possess a unique system for tissue oxygen supply, where oxygen is delivered to the retina at partial pressures that exceed one atmosphere, providing a steep gradient for oxygen diffusion through their thick avascular retinas. This exceptional physiological system works through the elaborate interplay between highly pH-sensitive hemoglobins, acid-producing metabolic pathways, and a retinal vasculature with specialized structural and functional properties. This graphical review summarizes recent advances in understanding the mechanisms underlying retinal oxygen secretion and their impact on visual processing. Further, it discusses how the evolution of this complex physiological system provided the essential physiological exaptations for the adaptive improvements of vision in early teleost evolution. Finally, it summarizes knowledge gaps and directions for future research on this unique system for tissue oxygen supply.
The Krogh cylinder as a model for retinal oxygen supply
The retina within the vertebrate eye is an outgrowth of the forebrain and shares the high rate of aerobic metabolism with the rest of the central nervous system (Country, 2017). Typically, blood fuels the central nervous system's aerobic metabolism with oxygen from a densely packed capillary network, but this does not apply to the retina of most vertebrates: The vertebrate retina has an inverted design, where light must pass through the entire retina before reaching the light-sensitive
Physiological mechanisms underlying retinal oxygen supply in fishes
Many ray-finned fishes show the unique ability to raise blood PO2 in specific capillaries well above the PO2 in the central arteries (Wittenberg and Wittenberg, 1962; Steen, 1963). This phenomenon has (imprecisely) been termed oxygen secretion, despite Krogh's early work demonstrating that respiratory gasses move by diffusion rather than by active secretion (Krogh, 1910). Oxygen secretion occurs within the capillaries supplying the swimbladder and eyes of many ray-finned fishes, conferring
Co-evolutionary interactions between oxygen secretion and retinal morphology
Krogh's prediction that an increase in PO2-gradient permitted oxygen diffusion across greater distances suggests that the origin of retinal oxygen secretion may have permitted an evolutionary thickening of the retina. A recent comparative study modeled the co-evolutionary interactions between the retina's oxygen supply and retinal morphology. This analysis showed that the ancestral state for retinal oxygen supply in bony fishes was a dual oxygen supply from the choriod behind the retina as well
Conclusions and future directions
The retinal oxygen supply system represents a unique and highly efficient oxygen supply system that enables supreme oxygen fluxes through avascular neural tissues. This system was most likely present in the earliest teleost fishes more than 200 million years ago (Berenbrink et al., 2005; Damsgaard et al., 2019), where the system served as the physiological exaptation for the adaptive improvements in retinal morphology (Damsgaard et al., 2019). This geological period is characterized by
Declaration of Competing Interest
I declare no conflicts of interest.
This work has received funding from the Carlsberg Foundation (CF18-0658), the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (No. 754513), and The Aarhus University Research Foundation.
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A novel acidification mechanism for greatly enhanced oxygen supply to the fish retina
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Nitrosylation of ferric zebrafish nitrobindin: A spectroscopic, kinetic, and thermodynamic study
2022, Journal of Inorganic Biochemistry
Citation Excerpt :
This feature indeed suggests a much faster NO exchange rate for Nbs than for other hemoproteins, rendering them more suitable as regulators of NO levels in the blood thanks to the fast re-equilibration of NO. Such a property turns out to be important also for speeding up the reductive nitrosylation, which occurs at alkaline pH values. A final comment deals with the importance of these functional properties for a potential role of Nbs as regulators of NO levels in poorly oxygenated tissues, such as retina [22,24], a role of the utmost importance mainly in eye fishes, which experience high hydrostatic pressure under deep diving conditions . Conception of study: P. Ascenzi, M. Coletta.
Nitrobindins (Nbs) are all-β-barrel heme-proteins present in all the living kingdoms. Nbs inactivate reactive nitrogen species by sequestering NO, converting NO to HNO2, and isomerizing peroxynitrite to NO3− and NO2−. Here, the spectroscopic characterization of ferric Danio rerio Nb (Dr-Nb(III)) and NO scavenging through the reductive nitrosylation of the metal center are reported, both processes being relevant for the regulation of blood flow in fishes through poorly oxygenated tissues, such as retina. Both UV–Vis and resonance Raman spectroscopies indicate that Dr-Nb(III) is a mixture of a six-coordinated aquo- and a five-coordinated species, whose relative abundancies depend on pH. At pH≤7.0, Dr-Nb(III) binds reversibly NO, whereas at pH≥7.8 NO induces the conversion of Dr-Nb(III) to Dr-Nb(II)-NO. The conversion of Dr-Nb(III) to Dr-Nb(II)-NO is a monophasic process, suggesting that the formation of the transient Dr-Nb(III)-NO species is lost in the mixing time of the rapid-mixing stopped-flow apparatus (∼ 1.5ms). The pseudo-first-order rate constant for the reductive nitrosylation of Dr-Nb(III) is not linearly dependent on the NO concentration but tends to level off. Values of the rate-limiting constant (i.e., klim) increase linearly with the OH− concentration, indicating that the conversion of Dr-Nb(III) to Dr-Nb(II)-NO is limited by the OH−-based catalysis. From the dependence of klim on [OH−], the value of the second-order rate constant kOH− was obtained (5.2×103M−1s−1). Reductive nitrosylation of Dr-Nb(III) leads to the inactivation of two NO molecules: one being converted to HNO2, and the other being tightly bound to the heme-Fe(II) atom.
Dissociation of the proximal His-Fe bond upon NO binding to ferrous zebrafish nitrobindin
2022, Journal of Inorganic Biochemistry
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On the other hand, denitrosylation kinetics of Dr-Nb(II)-NO turns out to be as fast as for other Nbs, a feature which likely reflects a similarly easy pathway for the ligand escape into the outer solvent. Such an information has also important physio-pathological consequences for the comprehension of the vascular regulation of the blood flow in fishes, this being an important point in view of the oxygen supply to poorly oxygenated tissues, such as the retina, which is crucial for fishes during deep diving . In addition, a too slow regulation of NO (through its scavenging and release) may result in the production of toxic oxidative radicals that participate in neurotoxicity and in ocular diseases .
Nitrobindins (Nbs) are all-β-barrel heme-proteins present in prokaryotes and eukaryotes. Although the physiological role(s) of Nbs are still unclear, it has been postulated that they are involved in the NO/O2 metabolism, which is particularly relevant in fishes for the oxygen supply. Here, the reactivity of ferrous Danio rerio Nb (Dr-Nb(II)) towards NO has been investigated from the spectroscopic and kinetic viewpoints and compared with those of Mycobacterium tuberculosis Nb, Arabidopsis thaliana Nb, Homo sapiens Nb, and Equus ferus caballus myoglobin. Between pH 5.5 and 9.1 at 22.0 °C, Dr-Nb(II) nitrosylation is a monophasic process; values of the second-order rate constant for Dr-Nb(II) nitrosylation and of the first-order rate constant for Dr-Nb(II)-NO denitrosylation are pH-independent ranging between 1.6 × 106 M−1 s−1 and 2.3 × 106 M−1 s−1 and between 5.3 × 10−2 s−1 and 8.2 × 10−2 s−1, respectively. Interestingly, both UV–Vis and EPR spectroscopies indicate that the heme-Fe(II) atom of Dr-Nb(II)-NO is five-coordinated. Kinetics of Dr-Nb(II) nitrosylation may reflect the ligand accessibility to the metal center, which is likely impaired by the crowded network of water molecules which shields the heme pocket from the bulk solvent. On the other hand, kinetics of Dr-Nb(II)-NO denitrosylation may reflect an easy pathway for the ligand escape into the outer solvent.
Role of hemoglobin structural-functional relationships in oxygen transport
2022, Molecular Aspects of Medicine
Citation Excerpt :
In this context the mechanism of oxygen release and the relevance of O2-dependent conformational changes, described above, plays a role of the utmost importance. In this respect, such a process of retinal O2 delivery is very important in teleost fishes, which possess a unique system for oxygen supply, where O2 is delivered to the retina at partial pressures exceeding the atmospheric one (Root, 1931; Brunori, 1975; Damsgaard, 2021). Thus, retina is an avascular tissue and its oxygen supply occurs through O2 release from the choroid vessels and its diffusion across retinal layers of variable thickness (e.g., 450 μm in rainbow trout, see Damsgaard et al., 2020).
The molecular mechanism of O2 binding to hemoglobin (Hb) has been critically reviewed on the basis of the information built up in the last decades. It allows to describe in detail from the kinetic and thermodynamic viewpoint the process of O2 uptake in the lungs and release to the tissues, casting some light on the physiological and pathological aspects of this process. The relevance of structural-functional relationships for O2 binding is particularly outlined in the case of poorly vascularized tissues, such as retina, briefly discussing of strategies employed for optimization of oxygen supply to this type of tissues.
Introduction to the special issue: Comparative physiology and the legacy of August Krogh, 1920–2020
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Teleost red blood cells actively enhance the passive diffusion of oxygen that was discovered by August Krogh
2021, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative Physiology
Citation Excerpt :
Today, this exceptional pH-sensitivity of Hb-O2 binding in teleost fishes is known as the Root effect (Root, 1931) that prevents acidified blood from becoming fully oxygenated even at super-atmospheric PO2 (Scholander and Van Dam, 1954). Teleost fishes have evolved specialized organs, the retia mirabilia, that acidify the blood locally to induce the Root effect and produce staggering PO2 levels that can inflate their gas-filled swimbladders at depth (Pelster, 1997) and that can bridge the large diffusion distances to the avascular retina in the eye (Damsgaard, 2021; Wittenberg and Wittenberg, 1962). Krogh and Leitch also recognized the importance of the intracellular location of Hb and in fact, recent work has found that teleost RBCs themselves can actively acidify Hb to enhance the PO2 at which they unload O2 to all tissues (Randall et al., 2014; Rummer et al., 2013); a novel mechanism that is described in detail in Fig. 2 and elsewhere (Harter and Brauner, 2017).
In the early 20th century, August and Marie Krogh settled one of the most controversial questions in physiology, showing through elegant experiments that oxygen (O2) uptake at the lung is driven by passive diffusion alone. Krogh's later work, on the regulation of local blood flow and capillary recruitment at the tissues, was awarded with the Nobel Prize in 1920. A century later it is still undisputed that O2 moves across tissues by diffusion, however, animals use active mechanisms to regulate and facilitate the passive process. Teleost fishes have evolved a mechanism by which adrenergic sodium-proton-exchangers (β-NHEs) on the red blood cell (RBC) membrane actively create H+ gradients that are short-circuited in the presence of plasma-accessible carbonic anhydrase (CA) at the tissue capillaries. The rapid acidification of the RBC reduces the O2 affinity of pH-sensitive haemoglobin, which increases the O2 diffusion gradient to the tissues. When RBCs leave the site of plasma-accessible CA, β-NHE activity recovers RBC pH during venous transit, to promote renewed O2 loading at the gills. This mechanism allows teleosts to unload more O2 at their tissues without compromising O2 diffusion gradients and therefore, to use the available O2 carrying capacity of the blood to a greater degree. In Atlantic salmon, β-NHE short-circuiting reduces the requirements on the heart by up to 30% during moderate exercise and even at rest, with important ecological implications. Thus, in some teleosts, the RBCs participate in regulating the systemic O2 flux by actively altering the passive diffusion of O2 that Krogh discovered.
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