Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria

Kooragayala, Keshav; Gotoh, Noriko; Cogliati, Tiziana; Nellissery, Jacob; Kaden, Talia R; French, Stephanie; Balaban, Robert S.; Li, Wei; Covián, Raúl; Swaroop, Anand

doi:10.1167/iovs.15-17901

Cited by 116 publications

(121 citation statements)

References 42 publications

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“…For example, early expressed genes were associated with RNA processing and metabolism, whereas photoreceptor development was among the highly enriched pathways at later stages. Enrichment of genes for ATP synthesis coupled proton transport and hexose catabolic process was consistent with high-energy requirement for photoreceptor morphogenesis and function (Kooragayala et al, 2015). …”

Section: Resultsmentioning

confidence: 65%

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

et al. 2016

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SUMMARY Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. As the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal day 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously un-annotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor.

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Section: Resultsmentioning

confidence: 65%

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

et al. 2016

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“…Photoreceptors are one of the most metabolically active cells of the body with demanding energy requirements (Ames et al, 1992; Okawa et al, 2008) but limited mitochondrial reserve capacity (Kooragayala et al, 2015). Therefore, we hypothesized that photoreceptors depend on NAMPT-mediated NAD + biosynthesis to meet their catalytic requirements.…”

Section: Resultsmentioning

confidence: 99%

“…These hallmarks of metabolic dysfunction can be identified prior to cell death and vision loss, supporting the possibility of probing mitochondrial function to predict subsequent photoreceptor death (Perron et al, 2013). These findings are interesting, especially considering recent studies that show that photoreceptors have limited mitochondrial reserve capacity, which may make them susceptible to defects in energy homeostasis (Kooragayala et al, 2015). We speculate that defects in the Krebs cycle cause broad energetic failure, which contributes to downstream defects in numerous metabolic pathways, such as protein biosynthesis and propanoate metabolism.…”

Section: Discussionmentioning

confidence: 97%

“…Rod photoreceptors mediate dim vision, while cone photoreceptors mediate precise central vision in ambient light. Photoreceptors make up a significant portion of the neurosensory retina, one of the most metabolically active tissues in the body (Ames et al, 1992; Kooragayala et al, 2015; Okawa et al, 2008). Although terminally differentiated and non-proliferative, photoreceptors have tremendous metabolic demands throughout their lives and experience significant light-induced oxidative stress due to their function of performing light transduction (Fu and Yau, 2007; Yau and Hardie, 2009).…”

Section: Introductionmentioning

confidence: 99%

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NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

et al. 2016

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SUMMARY Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD+ biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD+ deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction. Mechanistically, NAD+ deficiency caused metabolic dysfunction and consequent photoreceptor death. We further demonstrate that the NAD+-dependent mitochondrial deacylases SIRT3/SIRT5 play important roles in retinal homeostasis and that NAD+ deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD+ biosynthesis is essential for vision, provide a foundation for future work to further clarify the mechanisms involved, and identify a unifying therapeutic target for diverse blinding diseases.

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“…Also in mice, similar as in frogs, inhibitors of the mitochondrial electron transport chain as well as uncouplers of the mitochondrial proton gradient changed the oxygen consumption rate confirming the high vulnerability of photoreceptors to altered energy homeostasis in mice [27].…”

Section: Quantification Of Required Oxygen and Effects Of Electron Trmentioning

confidence: 64%

Selected aspects of retinal signaling and energy metabolism and its perspective as a cerebral surrogate model

Albanna¹,

Lüke²,

Alpdogan³

et al. 2018

New Front Ophthalmol

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Purpose: The isolated and superfused retina from vertebrates is routinely used for neurophysiological measurements of basic retinal signal generation and transduction. Such an ex vivo isolated neural network moreover represents a useful model system for the investigation of drugs and toxins and may also be helpful to elucidate molecular mechanisms of CNS diseases. The present overview aims to bring observations to the reader's attention, which, in part, have been made more than 50 years ago and were sparsely followed up upon in subsequent research, but may support the idea that the isolated bovine retina represents a useful system to investigate the physiology and pathophysiology of energy supply to neuronal tissue. Material and methods:Parallel recording of ERGs and pyridine nucleotide oxidation in the isolated and superfused vertebrate retina. The review will focus on topics, which discuss the connection between retinal electrophysiology and underlying energy metabolism.Results: Previous and present reports about (i) transretinal signaling cascades, (ii) the involvement of the pharmacoresistant Cav2.3 / R-type calcium channel in transretinal signaling and (iii) data about the retinal oxygen demands and concentration in different layers are collected, which elucidate that the retina may be used as a cerebral surrogate model in different research areas. Retinal tolerance to ischemia is several times larger than the tolerance in the remaining brain. Conclusions:The retinal energy supply through retinal vessels is regulated and controlled by neurovascular coupling. Classical retinal recording techniques and special retinal abilities in electrical-vascular coupling will be set in perspective with novel recording techniques, currently brought into clinical application for the detection of impaired neurovascular coupling after aneurysmal subarachnoid hemorrhage in the brain. The present review elucidates that important pathophysiological aspects related to the upregulation of pharmacoresistant Cav2.3 / R-type calcium channels during SAH may be investigated in the isolated vertebrate retina. Ischemic tolerance in the vertebrate retinaThe oxygen consumption of the vertebrate retina on a per gram basis has been described as higher than that of the brain [1,2]. Oxygen cannot be "stored" in tissue so that a constant and adequate supply must be guaranteed to preserve function. Metabolic dysfunction regarding to impaired vascular supply is directly reflected by retinal oxygen saturation which can be detected noninvasively by dual wavelength fundus photography [3]. Normally, the oxygen saturation in retinal vessels differs along vascular segments and is higher in the macular region than retinal periphery [4]. Many retinal diseases are caused by a dysfunction of the vascular network. Interestingly, the venous oxygen saturation in diabetic retinopathy was higher in venules draining the macular surroundings than retinal periphery that reflect specific metabolic conditions [5,6].Since a relatively unobstructed light path...

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Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria

Cited by 116 publications

References 42 publications

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

Selected aspects of retinal signaling and energy metabolism and its perspective as a cerebral surrogate model

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