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      Elimination of a Retinal Riboflavin Binding Protein Exacerbates Degeneration in a Model of Cone-Rod Dystrophy

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          Abstract

          Purpose

          Riboflavin and its cofactors are essential for cellular energy generation, responses to oxidative stress, and overall homeostasis. Retbindin is a novel retina-specific riboflavin binding protein essential for the maintenance of retinal flavin levels, but its function remains poorly understood. To further elucidate the function of retbindin in retinal health and disease, we evaluated its role in retinal degeneration in a cone-rod dystrophy model associated with the R172W mutation in the photoreceptor tetraspanin Prph2.

          Methods

          We performed structural, functional, and biochemical characterization of R172W-Prph2 mice with and without retbindin ( Rtbdn / /Prph2 R172W) .

          Results

          Retbindin is significantly upregulated during degeneration in the R172W model, suggesting that retbindin plays a protective role in retinal degenerative diseases. This hypothesis was supported by our findings that R172W mice lacking retbindin ( Rtbdn / /Prph2 R172W ) exhibit functional and structural defects in rods and cones that are significantly worse than in controls. Retinal flavin levels were also altered in the Rtbdn / /Prph2 R172W retina. However, in contrast to the Rtbdn / retina which has reduced flavin levels compared to wild-type, Rtbdn / /Prph2 R172W retinas exhibited elevated levels of riboflavin and the flavin cofactor FMN.

          Conclusions

          These results indicate that retbindin plays a protective role during retinal degeneration, but that its function is more complex than previously thought, and suggest a possible role for retbindin in protecting the retina from phototoxicity associated with unbound flavins. This study highlights the essential role of precisely regulated homeostatic mechanisms in photoreceptors, and shows that disruption of this metabolic balance can contribute to the degenerative process associated with other cellular defects.

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          Most cited references 49

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          Molecular characterization of mitochondrial apoptosis-inducing factor.

          Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.
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            Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function.

            During ischemic brain injury, glutamate accumulation leads to overstimulation of postsynaptic glutamate receptors with intracellular Ca2+ overload and neuronal cell death. Here we show that glutamate can induce either early necrosis or delayed apoptosis in cultures of cerebellar granule cells. During and shortly after exposure to glutamate, a subpopulation of neurons died by necrosis. In these cells, mitochondrial membrane potential collapsed, nuclei swelled, and intracellular debris were scattered in the incubation medium. Neurons surviving the early necrotic phase recovered mitochondrial potential and energy levels. Later, they underwent apoptosis, as shown by the formation of apoptotic nuclei and by chromatin degradation into high and low molecular weight fragments. These results suggest that mitochondrial function is a critical factor that determines the mode of neuronal death in excitotoxicity.
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              Energy metabolism of the visual system.

               William Riley (2009)
              The visual system is one of the most energetically demanding systems in the brain. The currency of energy is ATP, which is generated most efficiently from oxidative metabolism in the mitochondria. ATP supports multiple neuronal functions. Foremost is repolarization of the membrane potential after depolarization. Neuronal activity, ATP generation, blood flow, oxygen consumption, glucose utilization, and mitochondrial oxidative metabolism are all interrelated. In the retina, phototransduction, neurotransmitter utilization, and protein/organelle transport are energy-dependent, yet repolarization-after-depolarization consumes the bulk of the energy. Repolarization in photoreceptor inner segments maintains the dark current. Repolarization by all neurons along the visual pathway following depolarizing excitatory glutamatergic neurotransmission preserves cellular integrity and permits reactivation. The higher metabolic activity in the magno- versus the parvo-cellular pathway, the ON- versus the OFF-pathway in some (and the reverse in other) species, and in specialized functional representations in the visual cortex all reflect a greater emphasis on the processing of specific visual attributes. Neuronal activity and energy metabolism are tightly coupled processes at the cellular and even at the molecular levels. Deficiencies in energy metabolism, such as in diabetes, mitochondrial DNA mutation, mitochondrial protein malfunction, and oxidative stress can lead to retinopathy, visual deficits, neuronal degeneration, and eventual blindness.
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                Author and article information

                Journal
                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                iovs
                IOVS
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                0146-0404
                1552-5783
                09 June 2020
                June 2020
                : 61
                : 6
                Affiliations
                [1 ]Department of Biomedical Engineering, University of Houston, Houston, Texas, United States
                [2 ]Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
                Author notes
                Correspondence: Muayyad R. Al-Ubaidi or Muna I. Naash, Department of Biomedical Engineering, University of Houston, 3517 Cullen Blvd. SERC 2009, Houston, TX, USA; mnaash@ 123456central.uh.edu . or malubaid@ 123456central.uh.edu .
                Article
                IOVS-20-29674
                10.1167/iovs.61.6.17
                7415289
                32516403
                Copyright 2020 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                Page count
                Pages: 12
                Product
                Categories
                Biochemistry and Molecular Biology
                Biochemistry and Molecular Biology

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