Mitochondria Contribute to NADPH Generation in Mouse Rod Photoreceptors

Adler, Leopold; Chen, Chunhe; Koutalos, Yiannis

doi:10.1074/jbc.m113.511295

Cited by 46 publications

(62 citation statements)

References 50 publications

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“…Pyruvate dehydrogenase (PDH) is the “gatekeeper” for aerobic glycolysis, and it catalyzes acetyl CoA production from glucose-derived pyruvate for fatty acid synthesis. Notably, acetyl CoA is also the entry point into the TCA cycle, where resulting isocitrate and malate act as precursors for most of the NADPH used in the visual cycle (Adler et al 2014). Consistent with an important role for PDH in cone function, patients with PDH deficiency not only display neurologic abnormalities, they also progress to central vision loss (Brown et al 1994).…”

Section: Resultsmentioning

confidence: 99%

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

et al. 2016

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Most Retinitis Pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nightime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE), and thus is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment -rich outer segments (OS), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.

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Section: Resultsmentioning

confidence: 99%

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

et al. 2016

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“…The released all- trans retinal is reduced within the rod outer segment to all- trans retinol, which is then transported to the RPE where it is recycled to make 11- cis retinal (Lamb and Pugh, 2004; Saari, 2000; Tang et al, 2013). The reduction of all -trans retinal to retinol is catalyzed by the enzyme retinol dehydrogenase RDH8 (Chen et al, 2012; Maeda et al, 2005) and requires metabolic input in the form of NADPH (Adler et al, 2014; Futterman et al, 1970). 11- Cis and all- trans retinal can both generate lipofuscin precursorsin rod outer segments, as evidenced by measurements of single cell fluorescence (Boyer et al, 2012), as well as of bis -retinoids (Ben-Shabat et al, 2002; Liu et al, 2000; Mata et al, 2000; Quazi and Molday, 2014).…”

Section: Introductionmentioning

confidence: 99%

All-trans retinal levels and formation of lipofuscin precursors after bleaching in rod photoreceptors from wild type and Abca4 mice

Adler

Chen

Koutalos

2017

Experimental Eye Research

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The accumulation of lipofuscin in the cells of the retinal pigment epithelium (RPE) is thought to play an important role in the development and progression of degenerative diseases of the retina. The bulk of RPE lipofuscin originates in reactions of the rhodopsin chromophore, retinal, with components of the photoreceptor outer segment. The 11-cis retinal isomer is generated in the RPE and supplied to rod photoreceptor outer segments where it is incorporated as the chromophore of rhodopsin. It is photoisomerized during light detection to all-trans and subsequently released by photoactivated rhodopsin as all-trans retinal, which is removed through reduction to all-trans retinol in a reaction requiring metabolic input in the form of NADPH. Both 11-cis and all-trans retinal can form lipofuscin precursor fluorophores in rod photoreceptor outer segments. Increased accumulation of lipofuscin has been suggested to result from excess formation of lipofuscin precursors due to buildup of all-trans retinal released by light exposure. In connection with this suggestion, the Abca4 transporter protein, an outer segment protein defects in which result in recessive Stargardt disease, has been proposed to promote the removal of all-trans retinal by facilitating its availability for reduction. To examine this possibility, we have measured the outer segment levels of all-trans retinal, all-trans retinol, and of lipofuscin precursors after bleaching by imaging the fluorescence of single rod photoreceptors isolated from wild type and Abca4−/− mice. We found that all-trans retinol and all-trans retinal levels increased after bleaching in both wild type and Abca4−/− rods. At all times after bleaching, there was no significant difference in all-trans retinal levels between the two strains. All-trans retinol levels were not significantly different between the two strains at early times, but were lower in Abca4−/− rods at times longer than 20 min after bleaching. Bleaching in the presence of lower metabolic substrate concentrations resulted in higher all-trans retinal levels and increased formation of lipofuscin precursors in both wild type and Abca4−/− rods. The results show that conditions that result in buildup of all-trans retinal levels result in increased generation of lipofuscin precursors in both wild type and Abca4−/− rods. The results are consistent with the proposal that Abca4 facilitates the reduction of all-trans retinal to retinol; absence of Abca4 however does not appear to be associated with higher all-trans retinal levels compared to wild type.

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“…5B) while decreasing flux through citric acid cycle intermediates. Previous studies (47,48) indicated that isocitrate dehydrogenase and malic enzyme can produce NADPH in the photoreceptor cytoplasm. Citrate, made in the matrix, can be transported to the cytoplasm to fuel those enzymes.…”

Section: Evidence For Changes In Anabolic Metabolismmentioning

confidence: 99%

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Rountree

Cleghorn³

et al. 2016

Journal of Biological Chemistry

100

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Production of energy in a cell must keep pace with demand.Photoreceptors use ATP to maintain ion gradients in darkness, whereas in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production directly to consumption. Alternatively, production can be set by a signal that anticipates demand. In this report we investigate the hypothesis that signaling through phototransduction controls production of energy in mouse retinas. We found that respiration in mouse retinas is not coupled tightly to ATP consumption. By analyzing metabolic flux in mouse retinas, we also found that phototransduction slows metabolic flux through glycolysis and through intermediates of the citric acid cycle. We also evaluated the relative contributions of regulation of the activities of ␣-ketoglutarate dehydrogenase and the aspartate-glutamate carrier 1. In addition, a comprehensive analysis of the retinal metabolome showed that phototransduction also influences steady-state concentrations of 5-GMP, ribose-5-phosphate, ketone bodies, and purines. Warburg et al.(1) and Krebs (2) reported in the 1920s that tumors and retinas rely on aerobic glycolysis. Some of the biochemical mechanisms by which cancer cells adapt to aerobic glycolysis have been gleaned from investigations of specific metabolic adaptations of cancer cells either in culture or in a tumor (3, 4). Retinas offer distinct advantages for investigating aerobic glycolysis. They have high metabolic rates, a uniquely laminated structure, and the primary signaling pathway by which retinas respond to light is defined clearly.Retinas convert 80 -96% of glucose they consume into lactic acid (5-9), similar to the extent of aerobic glycolysis that fuels cancer cells (3). Aerobic glycolysis occurs primarily in photoreceptors (10) where the energy demands are very different in darkness than in light (5,7,(11)(12)(13). In darkness energy is consumed within the inner segments to support ion pumping (5, 13). In light energy is consumed by the outer segments (OS) 2 to support phototransduction and regeneration of visual pigments. A photoreceptor neuron also performs anabolic metabolism to replace the ϳ10% of its OS material that is lost each day to phagocytosis by the retinal pigmented epithelium (14, 15).Some of the carbons in glucose consumed by a retina reach the mitochondrial matrix where they are oxidized in biochemical reactions that reduce NAD ϩ to NADH. Transfer of electrons from NADH to O 2 then generates a proton gradient across the mitochondrial inner membrane. In some tissues dissipation of the proton gradient is coupled tightly to ATP demand. In others, proton leakage can dissipate the gradient even without ATP synthesis (16). In this report we show that mitochondria in retinas are more uncoupled than mitochondria in other tissues.The ability of a photoreceptor to respond to light, to release neurotransmitter, to regenerate visual pigment, to renew itself, and to remain viable requires that production of energy keeps pace...

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Mitochondria Contribute to NADPH Generation in Mouse Rod Photoreceptors

Cited by 46 publications

References 50 publications

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

All-trans retinal levels and formation of lipofuscin precursors after bleaching in rod photoreceptors from wild type and Abca4 mice

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

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