Differential expression of the five redox complexes in the retinal mitochondria or rod outer segment disks is consistent with their different functionality

Bruschi, Maurizio; Bartolucci, Martina; Petretto, Andrea; Calzia, Daniela; Caicci, Federico; Manni, Lucia; Traverso, Carlo Enrico; Candiano, Giovanni; Panfoli, Isabella

doi:10.1096/fba.2019-00093

Cited by 20 publications

(23 citation statements)

References 53 publications

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“…Ocular RPE cells are damaged through various pathways, such as apoptosis, cell cycle arrest, cell death, oxidative damage, and inflammation, due to UVB irradiation and oxygen use [ 22 ]. In addition, stress caused by light performs oxidative phosphorylation (OxPhos) of the retinal rod outer segment (OS) disk film without mitochondria and generates reactive oxygen intermediates (ROI), causing damage and loss to the OS of the rod cell [ 26 , 27 ]. To protect against such damage, cells use an antioxidant defense system to negate damage and increase viability.…”

Section: Discussionmentioning

confidence: 99%

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

Park

Lee

Jeong³

et al. 2021

Antioxidants

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Age-related macular degeneration (AMD) is caused by the chronic and gradual oxidative degeneration of the retina. Unfortunately, the general purpose of current treatments is to slow AMD progression, as the retina cannot be restored to its pre-AMD condition. We aimed to identify natural products that can be potential treatments that prevent AMD and can delay the development of late-AMD and selected Centella asiatica extract (CA-HE50), which shows excellent efficacy in cytoprotection. In animal experiments using N-methyl-N-nitrosourea (MNU), CA-HE50 dramatically increased the thickness of photoreceptors and the outer nuclear layer (ONL) and the number of nuclei in the ONL (p < 0.05). Using retinal epithelial ARPE-19 cells showed that CA-HE50 inhibited apoptosis through inhibition of the intrinsic apoptosis signaling pathway and cell cycle regulation (p < 0.05). The anti-apoptotic efficacy was confirmed to be due to activation of the Nrf2/HO-1 antioxidation pathway (p < 0.05). These results were also observed with asiaticoside, a functional substance of CA-HE50. In addition, the accumulation of oxidized-N-retinylidene-N-retinylethanolamine (A2E), which induces AMD, was inhibited by CA-HE50, resulting in increased ARPE-19 cell viability (p < 0.05). This study demonstrates that CA-HE50 is worth further research and human application tests, to develop it as a raw material for treatment or dietary supplement for the prevention of AMD.

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Section: Discussionmentioning

confidence: 99%

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

Park

Lee

Jeong³

et al. 2021

Antioxidants

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“…In order to localize the ATP synthase β-subunit, immunogold transmission electron microscopy (TEM) was performed as described [ 31 , 33 ]. Bovine eye semi-cups were dissected and fixed with 4% paraformaldehyde and 0.1% glutaraldehyde in PBS buffer.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

et al. 2020

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Rod outer segments (OS) express the FoF1-ATP synthase and the respiratory chain, conducting an ectopic aerobic metabolism that produces free radicals in vitro. Diabetic retinopathy, a leading cause of vision loss, is associated with oxidative stress in the outer retina. Since metformin and glibenclamide, two anti-type 2 diabetes drugs, target the respiratory complexes, we studied the effect of these two drugs, individually or in association, on the free radical production in purified bovine rod OS. ATP synthesis, oxygen consumption, and oxidative stress production were assayed by luminometry, oximetry and flow cytometry, respectively. The expression of FoF1-ATP synthase was studied by immunogold electron microscopy. Metformin had a hormetic effect on the OS complex I and ATP synthetic activities, being stimulatory at concentrations below 1 mM, and inhibitory above. Glibenclamide inhibited complexes I and III, as well as ATP production in a concentration-dependent manner. Maximal concentrations of both drugs inhibited the ROI production by the light-exposed OS. Data, consistent with the delaying effect of these drugs on the onset of diabetic retinopathy, suggest that a combination of the two drugs at the beginning of the treatment might reduce the oxidative stress production helping the endogenous antioxidant defences in avoiding retinal damage.

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“…One of the principal sources of ROI is represented by the Electron Transport Chain (ETC), 6,21 which is usually described in the inner mitochondrial membrane. However, over the last years, we have demonstrated that the complete oxidative phosphorylation (OxPhos) machinery is expressed also in the rod outer segments (OS) disks 22‐24 . In particular, our data show that the OS disks are able to produce ATP through oxygen consumption, in a manner sensitive to the common inhibitors of aerobic metabolism, such as rotenone, antimycin A and KCN 25‐29 .…”

Section: Introductionmentioning

confidence: 80%

The diterpene Manool extracted from Salvia tingitana lowers free radical production in retinal rod outer segments by inhibiting the extramitochondrial F₁F_o ATP synthase

Ravera

Esposito

Degan

et al. 2021

Cell Biochemistry & Function

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Uncontrolled oxidative stress production, especially in the outer retina is one of the causes of retinal degenerations. Mitochondria are considered the principal source of oxidative stress. However, a Reactive Oxygen Intermediates (ROI) production in the retinal photoreceptor layer seems to depend also on the expression of an extramitochondrial oxidative phosphorylation (OxPhos) machinery in the rod outer segments (OS). In fact, OS conduct aerobic metabolism, producing ATP through oxygen consumption, although it is devoid of mitochondria. As diterpenes display an antioxidant effect, we have evaluated the effect Manool, extracted from Salvia tingitana, on the extramitochondrial OxPhos and the ROI production in the retinal rod OS. Results confirm that the OxPhos machinery is ectopically expressed in the OS and that F1Fo‐ATP synthase is a target of Manool, which inhibited the OS ATP synthesis, binding the F1 moiety with high affinity, as analysed by molecular docking. Moreover, the overall slowdown of OxPhos metabolism reduced the ROI production elicited in the OS by light exposure, in vitro. In conclusion, data are consistent with the antioxidant properties of Salvia spp., suggesting its ability to lower oxidative stress production, a primary risk factor for degenerative retinal diseases. Significance of the study Here we show that Manool, a diterpene extracted from Salvia tingitana has the potential to lower the free radical production by light‐exposed rod outer segments in vitro, by specifically targeting the rod OS F1Fo‐ATP synthase belonging to the extramitochondrial OxPhos expressed on the disk membrane. The chosen experimental model allowed to show that the rod OS is a primary producer of oxidative stress linked to the pathogenesis of degenerative retinal diseases. Data are also consistent with the antioxidant and anti‐inflammatory action of Salvia spp., suggesting a beneficial effect also in vivo.

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Differential expression of the five redox complexes in the retinal mitochondria or rod outer segment disks is consistent with their different functionality

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 20 publications

References 53 publications

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

The diterpene Manool extracted from Salvia tingitana lowers free radical production in retinal rod outer segments by inhibiting the extramitochondrial F₁F_o ATP synthase

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Differential expression of the five redox complexes in the retinal mitochondria or rod outer segment disks is consistent with their different functionality

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 20 publications

References 53 publications

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

Preventive Effects against Retinal Degeneration by Centella asiatica Extract (CA-HE50) and Asiaticoside through Apoptosis Suppression by the Nrf2/HO-1 Signaling Pathway

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

The diterpene Manool extracted from Salvia tingitana lowers free radical production in retinal rod outer segments by inhibiting the extramitochondrial F1Fo ATP synthase

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The diterpene Manool extracted from Salvia tingitana lowers free radical production in retinal rod outer segments by inhibiting the extramitochondrial F₁F_o ATP synthase