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Int. J. Mol. Sci. 2020, 21, 2370 10 of 20 3. Discussion While RL/NIRL treatment is already in clinical use, including the application for retinal disorders, the molecular mechanisms underlying its therapeutic effect are not yet fully known. Consequently, in this study, we addressed the neuroprotective activities of 670 nm RL and 810 nm NIRL against BL toxicity in photoreceptors focusing on the molecular implications of RL/NIRL. Several studies showed that stress markers and inflammatory markers in diseased retinas can be reduced by 670 nm red light exposure in the outer retina. RL is selectively absorbed by CCO of mitochondria; however, the exact mechanism or impact on transcription factors and gene expression is largely unknown [21,24,25,28]. While authors postulate CCO to be the main target of RL action leading to improved mitochondrial function and thus reduced cell death, there is still limited information about the impact of RL/NIRL on other respiratory complexes or mitochondria-induced apoptosis in retinal diseases. In detail, we examined the ability of RL and NIRL to reduce oxidative damage and cell death, as well as the impact on the respiratory chain complexes and regulatory mechanisms based on differentially expressed genes that might explain the observed effects on protein level. Our data concerning the role of intrinsic mitochondria-driven apoptotic pathways as well as those of Gu et al. show that light-induced retinal damage particularly stresses mitochondria, leading to cytochrome c release into the cytosol triggering apoptosis [37]. Here, we demonstrate for the first time a decreased Caspase-9 expression in mitochondria-rich IS, suggesting reduced mitochondria related apoptosis of RL/NIRL stimulated photoreceptors. Only for visual cortical neurons, an effect of 670 nm RL on Caspase-9 was shown before [38]. The speculated increased loss of cytochrome c after BL damage from both IS mitochondria and OS disks is probably responsible for the reported increased rod apoptosis, in turn triggering the retinal damage [39]. Ghafourifar et al. described a lack in transferring electrons from complex III to IV that arises through membrane opening and the release of cytochrome c into the cytosol leading to reduced respiration rates in cells [40]. Few studies showed the effect of PBM on mitochondria induced apoptosis focusing on Bcl-2, Bcl-xl and Bax. These studies were performed using PC12 cells [41], skeletal muscle cells [42] and visual cortical neurons [38]. They confirm our results of increased cell survival protein Bcl-2 and decreased cell death protein Bax. Altered Bax and Bcl-2 expression strongly indicate that RL/NIRL lowers membrane channel formation, causing a smaller amount of cytochrome c release, ultimately preventing BL irradiated cells undergoing mitochondria related apoptosis. The inhibitory effect of RL/NIRL on cell apoptosis goes hand in hand with increased Bcl-2 and decreased Bax expression. In particular, RL exposure reverted Bax and Caspase-9 after a 50% increase caused by BL treatment, while increasing Bcl-2 by 50%, as compared to controls. This may appear inconsistent with the fact that BL reduces mitochondrial ATP, necessary to protein synthesis. One hypothesis is that in case of damage ATP is diverted towards its use for the synthesis of proteins that help the cell to avoid the injury. Due to blue light stress conditions, ATP molecules might be captured for the synthesis of stress related proteins, i.e., Bax or survival proteins. This BL-triggered cell reaction might lead to a reduced total amount of ATP. Further ATP production may not be sufficient due to inhibition of respiratory chain complexes. Another intriguing possibility is that the ATP content of the retinal lysates is mainly affected by the absolute content of ATP in the rod OS, which displays a considerable ATP synthetic ability (about 0.6 micromoles/min/mg of protein) [43]. Consequently, the total ATP content of the retinas would not be representative of the actual fluctuations in ATP content of retinal components other than the OS. Moreover, the measurement of total ATP cannot represent its nano-local turnover fluctuations. The rod OS cannot carry out protein synthesis, being devoid of ribosomes and DNA: consistently neither BL nor RL stimulation altered the protein expression level of the OXPHOS complexes. Along with this view, it is conceivable that RL increases Bcl-2 by 50% compared with controls and that BL increases Bax by 50%, as data show, regardless of the measures of total ATP. On the other hand, an experimental time of 6 h and 9 h is sufficient to involve protein synthesis in those parts of the retina that can actually conduct it.PDF Image | Photobiomodulation Mediates Neuroprotection against Retinal
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