# The Potential of Visible and Far-Red to Near-Infrared Light in Glaucoma Neuroprotection
## 3 Pathophysiology of Glaucoma: Increased IOP, Mitochondrial Dysfunction, and Altered Ion Fluxes
Due to their peculiar structural and energetic constraints, RGCs appear to be acutely susceptible to mitochondrial dysfunction; for this reason, the death of RGCs is the hallmark of glaucomatous optic neuropathy. Moreover, as mitochondrial function is also deemed to decline in neurons with aging, mitochondrial dysfunction, as either a cause or consequence of injury, renders RGCs sensitive to degeneration, which may be related to the increasing incidence of glaucoma with advancing age [28]. A further alteration observed in primary glaucoma--especially in the intermittent stage of angle closure glaucoma--is the change in quality and quantity of mitochondria in the iris tissue cells; for example, the disappearance of the mitochondrial crest and vacuole changes were reported. These morphological alterations are accompanied by an increase in intracellular reactive oxygen species (ROS) generation, higher intracellular calcium levels, and lower anti-oxidant expression in glaucomatous lamina cribosa (LC) cells compared to that in normal cells; the alterations are also related to the pathogenesis of glaucoma to some extent [22]. Similar to the neurons of the central nervous system, RGCs depend on ATP generated by mitochondria in order to preserve ionic gradients and survive [8], and any mitochondrial dysfunction will lead to cell damage [29]. The inhibition of enzyme processes, which affect oxidative phosphorylation [29], leads to reduced ATP formation and increased oxidative stress, and finally results in cell death [8]. A decreased energy availability can have a strong impact on the maintenance of ion fluxes which are responsible for neuronal activity. As a consequence, or in addition, defects in ion channel activity can contribute to neuronal death. In glaucoma and other retinal disorders, the expression and function of K\({}^{+}\) channels in Muller glia (critical for preserving the proper physiology of RGCs) are altered [30]. The results of a recent study suggest that both K\({}^{+}\) and Na\({}^{+}\) homeostasis may be chronically changed in glaucoma [31]. In fact, it was demonstrated in vitro that, in Muller glia, the elevated pressure alters cation homeostasis and cation channel flux. The prolonged disruption of these gradients could contribute to the reported alterations in the electrophysiological properties of RGCs in glaucomatous retina [32; 33]. Transient receptor potential vanilloid 4 (TRPV4) cation channels are important Ca\({}^{2+}\) entry pathways that are sensitive to shear stress. Their activation triggers localized calcium influx and lowers IOP in rats and mice [34]. An interesting recent work carried out on human TM cells showed that the mechanism of action of TRPV4 channels is mediated by calcium-induced eNOS (endothelial NO synthase) activation and NO (nitric oxide) production [35]. The consequent vasodilation can explain the decrease in IOP observed in animals. The study demonstrated that TM cells are insensitive to shear stress, as the activity of TRPV4 channels is impaired in glaucoma. Glaucoma-associated functional impairment of TRPV4 channels may contribute to IOP elevation over time, leading to glaucomatous neurodegeneration. Upon calcium entry, its physiological levels are balanced by energy-dependent calcium efflux mechanisms; therefore, mitochondrial activity must be strictly coupled to the activity of ion channels. If this balancing mechanism should fail, the excessive calcium influx could be detrimental to TM physiology and could justify the observations obtained in both human and animal models, which link TRPV4 activity with TRPV4-dependent cytoskeletal remodeling, TM stiffness, and outflow, leading to elevated IOP [36]. Calcium mishandling damages mitochondria and unlashes mitochondrial apoptotic pathways involved in caspase activation. Additionally, the caspase-dependent apoptotic pathway induced by a prolonged inflammatory condition can lead to RGC death.