Mitochondrial mechanisms of photobiomodulation in context of new data about multiple roles of ATP.

Various cellular responses to visible and IR-A radiation have been studied for decades in the context of molecular mechanisms of laser phototherapy [also called photobiomodulation, low-level light therapy (LLLT)]. LLLT uses monochromatic and quasimonochromatic light in the optical region of *600–1,000 nm to treat in a nondestructive and nonthermal fashion various soft-tissue and neurologic conditions. This modality also was recently used to reverse toxic effects of neurotoxins, to treat strokes and acute myocardial infarction, and to stimulate stem cell proliferation. This multiplicity of conditions treated with photobiomodulation has persuaded many unbelievers of the value of such an universal method. It is generally accepted that the mitochondria are the initial site of light action in cells, and cytochrome c oxidase (the terminal enzyme of the mitochondrial respiratory chain) is the responsible molecule. Mixed-valence copper components of cytochrome c oxidase, CuA and CuB, are believed to be the photoacceptors. The same photoacceptor molecule for different cellular responses can explain, at least partly, the versatility of low-power laser effects. The excitation of the photoacceptor molecule sets in motion cellular metabolism through cascades of reactions called cellular signaling or retrograde mitochondrial signaling. At least two reactions are starting points for monitoring cellular-signaling reactions after light action on the cytochrome c oxidase molecule. One of them is dissociation of NO from the catalytic center of cytochrome c oxidase. Spectroscopic studies of irradiated cellular monolayer show that two charge-transfer channels putatively to CuAred and CuBoxid , as well as two reaction channels putatively connected with d-d transition in CuBred and CuAoxid chromophores, are reorganized dependent on NO presence or absence. It has been suggested that the dissociation of NO (a physiologic regulator of cytochrome c oxidase activity) rearranges downstream signaling effects. Another signaling pathway starting from the mitochondria is connected with ATP. The ATP extrasynthesis in isolated mitochondria and intact cells of various types, under irradiation with light of different wavelengths, is well documented. ATP is a universal fuel inside living cells that drives all biologic reactions. It is known that even small changes in the ATP level can significantly alter cellular metabolism. Increasing the amount of this energy may improve the cellular metabolism, especially in suppressed or otherwise ill cells. In connection with the versatility of LLLT effects, I draw the readers’ attention to a comparatively new aspect of the ATP molecule. A long series of discoveries has demonstrated that ATP is not only an energy currency inside cells, but it is also a critical signaling molecule that allows cells and tissues throughout the body to communicate with one another. This new aspect of ATP as an intercellular signaling molecule allows broadening the understanding of universality phenomenon of LLLT as well. It is known now that neurons release ATP into muscle, gut, and bladder tissue as a messenger molecule. The specific receptors for ATP as the signaling molecule (P2 family) and for its final breakdown product, adenosine (P1 family), were found and identified. ATP activation of P2 receptors (subtypes P2X and P2Y) can produce different cellular effects. A recent article by Anders et al. demonstrated that P2Y2 and P2Y11 receptors were expressed in the irradiated at l1⁄4 810-nm normal human neural progenitor cells in vitro. It appeared that the irradiation could be used as a replacement for growth factors. This line of research opens a new understanding of the complicated mechanisms of LLLT. From the point of view of the topic of the present article, the role of ATP as a signaling molecule provides a new basis for explaining the versatility of LLLT effects. The second important point in connection with multiple functions of ATP and P2X and P2Y receptors is the following. When bound by ATP, P2X receptors form a channel that allows sodium and calcium ions to enter the cells. ATP binding to the extracellular surface of P2Y receptors starts a cascade of molecular interactions inside cells, with those resulting in intracellular calcium stores being released. The increase in intracellular Ca2þ ions ([Ca]i) due to the irradiation has been measured by many authors, but the mechanism of the phenomenon of [Ca]i increase in the irradiated cells has not been explained. Ca2þ is a global positive effector of mitochondrial function, and thus, any perturbation in mitochondrial or cytosolic Ca2þ homeostasis will have implications on mitochondrial functions. This concerns the regulation of [Ca]i from outside by binding ATP to P2X receptors. It is important to remember that both Ca2þ uptake and efflux from mitochondria consume DCm