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Mitochondrial Mechanisms of Photobiomodulation
in Context of New Data About Multiple Roles of ATP
Tiina Karu, Dr. Sci., Ph.D.
Various cellular responses to visible and IR-A radia-
tion 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
This modality also was recently used to reverse
toxic effects of neurotoxins, to treat strokes and acute myo-
cardial infarction, and to stimulate stem cell proliferation.
This multiplicity of conditions treated with photo-
biomodulation has persuaded many unbelievers of the value
of such an universal method.
It is generally accepted that the mitochondria are the ini-
tial site of light action in cells, and cytochrome coxidase (the
terminal enzyme of the mitochondrial respiratory chain) is
the responsible molecule.
Mixed-valence copper compo-
nents of cytochrome coxidase, Cu
, are believed to
be the photoacceptors.
The same photoacceptor mole-
cule for different cellular responses can explain, at least
partly, the versatility of low-power laser effects.
The excitation of the photoacceptor molecule sets in mo-
tion cellular metabolism through cascades of reactions called
or retrograde mitochondrial signaling.
At least two reactions are starting points for monitoring
cellular-signaling reactions after light action on the cyto-
chrome coxidase molecule. One of them is dissociation of
NO from the catalytic center of cytochrome coxidase.
Spectroscopic studies of irradiated cellular monolayer
show that two charge-transfer channels putatively to
CuAred and CuBoxid , as well as two reaction channels puta-
tively connected with d-d transition in CuBred and CuAoxid
chromophores, are reorganized dependent on NO presence
It has been suggested that the dissociation of NO
(a physiologic regulator of cytochrome coxidase activity)
rearranges downstream signaling effects.
Another signaling pathway starting from the mitochon-
dria is connected with ATP. The ATP extrasynthesis in iso-
lated mitochondria and intact cells of various types, under
irradiation with light of different wavelengths, is well
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 me-
tabolism. Increasing the amount of this energy may improve
the cellular metabolism, especially in suppressed or other-
wise 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 phe-
nomenon of LLLT as well. It is known now that neurons
release ATP into muscle, gut, and bladder tissue as a mes-
senger molecule. The speciﬁc receptors for ATP as the sig-
naling molecule (P2 family) and for its ﬁnal breakdown
product, adenosine (P1 family), were found and identi-
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 l¼810-nm normal
human neural progenitor cells in vitro. It appeared that the
irradiation could be used as a replacement for growth fac-
tors. 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 re-
sulting in intracellular calcium stores being released.
increase in intracellular Ca
) due to the irra-
diation has been measured by many authors,
mechanism of the phenomenon of [Ca
increase in the ir-
radiated cells has not been explained. Ca
is a global posi-
tive effector of mitochondrial function, and thus, any
perturbation in mitochondrial or cytosolic Ca
will have implications on mitochondrial functions. This
concerns the regulation of [Ca
from outside by binding
ATP to P2X receptors. It is important to remember that both
uptake and efﬂux from mitochondria consume DC
Institute of Laser and Information Technologies of Russian Academy of Sciences, Troitsk, Moscow region, Russian Federation.
Photomedicine and Laser Surgery
Volume 28, Number 2, 2010
ªMary Ann Liebert, Inc.
and, in this way, depend on mitochondrial activity (and
therefore on ATP synthesis), which can be regulated by
Understanding of the multiple role of ATP in cellular
metabolism will also provide a better appreciation of the cel-
lular and molecular mechanisms of LLLT. A recent review
indicates that laboratories worldwide are now racing to turn
the data about ATP as a neurotransmitter into therapies. As a
neurotransmitter, ATP is directly involved in brain function,
sensory reception, and the neuron system control of muscles
and organs. When released by nonneuronal cells, it often
triggers protective responses, such as bone building and cell
Even a very brief look at all the conditions
in the human body in which ATP is now believed to play a
role as the signaling molecule,
and comparison of these
data with the data on the versatile clinical actions of LLLT
provides grounds for a new way of thinking.
First, chronic and neuropathic pains are the disorders
treated successfully with LLLT for many years.
naling is believed to be involved into pain therapy.
Second, it is proposed that acupuncture (mechanical de-
formation of the skin by needles and application of heat or
electrical current) leads to release of large amounts of ATP
from keratinocytes, ﬁbroblasts, and other cells in the skin.
Recall that acupuncture by laser light is a well-known
Third, the tumor-killing action of the photobiomodulation
technique has been documented
but met with skepticism.
A tumor-killing effect of ATP has been described.
Perhaps it is now time to reconsider the skepticism about
treating tumors with LLLT, taking into account that ATP
signaling acts, in part, to promote the suicide of the tumor
cells and, in part, to promote cell differentiation, which slows
tumor cell proliferation.
This offers grounds to hope that the new data about the
multiple functions of ATP help to bring the LLLT method
closer to mainstream medicine.
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Address correspondence to:
Prof. Tiina Karu, Dr. Sci., Ph.D.
Institute of Laser and Information Technologies
of Russian Academy of Sciences, Troitsk,
Moscow region 142190, Russian Federation
160 GUEST EDITORIAL
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