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Mitochondrial Mechanisms of Photobiomodulation in Context of New Data About Multiple Roles of ATP

  • Laser Technology Research Center of Russian Academy of Science, Moscow, Russia
Guest Editorial
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
and 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
cellular signaling
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
or absence.
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
ions ([Ca
) due to the irra-
diation has been measured by many authors,
but the
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.
Pp. 159–160
DOI: 10.1089=pho.2010.2789
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.
ATP sig-
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
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Mitochondrial signaling is an information channel between the mitochondrial respiratory chain and the nucleus for the transduction signals regarding the functional state of the mitochondria. The present review examines the question whether radiation of visible and near-IR (IR-A) radiation can activate this retrograde-type cellular signaling pathway. Experimental data about modulation of elements of mitochondrial retrograde signaling by the irradiation (mitochondrial membrane potential DeltaPsi(m), reactive oxygen species ROS, Ca(2+), NO, pH(i), fission-fusion homeostasis of mitochondria) are reviewed. The terminal enzyme of the mitochondrial respiratory chain cytochrome c oxidase is considered as the photoacceptor. Functions of cytochrome c oxidase as a signal generator as well as a signal transducer in irradiated cells are outlined.
The molecule ATP, famous as an essential energy source inside cells, also carries critical messages between cells. That dual role is suggesting fresh ideas for fighting human diseases
Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pain. We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale. We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1.69 (95% CI 1.22-2.33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4.05 (2.74-5.98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19.86 mm (10.04-29.68). Seven trials provided follow-up data for 1-22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22.07 mm (17.42-26.72). Side-effects from LLLT were mild and not different from those of placebo. We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain. None.
P2X and P2Y nucleotide receptors are described on sensory neurons and their peripheral and central terminals in dorsal root, nodose, trigeminal, petrosal, retinal and enteric ganglia. Peripheral terminals are activated by ATP released from local cells by mechanical deformation, hypoxia or various local agents in the carotid body, lung, gut, bladder, inner ear, eye, nasal organ, taste buds, skin, muscle and joints mediating reflex responses and nociception. Purinergic receptors on fibres in the dorsal spinal cord and brain stem are involved in reflex control of visceral and cardiovascular activity, as well as relaying nociceptive impulses to pain centres. Purinergic mechanisms are enhanced in inflammatory conditions and may be involved in migraine, pain, diseases of the special senses, bladder and gut, and the possibility that they are also implicated in arthritis, respiratory disorders and some central nervous system disorders is discussed. Finally, the development and evolution of purinergic sensory mechanisms are considered.
The hypothesis is summarised schematically in Fig. 1. It is proposed that mechanical deformation 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 skin; the ATP then occupies specific receptor subtypes expressed on sensory nerve endings in the skin and tongue; the sensory nerves send impulses through ganglia to the spinal cord, the brain stem, hypothalamus and higher centres; the brain stem and hypothalamus contain neurons that control autonomic functions, including cardiovascular, gastrointestinal, respiratory, urinogenital and musculo-skeletal activity. Impulses generated in sensory fibres in the skin connect with interneurons to modulate (either inhibition or facilitation) the activities of the motoneurons in the brain stem and hypothalamus to change autonomic functions; specifically activated sensory nerves, via interneurons, also inhibit the neural pathways to the pain centres in the cortex.