Mitochondrial Dysfunction and Parkinson's Disease-Near-Infrared Photobiomodulation as a Potential Therapeutic Strategy

Abstract

As the main driver of energy production in eukaryotes, mitochondria are invariably implicated in disorders of cellular bioenergetics. Given that dopaminergic neurons affected in Parkinson's disease (PD) are particularly susceptible to energy fluctuations by their high basal energy demand, it is not surprising to note that mitochondrial dysfunction has emerged as a compelling candidate underlying PD. A recent approach towards forestalling dopaminergic neurodegeneration in PD involves near-infrared (NIR) photobiomodulation (PBM), which is thought to enhance mitochondrial function of stimulated cells through augmenting the activity of cytochrome C oxidase. Notwithstanding this, our understanding of the neuroprotective mechanism of PBM remains far from complete. For example, studies focusing on the effects of PBM on gene transcription are limited, and the mechanism through which PBM exerts its effects on distant sites (i.e., its "abscopal effect") remains unclear. Also, the clinical application of NIR in PD proves to be challenging. Efficacious delivery of NIR light to the substantia nigra pars compacta (SNpc), the primary site of disease pathology in PD, is fraught with technical challenges. Concerted efforts focused on understanding the biological effects of PBM and improving the efficiency of intracranial NIR delivery are therefore essential for its successful clinical translation. Nonetheless, PBM represents a potential novel therapy for PD. In this review, we provide an update on the role of mitochondrial dysfunction in PD and how PBM may help mitigate the neurodegenerative process. We also discussed clinical translation aspects of this treatment modality using intracranially implanted NIR delivery devices.

Keywords: Parkinson’s disease; energy dysregulation; mitochondria dysfunction; near infrared; neurodegeneration.

Figure 1

Near-infrared (NIR) stimulation and its potential neuroprotective role in Parkinson’s disease (PD). (A) A wirelessly powered intracranial device implanted in the human brain for delivery of NIR PBM to the SNpc. (B) Mitochondrial oxidative phosphorylation chain consisting of 5 different transmembrane protein complexes on the IMM that comprise the electron transport chain (ETC). The ETC pumps electrons derived from the Krebs cycle across the IMM into the intermembranous space through the actions of NADH dehydrogenase (complex I) and succinate dehydrogenase (complex II). The electrons are subsequently transferred to ubiquinone, which is reduced to ubiquinol upon electron receival. Cytochrome bc1 complex (complex III) then transfers these ubiquinol bound electrons to cytochrome C, which in turn binds to cytochrome C oxidase (complex IV) and facilitates the final electron transfer to oxygen. This transfer of electrons is coupled with the outward movement of protons across the IMM, establishing a transmembrane electrochemical gradient. Potential energy stored in the transmembrane gradient [proton motive force ΔP_m] is utilized by adenosine triphosphate (ATP) synthetase (complex V) to drive the production of ATP from ADP and phosphate, which is coupled to the inward flow of protons across the IMM. (C) Energy-demanding features of SNpc dopaminergic neurons. These neurons possess extensive axonal arborization, long and poorly myelinated axonal projections, as well as L-type Cav1.3 channel-mediated pacemaker-type firing. Cumulatively these properties deplete the reserve capacity of these neurons to respond to an energy crisis. (D) The mitochondria life cycle depicting the processes of biogenesis, fusion, fission, and degradation. The effects of NIR on these processes remain uncertain. (E) An illustration of mitochondrial complex IV, COX, with its heme and copper centers. Electrons are transferred from cytochrome C to O₂ via a series of redox reactions involving these centers. Binding of endogenous NO to O₂’s binding site on CuB and prevents the final electron transfer step in oxidative phosphorylation. NIR PBM is purported to act via photodissociation of NO from O₂’s binding site, releasing the NO’s inhibition on COX and thereby enhancing mitochondrial energy production. Abbreviations: ATP, Adenosine triphosphate; C I, Complex I; C II, Complex II; C III, Complex III; C IV, Complex IV; C V, Complex V; CuA, Copper A; CuB, Copper B; Cyt C, Cytochrome C; DA, Dopaminergic; IMM, Inner mitochondrial membrane; IMS, Intermembrane space; NIR, Near-infrared; NO, Nitric oxide; O₂, Oxygen; Q, Coenzyme Q; PBM, Photobiomodulation; SNpc, Substantia nigra pars compacta.

Figure 2

Alternative sites for implantation of NIR delivery device apart from the ventral midbrain. Wirelessly powered NIR delivery devices in the 3rd ventricle and the sphenoid sinus (SS), both of which are close to the ventral midbrain. Insertion of the device into the 3rd ventricle can be achieved safely via a straight trajectory traversing the Foramen of Monroe. Insertion of the NIR device within the SS in the posterior part of the nasal cavity can be achieved using an endoscopic endonasal approach. Abbreviations: FoM, foramen of Monroe; NIR, near-infrared; SNpc, substantia nigra pars compacta; SS, sphenoid sinus.