Putative biomolecular pathways of retinal pigmented epithelial cytochrome c oxidase rescue by 670 nm red light as outlined in a virtual study environment.

Abstract

Purpose : Multiple studies have shown low intensity red light, typically 670nm in wavelength, reduces oxidative stress and rescues function of mitochondrial cytochrome c oxidase (COX). Downstream signaling effects of red light exposure have been proposed, however putative global effects of red light treatment by identifiable biomolecular signatures remain enigmatic. The purpose of this study is to identify the interface of mediators of retinal pigmented epithelial cell mitochondrial cytochrome c oxidase (COX) inhibition with the molecular signature of mitochondrial COX rescue by photobiomodulation though use of a machine learning environment.

Methods : An open source concept and content matrix application (Visual Understanding Environment v3.3.0, Tufts University) was employed to integrate pathways found through literature review that influence interactions between reactive oxygen species, oxidative stress, COX and retinal degeneration. Connectivity matrices were then imported into a predictive pathway analysis program (Ingenuity Pathway Analysis, Qiagen Bioinformatics, Hilden, Germany) and subjected to iterative sensitivity analysis to determine a legitimate biomolecular interface linking oxidative insult, COX inhibition, retinal degeneration and red light COX salvage.

Results : The gene MT-TL1 was found to be a key link between oxidative stress, retinal degeneration and COX deficiency. Complement factors CFHR1, CFH, and CFHR3 and the ATP binding cassette ABCA4 were linked to complement component C3 and oxidative stress. APOE was linked to production of reactive oxygen species (ROS), as well as oxidative stress and HtrA serine peptidase 1 (HTRA1). Excision repair cross-complementation group 6 (ERCC6), cystain C (CST3) and APOE were found to contribute to oxidative stress but were unrelated to COX inhibition. The complement component C3, a marker for inflammation in the retina, was found to be a key nodal point in ROS production.

Conclusions : While there were many links between AMD, oxidative stress response, and the production of ROS, the most important part of this network in terms of photobiomodulation appears to be the single link of mutant MT-TL1 between retinal degeneration and COX deficiency. MT-TL1 is a mitochondrial gene which codes for tRNA^Leu(UUR) and may be a key signature of photobiomodulation induced COX salvage.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.