Lucynda Pham, MS
Molecular Genetics and Genomics PhD Candidate, Laboratory of Maik Hüttemann, PhD
“Mitochondrial Rejuvenation and Restoration Through Photo-Biomodulation Using Cytochrome C Oxidase-Inhibitory Infrared Light: A Multi-Spectrum Therapeutic”

Abstract

Cytochrome c oxidase (COX) is the proposed rate-limiting step of the electron transport chain (ETC) and has major influence on the mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) production. The regulation of the reaction of Cytc and COX controls ΨΔm and it is therefore tightly regulated through various means including ATP/ ADP allosteric regulation, tissue-specific isoforms, and post-translational modifications. The discovery of two COX-inhibitory wavelengths (750 nm and 950 nm) provides an additional way to regulate this reaction. Photo-biomodulation by mild inhibition of COX allows fine-tuning of ΨΔm to treat conditions of cellular dysfunction when the membrane potential is above the optimal intermediate range or below. This therapeutic has strong potential to treat human diseases non-invasively and is a multi-spectrum tool. In conditions where ΨΔm is hyperpolarized, IRL maintains its activity within the physiological range, preventing bursts of ROS. Such conditions include ischemia/reperfusion (I/R) injury as seen in cardiac arrest and resuscitation, cerebral stroke, or myocardial infarction. A novel mechanism presented here is that IRL-mediated reduction of ΨΔm stimulates  mitochondrial quality control (MQC) pathways leading to selective removal of damaged mitochondria through activation of mitophagy, improving bioenergetics. Decreased ΨΔm below the optimal range is a metric of damaged and dysfunctional mitochondria. Depolarization of ΨΔm using IRL can push damaged mitochondria over a threshold to be removed by targeting COX. The potential for this application applies to numerous diseases such as diabetes, neurodegenerative disease, and sarcopenia, which are highly age-associated and where accumulation of dysfunctional mitochondria is well established. Pre-treatment with IRL to improve mitochondrial function prevented oxidative damage-induced senescence. Previously, these wavelengths were shown to provide robust neuroprotection against I/R injury in animal modes of cardiac arrest and resuscitation and ischemic stroke. The contribution of this work opens the door for novel applications of these same IRL wavelengths to be applied to a larger number of pathophysiological conditions.