Emerging cellular-based therapies in carbon monoxide poisoning

Abstract

Carbon monoxide (CO) is an odorless and colorless gas with multiple sources that include engine exhaust, faulty furnaces, and other sources of incomplete combustion of carbon compounds such as house fires. The most serious complications for survivors of consequential CO exposure are persistent neurological sequelae occurring in up to 50% of patients. CO inhibits mitochondrial respiration by specifically binding to the heme a₃ in the active site of CIV-like hydrogen sulfide, cyanide, and phosphides. Although hyperbaric oxygen remains the cornerstone for treatment, it has variable efficacy requiring new approaches to treatment. There is a paucity of cellular-based therapies in the area of CO poisoning, and there have been recent advancements that include antioxidants and a mitochondrial substrate prodrug. The succinate prodrugs derived from chemical modification of succinate are endeavored to enhance delivery of succinate to cells, increasing uptake of succinate into the mitochondria, and providing metabolic support for cells. The therapeutic intervention of succinate prodrugs is thus potentially applicable to patients with CO poisoning via metabolic support for fuel oxidation and possibly improving efficacy of HBO therapy.

Keywords: carbon monoxide; cellular therapies; mitochondria; respiration; succinate prodrug.

Figure 1.

Oxidative phosphorylation (OXPHOS) is a series of complexes that transfer electrons from electron donors to electron acceptors via redox reactions and couples this electron transfer with the transfer of protons across a membrane. This ultimately leads to the phosphorylation of ADP to ATP by complex V (CV). (1) Carbon monoxide (CO): Downstream consequences of complex IV (CIV) inhibition from CO includes decreased ATP production, reverse redox leading to increased reactive species and decreased mitochondrial membrane potential. (2) Succinate prodrug: The use of a succinate prodrug with partial CIV inhibitionmay mitigate this dysfunction by providing more succinate for complex II (CII) that may increase ATP production, increase the mitochondrial membrane potential, and also decrease reactive oxygen species (ROS) production. An unintended consequence of increased CII activity with CIV inhibition may include increased ROS production. (3) S1QELs: Site I_Q of complex I (CI) make a substantial contribution to ROS production. S1QELs are site-specific supressors that decrease ROS production. The use of these site-specific supressors may alleviate ROS production from CIV inhibition from CO and/or the use of a succinate prodrug. (4) MitoQ: MitoQ is a ubiquinone moiety linked to a triphenylphosphonium (TPP) cation that acts to deliver the attached compound. The ubiquinol form of MitoQ acts as an antioxidant becoming oxidized to a ubiquinone which is then reduced by CII back to ubiquinol. ADP, adenosine diphosphate; ATP, adenosine triphosphate; c, cytochrome c; CO, carbon monoxide; mGPD, mitochondrial glycerophosphate dehydrogenase; Q, coenzyme Q or ubiquinone.