Mitochondrial-Directed Therapy in Carbon Monoxide Poisoning

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Carbon monoxide (CO) is a colorless and odorless gas that is an important cause of poisoning annually with an estimated 50,000 emergency department visits occurring in the US and it is a leading cause of poisoning death globally. Various sources include faulty heat generators, suicidal attempts and fires. It is estimated that CO poisoning in the US results in over $1 billion annually related to hospital costs and lost earnings. CO poisoning has high mortality and morbidity with effects at the cardiovascular and neurologic system. The most serious complication of consequential CO exposure is delayed neurological sequela which occurs in up to 50% of patients. There are multiple mechanisms of CO poisoning such as lipid peroxidation and hypoxia. Our own work demonstrates that there are alterations in mitochondrial function (both bioenergetic and dynamic) in CO poisoning. The standard treatment for CO poisoning recommended by the Undersea & Hyperbaric Medical Society is hyperbaric oxygen (HBO) therapy. At this time, both diagnostics and treatments are aimed at early supportive care and select use of hyperbaric therapy. However, there are significant gaps that include: (1) lack of biomarkers to gauge severity of disease; (2) limited mechanistic understanding at a cellular level with regard to mitochondrial function (bioenergetics and dynamics); (3) the effectiveness of HBO for CO poisoning is widely debated with treatment aimed at the underlying mitochondrial dysfunction imposed by CO being virtually non- existent and; (4) lack of any point of care therapy. We seek to investigate abnormal mitochondrial function in blood cells consisting of peripheral blood mononuclear cells (PBMCs) and platelets (PLTs) against tissue in an animal model of CO poisoning and to utilize a new pharmacological strategy to directly improve mitochondrial function. We propose to address the critical issues relevant to mitochondrial function: • What is the tissue-specific changes in mitochondrial function in an animal model of CO poisoning and can PBMCs and PLTs serve as a proxy for tissue mitochondrial function for the brain and heart? • Can PBMCs and PLTs serve as a reliable and informative marker of early mitochondrial dysfunction in CO poisoning which may enable intervention in the subclinical stages of disease? • How can our data obtained be leveraged to study mitochondrial-directed therapy in CO poisoning to address the lack of any existing point of care therapy for CO poisoning? Our central hypothesis is that there are decrements in mitochondrial function in response to CO poisoning and that our mechanistic-based treatment will restore normal cellular function. The long-term goals of our proposed research are to define specific mitochondrial defects in CO poisoning and evaluate a novel therapy now available for in vivo use. Our group currently has experience in both the in vitro and in vivo use of this compound with relevant publications.