Project Summary Poison-related incidents account for over 450,000 hospitalizations and 750,000 emergency department (ED) visits, with the yearly cost for ED visits exceeding $550 million. It is conservatively estimated that 5,000 deaths per year and 20,000 injuries in the US are due to mitochondrial poisons (e.g., carbon monoxide (CO), cyanide (CN), hydrogen sulfide (H2S), phosphides) resulting in mitochondrial inhibition leading directly to cardiac arrest and/or shock. Exposure to mitochondrial inhibitors occurs in a variety of settings, including fires, occupational and industrial exposures, suicide and potential air-, water- and food-borne terrorism agents such as weaponized gases and liquids. Treatment at this is time is limited and currently depends on supportive care and use of antidotal therapy of variable effectiveness. The primary cause of death to these mitochondrial inhibitors is circulatory shock and cardiac arrest. Despite currently available treatments, morbidity and mortality remains high due to significant gaps in knowledge, including the relationship between mitochondrial dysfunction in response to acute mitochondrial poisoning and the lack of adequate molecular or cell-based indices for goal-directed treatment. My long-term goal is to identify characteristic signatures of abnormalities in mitochondrial bioenergetics and dynamics in human blood cells as well as apply a new pharmacological strategy of mitochondrial-directed therapy. My central hypothesis, formulated on the basis of my relevant publications and preliminary data found in this grant, is that there are considerable changes in complex-linked activity, ROS and dynamics in response to acute poisoning. Also that blood cells may be used a surrogate marker of mitochondrial dysfunction of affected tissue. At this time there are no clinical tests that directly measure mitochondrial function in a time-sensitive manner relevant to acute patient care. The experiments proposed in this application will apply the measurement or assessment of various parameters defining mitochondrial bioenergetics and dynamics in isolated human blood cells obtained from poisoned patients. We will also apply a new pharmacologic strategy for mitochondrial directed treatment in human blood cells exposed to select mitochondrial poisons in a controlled manner. The rationale for the proposed research is develop a clear understanding of the dysfunction that appears in mitochondrial bioenergetics and motility in response to mitochondrial poisons and the restoration of normal mitochondrial function that occurs with implementation of effective treatment.

Project Narrative Acute toxicological poisoning is a leading causes of injury-related fatalities in the United States and the leading cause of cardiac arrest in victims under the age of 40. This project investigates a better understanding of mitochondrial dysfunction that occurs in shock and cardiac arrest from poisoning related to mitochondrial inhibitors of public health importance such as carbon monoxide and cyanide. We will also utilize a new pharmacologic strategy for directed mitochondrial treatment.