Mechanisms of oxygen toxicity in the context of mitochondrial dysfunction

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Background: Oxygen is one of the most important elements in the atmosphere, and is essential required for production of the body's main source of energy (adenosine triphosphate or ATP). ATP is produced by cellular structures called mitochondria through a process called oxidative phosphorylation (OXPHOS), which consumes oxygen. It has recently been observed that high oxygen levels can be acutely toxic in patients with faulty mitochondria. A similar situation has been observed in mouse models with mitochondrial dysfunction, but the mechanism involved is not yet understood. We propose that a 'block' in the OXPHOS pathway leads to a build-up of oxygen in the tissues, limiting the amount of energy that can be produced. Adding more oxygen can potentially exacerbate the situation and cause patients' symptoms to worsen. It is important for us to understand the mechanisms behind this oxygen toxicity to ensure that individual patients are treated appropriately without causing any further harm. The aim of this project is to learn more about the underlying reasons for oxygen toxicity in two experimental groups: Group 1: Patients with rare inherited mitochondrial disorders are known to have a specific defect in OXPHOS, which affects energy production in the brain and skeletal muscle. We predict that inhaling 55% oxygen will lead to reduced energy production in the patients with mitochondrial dysfunction, but not in healthy age-matched volunteers. Group 2: Patients with Traumatic Brain Injury (TBI). TBI is often associated with impaired mitochondrial function. Studying the effects of oxygen in this group of patients will help the interpretation of our results in a broader medical context. We will compare TBI patients who have impaired mitochondrial function to patients who have TBI with no impairment of mitochondrial function. Approach: We will test our theory in humans by comparing the effects of regular room air (roughly 20% oxygen) and high level oxygen (55%) inhaled for 1 hour. We will use the following measures: 1. Functional magnetic resonance (MR) scanning will let us measure energy production and mitochondrial function inside the body in real time in the brain and muscle. 2. A non-invasive probe will be used to measure blood oxygen levels and analyse how well oxygen is being taken up and utilised by the tissues (oximetry).3. Brain and tissue oxygen and metabolism levels will be measured by a technique called microdialysis in the TBI patients. This group already have brain tissue oxygen sensors in place, which allows us to directly measure oxygen delivery and metabolism within the brain. 4. Blood samples from all participants before and after oxygen inhalation will be taken to analyse blood cells for molecules called biomarkers, which can give further clues about the mechanisms involved in oxygen toxicity, and link the two study groups.Importance: Studying these parameters in both the body and the blood will guide the development of clinical biomarkers of oxygen toxicity, and will influence new approaches regarding the delivery of oxygen in the clinical setting. These findings will impact on the use of oxygen in rare mitochondrial diseases, and potentially influence the clinical management of common disorders including sepsis, critical illness, stroke, trauma and myocardial infarction.