Mechanisms of oxygen toxicity in the context of mitochondrial dysfunction

背景：氧是大气中最重要的元素之一，是产生人体主要能量来源(三磷酸腺苷或三磷酸腺苷)所必需的。三磷酸腺苷是由称为线粒体的细胞结构通过氧化磷酸化(OXPHOS)过程产生的，该过程消耗氧气。最近观察到，高氧水平对线粒体有缺陷的患者可能是剧毒的。在线粒体功能障碍的小鼠模型中也观察到了类似的情况，但其中涉及的机制尚不清楚。我们认为，OXPHOS途径的“阻断”会导致组织中氧气的积聚，从而限制了可以产生的能量。添加更多的氧气可能会加剧这种情况，并导致患者的症状恶化。了解氧中毒背后的机制对我们来说很重要，以确保个别患者得到适当的治疗，而不会造成任何进一步的伤害。这个项目的目的是在两个实验组中更多地了解氧中毒的潜在原因：第一组：罕见的遗传性线粒体疾病患者已知在OXPHOS中有特定的缺陷，这会影响大脑和骨骼肌的能量产生。我们预测，吸入55%的氧气会导致线粒体功能障碍患者的能量产生减少，但在年龄匹配的健康志愿者中不会。2组：创伤性脑损伤患者。脑外伤常与线粒体功能受损有关。研究氧气对这组患者的影响将有助于在更广泛的医学背景下解释我们的结果。我们将比较有线粒体功能受损的脑外伤患者和没有线粒体功能受损的脑损伤患者。方法：我们将在人体上测试我们的理论，方法是比较吸入普通室内空气(大约20%氧气)和吸入高水平氧气(55%)1小时的效果。我们将使用以下措施：1.功能磁共振(MR)扫描将使我们能够实时测量体内大脑和肌肉的能量产生和线粒体功能。2.将使用非侵入性探头测量血氧水平，并分析组织对氧气的吸收和利用情况(血氧仪)。脑损伤患者的大脑和组织的氧气和代谢水平将通过一种名为微透析的技术进行测量。这个小组已经安装了脑组织氧气传感器，使我们能够直接测量大脑内的氧气输送和新陈代谢。4.所有参与者吸氧前和吸氧后的血液样本将被用来分析血细胞中称为生物标记物的分子，这可以进一步提供有关氧中毒机制的线索，并将两个研究小组联系起来。重要：在体内和血液中研究这些参数将指导氧中毒临床生物标记物的开发，并将影响临床环境中氧气输送的新方法。这些发现将影响罕见线粒体疾病的氧气使用，并可能影响包括败血症、危重疾病、中风、创伤和心肌梗死在内的常见疾病的临床治疗。

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.