Mechanisms of oxygen toxicity in the context of mitochondrial dysfunction

线粒体功能障碍背景下的氧毒性机制

• 批准号: MR/S035699/1
• 负责人: Patrick Chinnery
• 金额: $ 85.88万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS035699%2F1
• 关键词: Mechanisms; oxygen; toxicity; context; mitochondrial

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.

背景资料：氧气是大气中最重要的元素之一，是生产人体主要能量来源（三磷酸腺苷或ATP）所必需的。ATP由称为线粒体的细胞结构通过称为氧化磷酸化（OXPHOS）的过程产生，该过程消耗氧气。最近观察到，高氧水平可能对线粒体缺陷患者有急性毒性。在线粒体功能障碍的小鼠模型中也观察到了类似的情况，但所涉及的机制尚不清楚。我们认为，OXPHOS通路中的“阻断”导致组织中氧气的积聚，限制了可以产生的能量。添加更多氧气可能会加剧情况并导致患者症状恶化。对我们来说，重要的是要了解这种氧毒性背后的机制，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。该项目的目的是在两个实验组中更多地了解氧毒性的根本原因：第1组：患有罕见遗传性线粒体疾病的患者已知具有OXPHOS的特定缺陷，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，但在健康的年龄匹配的志愿者中不会。第2组：创伤性脑损伤（TBI）患者。TBI通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。我们将比较线粒体功能受损的TBI患者与线粒体功能未受损的TBI患者。方法：我们将通过比较普通室内空气（约20%的氧气）和高水平氧气（55%）吸入1小时的效果来测试我们的理论。我们将采取以下措施：1.功能性磁共振（MR）扫描将使我们能够在大脑和肌肉中真实的时间内测量体内的能量产生和线粒体功能。2.将使用无创探头测量血氧水平，并分析组织吸收和利用氧气的情况（血氧测定）。3.脑和组织的氧气和代谢水平将通过一种称为微透析的技术在TBI患者中进行测量。这个小组已经有了脑组织氧传感器，这使我们能够直接测量大脑内的氧气输送和代谢。4.所有参与者在吸氧前后的血液样本将被用于分析血细胞中被称为生物标志物的分子，这可以提供有关氧毒性机制的进一步线索，并将两个研究组联系起来。重要性：研究身体和血液中的这些参数将指导氧毒性临床生物标志物的开发，并且将影响关于在临床环境中输送氧气的新方法。这些发现将影响罕见线粒体疾病中氧的使用，并可能影响常见疾病的临床管理，包括败血症，危重病，中风，创伤和心肌梗死。

项目成果

Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments.

• DOI: 10.1186/s13063-021-05965-4
• 发表时间: 2022-01-20
• 期刊: Trials
• 影响因子: 2.5
• 作者: Cake C;Ogburn E;Pinches H;Coleman G;Seymour D;Woodard F;Manohar S;Monsur M;Landray M;Dalton G;Morris AD;Chinnery PF;UK COVID-19 National Core Studies Consortium;Hobbs FDR;Butler C
• 通讯作者: Butler C

Single-molecule mitochondrial DNA sequencing shows no evidence of CpG methylation in human cells and tissues.

单分子线粒体 DNA 测序显示，人类细胞和组织中没有 CpG 甲基化的证据。

• DOI: 10.17863/cam.77972
• 发表时间: 2021
• 作者: Bicci I

Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.

心血管疾病中的杂质线粒体DNA变体。

• DOI: 10.1371/journal.pgen.1010068
• 发表时间: 2022-04
• 期刊: PLoS genetics
• 影响因子: 4.5

Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments

开发和评估基于数据的快速访问常规临床信息，以加强 COVID-19 社区治疗国家临床平台试验的早期招募

• DOI: 10.1101/2021.01.15.21249724
• 发表时间: 2021
• 作者: Cake C