How does respiratory complex I pumps protons? Finding the missing link using EPR spectroscopy.

呼吸复合体 I 如何泵送质子？

• 批准号: EP/M024393/1
• 负责人: Maxie Roessler
• 金额: $ 12.79万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM024393%2F1
• 关键词: How; does; respiratory; complex; pumps

The rising age of the UK population presents one of the major challenges to our society and economy and it is vital that we maximise the contribution of the most experienced individuals by increasing the number of years we live in best possible health. The mitochondrial respiratory chain, which is essential for the production of ATP and a prime source of reactive oxygen species, is thought to have a major influence on the rate at which we age. Moreover, defects in the respiratory chain are responsible for mitochondrial diseases - these are rare, but their outcome is often very severe, if not fatal. Their diagnosis is fraught with difficulties and there is no cure. Complex I is a crucial but poorly understood element in the mitochondrial respiratory chain and we propose to elucidate a particularly important aspect of the mechanism of this essential enzyme by employing a multidisciplinary approach. We will study the bovine enzyme, a close relative of human complex I, employing in particular electron paramagnetic resonance (EPR) spectroscopy, a powerful method for investigating chemical centres having unpaired electrons. In complex I such unpaired electrons are naturally present or can be generated in mechanistically highly informative locations and we will harness the information they provide through advanced pulse EPR and biochemical methods.Our work will constitute a major step forward in obtaining a complete picture of the molecular mechanism of one of the most important, largest and most enigmatic enzymes in our bodies, with long-term implications for increasing our healthy lifespan and for the recognition and treatment of mitochondrial diseases resulting from complex I dysfunction. Our proposed research program will have immediate impact on UK science, with academic beneficiaries in a diverse range of research disciplines. We will provide top-quality interdisciplinary training for the EPSRC PDRA (and at least two Queen Mary University undergraduate research project students), to provide expertise at the interface of chemistry and biology, with a quantitative approach to fundamental biochemical problems.

英国人口的年龄增长对我们的社会和经济提出了重大挑战之一，至关重要的是，我们通过增加我们生活在最佳健康状态的年数，最大限度地发挥最有经验的个人的贡献。线粒体呼吸链是产生ATP和活性氧的主要来源，被认为对我们衰老的速度有重大影响。此外，呼吸链的缺陷是造成线粒体疾病的原因--这些疾病很罕见，但其后果往往非常严重，如果不是致命的话。他们的诊断充满了困难，没有治愈的方法。复合物I是线粒体呼吸链中的一个重要但知之甚少的元素，我们建议通过采用多学科方法来阐明这种必需酶的机制的一个特别重要的方面。我们将研究牛的酶，人类复合物I的近亲，采用特别是电子顺磁共振（EPR）光谱，一个强大的方法，用于调查化学中心具有不成对电子。在复合体I中，这种未成对电子是天然存在的，或者可以在机械上高度信息化的位置产生，我们将通过先进的脉冲EPR和生物化学方法利用它们提供的信息。我们的工作将构成向前迈出的重要一步，以获得我们体内最重要，最大和最神秘的酶之一的分子机制的完整图片，对于延长我们的健康寿命以及识别和治疗由复合物I功能障碍引起的线粒体疾病具有长期意义。我们提出的研究计划将对英国科学产生直接影响，在不同的研究学科的学术受益者。我们将为EPSRC PDRA（以及至少两名玛丽女王大学本科研究项目学生）提供高质量的跨学科培训，以提供化学和生物学界面的专业知识，并对基本生物化学问题进行定量分析。

项目成果

Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I.

• DOI: 10.1016/j.bbabio.2015.12.009
• 发表时间: 2016-07
• 期刊: Biochimica et biophysica acta
• 作者: Hirst J;Roessler MM
• 通讯作者: Roessler MM

A conserved arginine residue is critical for stabilizing the N2 FeS cluster in mitochondrial complex I.

• DOI: 10.1016/j.jbc.2021.100474
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Hameedi MA;Grba DN;Richardson KH;Jones AJY;Song W;Roessler MM;Wright JJ;Hirst J
• 通讯作者: Hirst J