MitoBOX: The mitochondrial basis of hypoxia tolerance in marine mollusks

MitoBOX：海洋软体动物耐缺氧的线粒体基础

• 批准号: 415984732
• 负责人: Dr. Christian Bock
• 金额: --
• 依托单位: Alfred-Wegener-Institut (AWI) Helmholtz-Zentrum für Polar- und Meeresforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/415984732?language=en
• 关键词: MitoBOX; mitochondrial; basis; hypoxia; tolerance

Oxygen (O2) plays a key role in biological energy transductions, and O2 deficiency (hypoxia) has severe consequences for fitness and survival of an organism. Hypoxia induces cellular stress due to the low rates of ATP production, depletion of energy reserves and accumulation of metabolic wastes, whereas reoxygenation causes cellular injury due to the oxidative stress. Sensitivity to hypoxia greatly varies among animals. In hypoxia-sensitive organisms such as mammals, mitochondria are the hub of hypoxia/reoxygenation-induced damage leading to the loss of ATP synthesis capacity, oxidative damage and cell death. In contrast, some hypoxia-tolerant organisms (such as intertidal mollusks) endure daily hypoxia-reoxygenation cycles without any apparent ill effects. The mechanisms responsible for such exceptional mitochondrial resilience to O2 fluctuations are not known.In this study, we will expand the current concept of hypoxia tolerance in animals by identifying the mitochondrial mechanisms involved in adaptation to fluctuating O2 levels and determining how these mechanisms are integrated with the whole-organism bioenergetics.As a model system, we will use three species of marine bivalves (scallops, oysters and quahogs) that encompass a broad range of hypoxia tolerance with survival times ranging from hours to months in hypoxia. We will use the metabolic control analysis (MCA) to determine the effects of the hypoxia-reoxygenation (H/R) stress on the capacity of key mitochondrial subsystems and their control over respiration, ATP synthesis and ROS production. The molecular mechanisms underlying the mitochondrial resilience to H/R will be assessed by determining the activity of key mitochondrial enzymes and the regulatory role of the reversible protein phosphorylation during H/R stress. Whole-organism respirometry and magnetic resonance imaging (MRI) and NMR spectroscopy will be used to determine whether aerobic metabolism during post-hypoxic recovery is limited by the mitochondrial or systemic mechanisms. The proposed study will reveal novel mitochondrial mechanisms involved in adaptation to fluctuating O2 levels, produce a hierarchical (mitochondria-to-organism) model of metabolic control during hypoxia and recovery, and identify the metabolic ‘weak links’ that contribute to the susceptibility to H/R stress in mitochondria. Together with the previously published extensive research on mammalian models, the novel data on hypoxia-tolerant mollusks could discover the evolutionarily tested solutions to overcome the mitochondrial susceptibility to H/R stress and help generate new hypotheses to mitigate mitochondrial stress in vulnerable tissues such as occurs during cardiac failure or stroke. This project will also provide cross-disciplinary training in mitochondrial physiology, whole-organism bioenergetics and in state-of-the-art techniques for physiology research such as MRI to a Ph.D. student.

氧（O2）在生物能传递中起关键作用，而O2缺乏症（缺氧）对生物体的适应性和存活产生了严重的影响。缺氧会导致由于ATP产生率低，能量储量的部署和代谢废物的积累而引起的细胞应激，而Rexygyation因氧化应激而导致细胞损伤。对动物中缺氧多种多样性的敏感性。在低氧敏感的生物（例如哺乳动物）中，线粒体是缺氧/重氧诱导的损伤的枢纽，导致ATP合成能力，氧化损伤和细胞死亡的损失。相比之下，某些耐透透明的生物（例如潮间软体动物）会忍受每日低氧抗氧化循环，而没有任何明显的不良影响。尚不清楚使这种特殊线粒体对O2波动的特殊线粒体弹性的机制。在这项研究中，我们将扩展我们将通过确定适应O2含量的线粒体机制来使用代谢控制分析，并确定这些机制与整个模型系统的模型，我们将如何使用这些机制。牡蛎和Quahogs）包括广泛的低氧耐受性，生存时间范围从小时到缺氧。我们将使用代谢控制分析（MCA）来确定缺氧 - 抗氧化（H/R）应力对关键线粒体子系统能力的影响及其对呼吸，ATP合成和ROS产生的控制。线粒体弹性对H/R的分子机制将通过确定关键的线粒体酶的活性以及H/R胁迫期间可逆蛋白磷酸化的调节作用来评估。全体生物呼吸测定法和磁共振成像（MRI）和NMR光谱将用于确定在催产后恢复过程中有氧代谢是否受线粒体或系统机制的限制。拟议的研究将揭示针对适应波动的O2水平的适应性，在缺氧和恢复过程中产生代谢控制的分层（线粒体至有生物）模型，并确定对线粒体中H/R胁迫的敏感性。再加上先前发表的关于哺乳动物模型的广泛研究，有关耐多痛的软体动物的新数据可以发现经过进化测试的溶液，以克服线粒体易感性H/R应激的敏感性，并有助于产生新的假设，以减轻诸如心脏衰减期间的脆弱组织中的线粒体压力，例如在心脏失败期间发生。该项目还将提供线粒体生理学，全生物生物能学和最先进的生理学研究技术（例如MRI）的跨学科培训。学生。