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.

氧气 (O2) 在生物能量传导中发挥着关键作用，缺氧（缺氧）会对生物体的健康和生存造成严重后果，缺氧会导致细胞应激，因为 ATP 生成率低、能量储备耗尽和能量积累。不同动物对缺氧的敏感性差异很大，而线粒体是缺氧的枢纽。缺氧/复氧引起的损伤导致 ATP 合成能力丧失、氧化损伤和细胞死亡，相反，一些耐缺氧生物（例如潮间带软体动物）可以忍受日常的缺氧-复氧循环，而没有任何明显的不良影响。对于如此特殊的线粒体对氧气波动的恢复能力尚不清楚。在这项研究中，我们将通过确定参与适应波动的线粒体机制来扩展目前动物耐缺氧的概念氧气水平并确定这些机制如何与整个生物体生物能学相结合。作为模型系统，我们将使用三种海洋双壳类动物（扇贝、牡蛎和圆蛤），它们具有广泛的缺氧耐受性，生存时间从数小时不等我们将使用代谢控制分析 (MCA) 来确定缺氧-复氧 (H/R) 应激对关键线粒体子系统的能力及其控制的影响。通过确定关键线粒体酶的活性以及 H/R 应激期间可逆蛋白质磷酸化的调节作用，可以评估线粒体对 H/R 的恢复能力的分子机制。磁共振成像（MRI）和核磁共振波谱将用于确定缺氧后恢复期间的有氧代谢是否受到线粒体或全身机制的限制。这项研究将揭示参与适应的新线粒体机制。氧水平波动，产生缺氧和恢复期间代谢控制的分层（线粒体到生物体）模型，并与之前发表的文献一起确定导致线粒体对 H/R 应激易感性的代谢“薄弱环节”。通过对哺乳动物模型的广泛研究，耐缺氧软体动物的新数据可以发现经过进化测试的解决方案，以克服线粒体对 H/R 应激的敏感性，并有助于产生新的假设，以减轻脆弱群体的线粒体应激该项目还将为博士生提供线粒体生理学、整体生物能量学和最先进的生理学研究技术（例如 MRI）的跨学科培训。 。