MitoBOX: The mitochondrial basis of hypoxia tolerance in marine mollusks

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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.