19.The Signal Function of Succinate and Free Radicals in Mechanisms of Preconditioning and Long-term Adaptation to Hypoxia

摘要

A bioenergetic mechanism for development of urgent and long-term adaptation to hypoxia is considered. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD-related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, and compensatory activation of respiratory chain complex II are a major mechanisms of urgent adaptation to hypoxia necessary for (1) succinate- related energy synthesis in conditions of oxygen deficiency and formation of urgent resistance in the body; (2) succinate- related stabilization of HIF-1 and initiation of its transcriptional activity related with formation of long-term adaptation; and (3) succinate-related activation of a succinate-specific receptor GPR91. Therefore succinate is a signaling molecule, and its effects are realized at three levels in hypoxia, intramitochondrial, intracellular and intercellular. In this setting, succinate shows antihypoxic and antiradical activities. Suppression of free radical processes in early phase of hypoxia potentiates the effects of succinate and facilitates the development of urgent adaptation to hypoxia. Tactics and strategy for the antihypoxic defense and development of antihypoxants with energotropic action are considered.