The article is focused on the role of the cell bioenergetic apparatus, mitochondria, involved in development of immediate and delayed molecular mechanisms for adaptation to hypoxic stress in brain cortex. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD-related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of immediate adaptation to hypoxia necessary for (1) succinate-related energy synthesis in the conditions of oxygen deficiency and formation of urgent resistance in the body; (2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation; (3) succinate-related activation of the succinate-specific receptor, GPR91. This mechanism participates in at least four critical regulatory functions: (1) sensor function related with changes in kinetic properties of complex I and complex II in response to a gradual decrease in ambient oxygen concentration; this function is designed for selection of the most efficient pathway for energy substrate oxidation in hypoxia; (2) compensatory function focused on formation of immediate adaptive responses to hypoxia and hypoxic resistance of the body; (3) transcriptional function focused on activated synthesis of HIF-1 and the genes providing long-term adaptation to low pO2; (4) receptor function, which reflects participation of mitochondria in the intercellular signaling system via the succinate-dependent receptor, GPR91. In all cases, the desired result is achieved by activation of the succinate-dependent oxidation pathway, which allows considering succinate as a signaling molecule. Patterns of mitochondria-controlled activation of GPR-91- and HIF-1-dependent reaction were considered, and a possibility of their participation in cellular-intercellular-systemic interactions in hypoxia and adaptation was proved.

No abstract

Single exposure to moderate (10% O(2)) hypobaric, normobaric, and intermittent hypoxia is followed by a preconditioning response of the organism. The mechanisms for immediate adaptation are activated during the hypoxic period. Intermittent reoxygenation not only delays, but even suppresses this process. However, periods of oxygenation during the course of hypoxic training reduce the effect of hypoxia and prevent the possibility for "overdosage" of the adverse stimulus. Hence, they have a regulatory or normalizing role under these conditions. Our results indicate that hypoxitherapy in intermittent hypoxia mode provides optimum conditions for long-term adaptation.

Bioenergetic hypoxia is defined as a phasic process starting at the substrate site of the respiratory chain with injury to the mitochondrial enzymatic complex I and involving, as oxygen insufficiency progresses, the terminal cytochrome site of the respiratory chain. Different stages of the process, determined experimentally, are described from a bioenergetic viewpoint. The development of bioenergetic hypoxia in tissues of aninlals with different resistance to hypoxia is analyzed. Modern concepts of the trigger mechanisms of bioenergetic hypoxia and approaches to correcting the function of the energy system at different stages of hypoxia are discussed. Key Words: bioenergetic hypoxia; energy metabolism; respiratory enzymatic complexes; individual sensitivity to hypoxia; adaptation; antihypoxantsHypoxia is a highly prevalent phenomenon, which develops both under conditions of oxygen deficiency in the environment and as a result of a variety of diseases involving the respiratory and cardiovascular systems and impairing blood transporting function. All such disorders lead to a decrease in oxygen delivery to tissues to a level which is insufficient for maintaining function, metabolism, and structure of the cell. Thus, hypoxia is an important problem of practical and theoretical medicine.This problem has been researched for more than a hundred years. In Russia it attracted the attention of I. M. Sechenov, V. V. Pashutin, P. M. Al'bitskii, and E. A. Kartashevskii. Later it became the main object of research for N. N. Sirotinin, A. M. Charnyi, I. R. Petrov, Z. I. Barbashova, M. N. Gaevskaya, and lnany others. Due to these investigations, stndy of hypoxic states became an important branch of fundamental and applied medicine, which still remains a priority trend for the Russian science. At Department of Bioenergetics, Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow present, a vast data bank on the mechanisms of hypoxia has been accumulated, permitting the creation of classifications of hypoxic states, development of prognostic criteria for assessing them, and analysis of the succession of disorders occurring under conditions Of oxygen deficiency.The intricate time course of this process and involvement of a wide spectrum of functional and metabolic systems regulating it at different levels of organization determine the multiplicity of the limiting sites and mechanisms underlying hypoxia. This l~act explains why, despite an almost lO0-year history of investigation, many pathogenetic aspects of hypoxia and many questions in antihypoxic defense are still not solved.The crucial factor leading to the development of h3rpoxic states is oxygen delivery from tile environment to the cell, where it participates ha reactions of aerobic energy production as the substrate of cytochrome oxidase (CCO) --the terminal exlzyme of the mitochondrial respiratory system. That is why oxygen deficiency under some conditions can limit or completely suppress aerobic energy production. The levels