Mitochondria-controlled signaling mechanisms of brain protection in hypoxia

Abstract

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.

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

“…Besides, the greatest increase in HIF-1a mRNA expression under IHT was observed in the subjects with lower tolerance to hypoxia (Figure 2(d)). This observation is in accordance with previous findings from the rats with high or low resistance to hypoxia, 74,75 which reported higher increase in HIF-1 mRNA in the brain tissue of low tolerant animals following adaptation to intermittent hypoxia.…”

Fitness and therapeutic potential of intermittent hypoxia training: a matter of dose

“…In the range of 80 to 50 mm Hg, there is such a degree of hypoxia when the supply of reduced coenzymes in the electron transport chain of mitochondria slows down. This in no way affects the rate of ATP synthesis, but increases the concentration of superoxide anion which activates numerous intracellular adaptation mechanisms [53,54]. Thus, the data obtained by various authors about IHT therapeutic effects under the inhalation of 12% O 2 and less fits into this picture.…”

Sirtuin 3 (SIRT3) Regulates α-Smooth Muscle Actin (α-SMA) Production through the Succinate Dehydrogenase-G Protein-coupled Receptor 91 (GPR91) Pathway in Hepatic Stellate Cells

“…Succinate is an important metabolic intermediate that constitutes one of the intermediates of the citric acid cycle and is regarded as a signaling molecule (25,27,38), acting by binding to the succinate receptor, GPR91. There have been several reports showing that succinate and GPR91 are involved in renin release (39 -42) in the kidney.…”