Fig. 1.

Events contributing to the pathophysiology of IR injury. - (A) Under limited oxygen concentrations, the mitochondrial respiration is inhibited with consequent upregulation of glycolysis and acidosis. To counterbalance the low pH, Na⁺/H⁺ exchanger (NHE) exchanges protons for Na⁺, promoting the build-up of the ion in the cytosol. As Na⁺/K⁺ ATPase (NAK) activity is almost inhibited due to the reduced ATP availability, cells exploit the reverse activity of the Na⁺/Ca⁺ exchanger (NCX) to counterbalance the increased sodium level. In this way, NCX induces Ca²⁺ accumulation in the cytosol, while expelling sodium. At the same time, the transcription factor HIF1-α is stabilized and enters the nucleus to promote gene expression. (B) Upon reperfusion, the mitochondrial respiration resumes, re-establishing the normal pH. This rapid pH adjustment causes a large proton gradient that prompts a sustained NHE activity, which additionally rises the cytosolic concentration of sodium. As a consequence, the NCX reverse activity is potentiated, further incrementing the calcium level in the intracellular compartment. In this condition, calcium, in conjunction with the large mitochondrial ROS production, favours the opening of the mPTP, which stimulates the initiation of cell death mechanisms. In this condition, HIF1-α is constantly degraded.