Deficiency of oxygen leads to failure of many energy-dependent metabolic pathways, and ultimately to death of cells by necrosis. Most cellular ATP is produced from adenosine diphosphate (ADP) by oxidative phosphorylation during reduction of oxygen in the electron transport system of mitochondria. High-energy phosphate in the form of ATP is required for membrane transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary for phospholipid turnover. It is estimated that in total, the cells of a healthy human burn 50 to 75 kg of ATP every day! Not surprisingly, therefore, cells deprived of oxygen are at risk of suffering catastrophic failure of many essential functions. Oxygen deprivation is one of the most frequent causes of cell injury and necrosis in clinical medicine.
Cells subjected to the stress of hypoxia that do not immediately die activate compensatory mechanisms that are induced by transcription factors of the hypoxia-inducible factor 1 (HIF-1) family. HIF-1 simulates the synthesis of several proteins that help the cell to survive in the face of low oxygen. Some of these proteins, such as vascular endothelial growth factor (VEGF), stimulate the growth of new vessels and thus attempt to increase blood flow and the supply of oxygen. Other proteins induced by HIF-1 cause adaptive changes in cellular metabolism by stimulating the uptake of glucose and glycolysis and dampening mitochondrial oxidative phosphorylation. Anaerobic glycolysis can generate ATP in the absence of oxygen using glucose derived either from the circulation or from the hydrolysis of intracellular glycogen. Understandably, normal tissues with a greater glycolytic capacity because of the presence of glycogen (e.g., the liver and striated muscle) are more likely to survive hypoxia and decreased oxidative phosphorylation than tissues with limited glucose stores (e.g., the brain). Although it seems counterintuitive, rapidly proliferating normal cells and cancer cells rely on aerobic glycolysis to produce much of their energy, a phenomenon referred to as the Warburg effect. The reason for this is that although glycolysis yields less ATP per molecule of glucose burned than oxidative phosphorylation, metabolites generated by glycolysis and the TCA cycle serve as precursors for the synthesis of cellular constituents (e.g., proteins, lipids, and nucleic acids) that are needed for cell growth and division. Alterations in cellular metabolism are frequently seen in cancer cells, so they are discussed in more detail in Chapter 6.
Persistent or severe hypoxia and ischemia ultimately lead to failure of ATP generation and depletion of ATP in cells. Loss of this critical energy store has deleterious effects on many cellular systems (
Fig. 2.16
Reduced activity of plasma membrane ATP-dependent sodium pumps, resulting in intracellular accumulation of sodium and efflux of potassium. The net gain of solute is accompanied by isoosmotic gain of water, causing cell swelling and dilation of the ER.
The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation, decreased intracellular pH, and decreased activity of many cellular enzymes.
Prolonged or worsening depletion of ATP causes structural disruption of the protein synthetic apparatus,
Fig. 2.16 Thefunctionalandmorphologicconsequencesofhypoxiaandischemia.ER, Endoplasmicreticulum.
manifested as detachment of ribosomes from the rough ER (RER) and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis.
It also has been suggested that hypoxia per se increases the accumulation of ROS. Whether this is true is a matter of debate; however, there is ample evidence that hypoxia predisposes cells to ROS-mediated damage if blood flow (and oxygen delivery) is reestablished, a phenomenon called reperfusion injury (described later).