ATP depletion and decreased ATP synthesis are frequently associated with both hypoxic and chemical (toxic) injury.
High-energy phosphate in the form of ATP is required for many synthetic and degradative processes within the cell. These include membrane transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary for phospholipid turnover.
ATP production
ATP is produced in two ways. The major pathway in mammalian cells is oxidative phosphorylation of adenosine diphosphate, in a reaction that results in reduction of oxygen by the electron transfer system of mitochondria. The second is the glycolytic pathway, which can generate ATP in the absence of oxygen using glucose derived either from body fluids or from the hydrolysis of glycogen. Thus, tissues with greater glycolytic capacity (e.g., liver) have an advantage when ATP levels are falling because of inhibition of oxidative metabolism by injury.
ATP depletion
Depletion of ATP to <5% to 10% of normal levels has widespread effects on many critical cellular systems: The activity of the plasma membrane energy-dependent sodium pump (ouabain-sensitive Na+, K+-ATPase) is reduced.
Failure of this active transport system, due to diminished ATP concentration and enhanced ATPase activity, causes sodium to accumulate intracellularly and potassium to diffuse out of the cell.
The net gain of solute is accompanied by isosmotic gain of water, causing cell swelling, and dilation of the endoplasmic reticulum.
Cellular energy metabolism is altered. If the supply of oxygen to cells is reduced, as in ischemia, oxidative phosphorylation ceases and cells rely on glycolysis for energy production. This switch to anaerobic metabolism is controlled by energy pathway metabolites acting on glycolytic enzymes.
The decrease in cellular ATP and associated increase in adenosine monophosphate stimulate phosphofructokinase and phosphorylase activities. These result in an increased rate of anaerobic glycolysis designed to maintain the cell’s energy sources by generating ATP through metabolism of glucose derived from glycogen. As a consequence, glycogen stores are rapidly depleted.
Glycolysis results in the accumulation of lactic acid and inorganic phosphates from the hydrolysis of phosphate esters. This reduces the intracellular pH, resulting in decreased activity of many cellular enzymes.
Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components, described below.
With prolonged or worsening depletion of ATP, structural disruption of the protein synthetic apparatus occurs, manifested as detachment of ribosomes from the rough endoplasmic reticulum and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis. Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis.
protein misfolding
In cells deprived of oxygen or glucose, proteins may become misfolded, and misfolded proteins trigger a cellular reaction called the unfolded protein response that may lead to cell injury and even death. A protein misfolding is also seen in cells exposed to stress, such as heat, and when proteins are damaged by enzymes (such as Ca2+-responsive enzymes, described below) and free radicals.