In conditions of tissue hypoxia, what causes irreversible cell damage?

In conditions of tissue hypoxia, the primary factor leading to irreversible cell damage is the dysfunction of the Ca-ATPase pump, which allows excessive calcium influx into the cell. Under normal circumstances, the Ca-ATPase pump is responsible for maintaining low intracellular calcium levels by actively transporting calcium out of the cell. When hypoxia occurs, the lack of oxygen impairs ATP production via oxidative phosphorylation, which leads to decreased ATP levels.

As ATP levels fall, the activity of the Ca-ATPase pump diminishes, resulting in a failure to extrude calcium from the cell. Consequently, intracellular calcium concentrations rise, which can trigger various pathological processes, including activation of destructive enzymes like phospholipases, proteases, and endonucleases. These enzymes can damage cellular membranes, proteins, and nucleic acids, leading to irreversible injury and eventual cell death.

While decreased Na/K-ATPase activity is also a consequence of reduced ATP levels in hypoxia, it primarily contributes to cellular swelling and is more indicative of reversible injury in the early stages. In contrast, excessive cellular respiration does not occur in hypoxia, as oxygen is a critical substrate for aerobic respiration. Thus, the dysfunction of the Ca-ATPase pump and the consequent calcium overload