Reversible and irreversible cell injury

Most of a cell's ATP comes from oxidative phosphorylation in mitochondria, where oxygen is the final electron acceptor at cytochrome c oxidase (complex IV). When oxygen delivery falls, electron transport stalls and ATP production drops within moments. Everything you see early in ischemic injury traces back to that energy shortage.

The cell switches to anaerobic glycolysis, which does not use oxygen. It burns stored glycogen, but each glucose yields only 2 ATP, against roughly 30 from complete oxidation, so the shortfall persists. Pyruvate is converted to lactate, lactic acid accumulates and intracellular pH falls. The acid environment clumps nuclear chromatin and, early on, inhibits enzymes.

The Na⁺/K⁺-ATPase spends ATP to push sodium out and pull potassium in. As ATP falls the pump slows, sodium accumulates inside the cell, and water follows it osmotically. The result is cellular swelling (hydropic change): the whole cell, its endoplasmic reticulum and its mitochondria take on water. The membrane is still intact, and if oxygen returns, the pump restarts and the water leaves.

Predict the first change, then watch one schematic cell move from normal function through reversible injury to its outcome. Switch scenarios to restore flow while the cell is still viable or after calcium overload has begun.

Cell on a Clock followed one fixed timeline. Here you set the conditions yourself: how far oxygen delivery falls, for how long, and in which tissue. Predict the state the cell reaches (normal, reversible injury or irreversible injury), run it, and then predict what restoring oxygen does first. The same action rescues one cell and fails to rescue another, and the simulator shows why.

Cytosolic calcium is normally kept around ten thousand times lower than outside the cell by ATP-driven pumps in the plasma membrane and endoplasmic reticulum. If ischemia persists, those pumps fail, calcium is released from the ER and mitochondria, and damaged membranes let more in. Cytosolic Ca²⁺ rises, and calcium switches on enzymes the cell normally keeps silent.

Calcium also enters mitochondria and opens the mitochondrial permeability transition pore. Protons leak back, the inner membrane potential collapses, and oxidative phosphorylation cannot resume even if oxygen returns. Cytochrome c can escape into the cytosol, where it activates caspases (the intrinsic apoptosis pathway in 1.7).

No single molecule marks the point of no return, but two findings consistently accompany it: mitochondria that cannot restore ATP production (even after reperfusion) and severe damage to membranes, both plasma and lysosomal. Once lysosomal enzymes leak, the cell digests itself; once the plasma membrane fails, cell contents escape into the extracellular space and the blood. That leak is why troponin rises after a myocardial infarction and transaminases after hepatocyte injury.

These are often described as a sequence (pyknosis → karyorrhexis → karyolysis), driven by endonucleases and falling pH, but any one can be what you see in a given cell. Karyolysis is the most specific for necrosis. Pyknosis and fragmentation occur in both necrosis and apoptosis, so on their own they do not tell you which form of death occurred (1.7).