When cells run out of oxygen.

Strip a cell of oxygen for long enough and the ATP it makes by glycolysis alone cannot keep up with the ATP it spends just being alive. The cell has many ATP-consuming pumps, but two matter for injury physiology: Na⁺/K⁺-ATPase at the plasma membrane (three Na out, two K in, against gradient) and Ca²⁺-ATPase (both at the plasma membrane pumping Ca out, and at the smooth ER pumping Ca into stores). Both are doing the same job — keeping the cell's ionic composition different from the world outside, which is the entire substrate of being a living thing.

Na⁺/K⁺-ATPase fails. Na⁺ leaks into the cell down its concentration gradient. K⁺ leaks out. Water follows the Na⁺ osmotically. The cell swells — hydropic change on H&E, a clarified, glassy cytoplasm. Mitochondria also swell as their inner-membrane potential collapses. This is the reversible phase of injury. At this point, the cell can still recover if oxygen returns.

Ca²⁺-ATPase fails. Cytosolic Ca²⁺ rises — first from leak across the plasma membrane, then from release out of stalled ER stores. Ca²⁺ is the cell's universal alarm signal, and at the concentrations it now reaches in the cytosol it activates an army of catabolic enzymes:

• Phospholipases — degrade membrane phospholipids; the cell loses membrane integrity at the plasma membrane, the mitochondrial inner membrane, and the lysosome.
• Proteases — degrade cytoskeletal scaffolds; the cell loses its shape and its ability to anchor.
• Endonucleases — fragment nuclear DNA randomly (different from the orderly internucleosomal fragmentation of apoptosis).
• ATPases — paradoxically waste what little ATP remains, deepening the deficit.