Increased ICF Ca+2 results from failure of energy dependent Ca+2-Mg+2 ATPase pump and is also related to increased membrane permeability.

Sustained rise in intracellular Ca2+

• This event is considered the initial step of irreversible injury.
• Sustained increased ICF Ca+2 leads to activation of intracellular self-destructive lysosomal enzymes that destroy the mitochondrial membrane, cellular membrane and other organelle membranes.

But at which stage did the cell actually die? Which is the critical biochemical event (the "lethal hit") responsible for the point of no return? The phenomena consistently proposed to represent irreversibility is:

Mitochondrial membrane disruption leading to irreversible dysfunction and marked ATP depletion.
This statement adopted from Ref. (1)