ATP steal between cation pumps: A mechanism linking Na⁺ influx to the onset of necrotic Ca²⁺ overload

We set out to identify molecular mechanisms underlying the onset of necrotic Ca²⁺ overload, triggered in two epithelial cell lines by oxidative stress or metabolic depletion. As reported earlier, the overload was inhibited by extracellular Ca²⁺ chelation and the cation channel blocker gadolinium. However, the surface permeability to Ca²⁺ was reduced by 60%, thus discarding a role for Ca²⁺ channel/carrier activation. Instead, we registered a collapse of the plasma membrane Ca²⁺ ATPase (PMCA). Remarkably, inhibition of the Na⁺/K⁺ ATPase rescued the PMCA and reverted the Ca²⁺ rise. Thermodynamic considerations suggest that the Ca²⁺ overload develops when the Na⁺/K⁺ ATPase, by virtue of the Na⁺ overload, clamps the ATP phosphorylation potential below the minimum required by the PMCA. In addition to providing the mechanism for the onset of Ca²⁺ overload, the crosstalk between cation pumps offers a novel explanation for the role of Na⁺ in cell death.