Inhibition by Ca²⁺ of oxidative phosphorylation in myeloid tumor mitochondria

In tightly coupled respiring myeloid tumor mitochondria, the addition of Ca²⁺ in the presence of phosphate results in total inhibition of respiration with NAD-linked-substrates (e.g., glutamate and β-hydroxybutyrate) and partial inhibition with FAD-linked substrate (e.g., succinate). With those substrates, Ca²⁺ also completely inhibits both subsequent phosphorylating respiration in response to ADP and respiratory stimulation by an uncoupler. This latter was only partially inhibited in the absence of phosphate. Endogenous contents of Ca²⁺, Mg²⁺, and phosphate of the isolated mitochondria appeared to be in the normal range. Ruthenium red, a specific inhibitor of energy-dependent Ca²⁺ uptake, totally prevents the inhibitory effects of Ca²⁺. Moreover, Mg²⁺ and ATP added either singly or together could partially or completely prevent the Ca²⁺ inhibitory action. While the mechanism of protection by ATP is not known, protection by Mg²⁺ could be related to the inhibitory effect of this cation on Ca²⁺ accumulation. It is suggested that the inhibition of oxidative phosphorylation by Ca²⁺ in myeloid tumor mitochondria is primarily caused by a high calcium-phosphate salt precipitation into the matrix.