The relationship between mitochondrial membrane permeability, membrane potential, and the retention of Ca2+ by...

Ca2+ release from liver mitochondria induced by N-ethylmaleimide, diamide, inorganic phosphate, palmitoyl-coenzyme A, and oxaloacetate occurs by a common mechanism. With all agents, a collapse of membrane potential, uptake of hydrogen ion, progressive acceleration of respiration, and large amplitude swelling accompanies Ca2+ release. These findings indicate that the agents promote an increase in the permeability of the inner membrane and that Ca2+ release can be explained under these conditions without invoking the action of a Ca2+ release carrier. The increase in permeability produced by the Ca2+-releasing agents requires the accumulation of exogenouse Ca2+. Sr2+ and Mn2+ cannot substitute for Ca2+ and the permeability increase is prevented by nupercaine. Free fatty acid accumulation in the mitochondria accompanies the increase in permeability. Polyunsaturated fatty acids accumulate more rapidly than saturated plus monounsaturated fatty acids, which indicates the accumulation of 1-acyllysophospholipid. Any inhibitor or condition which prevents the permeability change also prevents the accumulation of lysophospholipid, suggesting that these compounds cause the permeability increase. As Ca2+ release and swelling proceed, there is an accompanying oxidation of pyridine nucleotides. This oxidation occurs both with releasing agents which can oxidize the nucleotides through the action of mitochondrial enzymes as well as with agents which cannot. Any inhibitor or condition which prevents the increase in permeability also largely prevents the oxidation of pyridine nucleotides. The increase in the NAD(P)+/NAD(P)H ratio produced by the releasing agents can be explained as an effect secondary to the increase in permeability and collapse of the mitochondrial pH gradient rather than a primary cause of Ca2+ release.