Substrate-depleted rat liver mitochondria will reaccumulate malate, succinate, oxoglutarate, beta-hydroxybutyrate and glutamate if provided with an energy source and Ca(2+) (or Ca(2+) and Mn(2+)). The energy requirement for ion uptake by fresh mitochondria causes a transient oxidation of their NADH and presumably this leads to an increased oxaloacetate concentration. A consequence is the promotion of formation of citrate, which tends to remain in the particles, provided the pH is above 7. Analyses made of systems blocked with fluorocitrate show that citrate accumulates when Ca(2+) is added with the following substrates; (a) pyruvate in the presence of ATP or malate, (b) palmitoyl-l(-)-carnitine in presence of malate and (c) oxoglutarate. Lowering the pH, even to 6.8, causes the citrate to emerge. This could be the basis of a cellular control mechanism. The generation of citrate in response to Ca(2+) can explain the stoichiometry of one proton ejected per Ca(2+) ion taken up. The new carboxyl group formed from acetyl-CoA when it condenses with oxaloacetate provides an internal anionic charge and a proton to emerge when Ca(2+) enters.

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