Rapid release of Mg2+ from liver mitochondria by nonesterified long-chain fatty acids in alkaline media

Long-chain fatty acids induce a rapid release of Mg2+ from both energized and nonenergized rat liver mitochondria suspended at pH 8 in isotonic saline but not sucrose media. The effect is observed only with fatty acids that possess protonophoric activity. The most active saturated fatty acids are myristic and palmitic, while the most active unsaturated acids are oleic, linolenic, and arachidonic. The rate of Mg2+ release drastically decreases with decreasing medium pH to 7.2–7.6. However, at those pH values this rate is doubled by energization of mitochondria with respiratory substrates. Mg2+ release is accompanied by cyclosporin A-insensitive large-amplitude swelling of mitochondria. This swelling is similar to that produced by the divalent metal ionophore A23187 and is interpreted as being due to activation of the inner membrane anion channel, the K+ uniporter, and the K+/H+ exchanger. In energized mitochondria, both swelling and Mg2+ release are blocked by the exogenous K+/H+ exchanger nigericin. It is proposed that fatty acids under conditions of alkaline mitochondrial matrix activate latent Mg2+-sensitive ion-conducting pathways in the inner mitochondrial membrane, which mediate swelling and Mg2+ release. It is hypothesized that fatty acids activate an intrinsic Mg2+/H+ exchanger that is related to, or identical with, the K+/H+ exchanger.