Regulation of Ca 2+ transport in brain mitochondria. I. The mechanism of spermine enhancement of Ca 2+ uptake and retention

Abstract

Spermine enhances electrogenic Ca 2+ uptake and inhibits Na +-independent Ca 2+ efflux in rat brain mitochondria. As a result, Ca 2+ retention by brain mitochondria increases greatly and the external free Ca 2+ level at steady-state can be lowered to physiologically relevant concentrations. The stimulation of Ca 2+ uptake by spermine is more pronounced at low concentrations of Ca 2+, effectively lowering the apparent K m for Ca 2+ uptake from 3 μM to 1.5 μM. However, the apparent V max is also increased. At low Ca 2+ concentrations, Ca 2+ uptake is diffusion-limited. Spermine strongly inhibits Ca 2+ binding to anionic phospholipids and it is suggested that this increases the rate of surface diffusion which reduces the apparent K m for uptake. The same effect could inhibit the Na +-independent efflux if the rate of efflux is limited by Ca 2+ dissociation from the efflux carrier. In brain mitochondria (but not in liver) the spermine effect depends on the presence of ADP. In a medium that contains physiological concentrations of P i, Mg +, K +, ADP and spermine, brain mitochondria sequester Ca 2+ down to 0.1 μM and below, depending on the matrix Ca 2+ load. Moreover, brain mitochondria under the same conditions buffer the external medium at 0.4 μM, a concentration at which the set point becomes independent of the matrix Ca 2+ content. Thus, mitochondria appear to be capable of modulating calcium oscillations in brain cells.