Cytosolic Ca(2+) signal induces mitochondrial Ca(2+) uptake that has far-reaching effect on several cellular functions. We have previously shown in H295R cells that the transfer of cytosolic Ca(2+) signal into mitochondria is attenuated by the simultaneous activation of p38 MAPK and novel-type PKC isoforms (Szanda et al. (2008) , Koncz et al. (2009) ). In the present study we show that (i) kinase-mediated inhibition of mitochondrial Ca(2+) uptake persists after clamping or dissipation of the mitochondrial membrane potential; (ii) kinase activation increases the [Ca(2+)] required for half-maximal Ca(2+) uptake rate in permeabilized cells; (iii) inhibition of the Ca(2+) uptake by the kinases is dependent on an intact mitochondrial outer membrane; (iv) when p38 MAPK and novel-type PKC isoforms are activated, the outer mitochondrial membrane may limit Ca(2+) diffusion even in the low micromolar [Ca(2+)] range. These findings confirm the concept that the outer mitochondrial membrane impedes mitochondrial Ca(2+) uptake by reducing the availability of Ca(2+) at the transport sites (i.e. the inner mitochondrial membrane), and suggest that Ca(2+) transport through the outer membrane is controlled by the activity of p38 MAPK and novel-type PKC isoforms.
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