The Mitochondrial Antioxidants MitoE(2) and MitoQ(10) Increase Mitochondrial Ca2+ Load upon Cell Stimulation by Inhibiting Ca2+ Efflux from the Organelle

Mitochondrial reactive oxygen species (ROS) production is recognized as a major pathogenic event in a number of human diseases, and mitochondrial scavenging of ROS appears a promising therapeutic approach. Recently, two mitochondrial antioxidants have been developed; conjugating alpha-tocopherol and the ubiquinol moiety of coenzyme Q to the lipophilic triphenylphosphonium cation (TPP+), denominated MitoE(2) and MitoQ(10), respectively. We have investigated the effect of these compounds on mitochondrial Ca2+ homeostasis, which controls processes as diverse as activation of mitochondrial dehydrogenases and pro-apoptotic morphological changes of the organelle. We demonstrate that treatment of HeLa cells with both MitoE(2) and MitoQ(10) induces (albeit with different efficacy) a major enhancement of the increase in matrix Ca2+ concentration triggered by cell stimulation with the inositol 1,4,5-trisphosphate-generating agonist histamine. The effect is a result of the inhibition of Ca2+ efflux from the organelle and depends on the TPP+ moiety of these compounds. Overall, the data identify an effect independent of their antioxidant activity, that: on the one hand may be useful in addressing disorders in which mitochondrial Ca2+ handling is impaired (e.g., mitochondrial diseases) and on the other may favor mitochondrial Ca2+ overload and thus increase cell sensitivity to apoptosis (thus possibly counteracting the benefits of the antioxidant activity).