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The Mitochondrial Antioxidants MitoE 2 and MitoQ 10 Increase Mitochondrial Ca 2+ Load upon Cell Stimulation by Inhibiting Ca 2+ Efflux from the Organelle
Author(s) -
Leo Sara,
Szabadkai György,
Rizzuto Rosario
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1427.019
Subject(s) - organelle , mitochondrion , chemistry , stimulation , efflux , cell , biophysics , biochemistry , biology , endocrinology
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 α‐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 Ca 2+ 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 Ca 2+ concentration triggered by cell stimulation with the inositol 1,4,5‐trisphosphate‐generating agonist histamine. The effect is a result of the inhibition of Ca 2+ 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 Ca 2+ handling is impaired (e.g., mitochondrial diseases) and on the other may favor mitochondrial Ca 2+ overload and thus increase cell sensitivity to apoptosis (thus possibly counteracting the benefits of the antioxidant activity).