The mitochondrial antioxidants MitoE(2) and MitoQ(10) increase mitochondrial Ca(2+) load upon cell stimulation by inhibiting Ca(2+) 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 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).
Leo
Sara
S
Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation and Emilia Romagna Laboratory for Genomics and Biotechnology, University of Ferrara, Ferrara, Italy.
Szabadkai
György
G
Rizzuto
Rosario
R
D000975:Antioxidants / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017136:Ion Transport; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism*
D000975:Antioxidants; D002118:Calcium