title: Mitochondrially targeted compounds and their impact on cellular bioenergetics.
abstract: Mitochondria are recognized as critical sites of localized injury in a number of chronic pathologies which has led to the development of organelle directed therapeutics. One of the approaches employed to target molecules to the mitochondrion is to conjugate a delocalized cation such as triphenylphosphonium (TPP+) to various redox active compounds. Mitochondrially targeted antioxidants have also been used in numerous cell culture based studies as probes of the contribution of the mitochondrial generation of reactive oxygen species on cell signaling events. However, concentrations usedin vitroare typically 10-100 times greater than those generated from oral dosing in a wide range of animal models and in humans. In the present study, we determined the effects of mitochondrial targeted antioxidants, MitoQ, MitoTempol, and MitoE on cellular bioenergetics of mesangial cells in culture and compared these to TPP+conjugated compounds which lack the antioxidant functional group. We found that all TPP+compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups. These findings show that the TPP+moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties. Moreover, TPP+moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of the mitochondrially targeted compounds that have been reportedin vivo.
authors.affiliation: Department of Pathology and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Reily
authors.forename: Tanecia
authors.initials: T
authors.lastname: Mitchell
authors.forename: Balu K
authors.initials: BK
authors.lastname: Chacko
authors.forename: Gloria
authors.initials: G
authors.lastname: Benavides
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
keywords: MitoQ; Mitochondrial targeted compounds; TPP+ derivatives; extracellular flux; mitochondria; redox; respiration