Author/Authors :
Geoffrey F. Kelso، نويسنده , , Andrej Maroz، نويسنده , , Helena M. Cochemé، نويسنده , , Angela Logan، نويسنده , , Tracy A. Prime، نويسنده , , Alexander V. Peskin، نويسنده , , Christine C. Winterbourn، نويسنده , , Andrew M. James، نويسنده , , Meredith F. Ross، نويسنده , , Sally Brooker، نويسنده , , Carolyn M. Porteous، نويسنده , , Robert F. Anderson، نويسنده , , Michael P. Murphy، نويسنده , , Robin A.J. Smith، نويسنده ,
Abstract :
Superoxide (O2⋅-) is the proximal mitochondrial reactive oxygen species underlying pathology and redox signaling. This central role prioritizes development of a mitochondria-targeted reagent selective for controlling O2⋅-. We have conjugated a mitochondria-targeting triphenylphosphonium (TPP) cation to a O2⋅--selective pentaaza macrocyclic Mn(II) superoxide dismutase (SOD) mimetic to make MitoSOD, a mitochondria-targeted SOD mimetic. MitoSOD showed rapid and extensive membrane potential-dependent uptake into mitochondria without loss of Mn and retained SOD activity. Pulse radiolysis measurements confirmed that MitoSOD was a very effective catalytic SOD mimetic. MitoSOD also catalyzes the ascorbate-dependent reduction of O2⋅-. The combination of mitochondrial uptake and O2⋅- scavenging by MitoSOD decreased inactivation of the matrix enzyme aconitase caused by O2⋅-. MitoSOD is an effective mitochondria-targeted macrocyclic SOD mimetic that selectively protects mitochondria from O2⋅- damage.
