Abstract
Superoxide (O-2(center dot-)) 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 O-2(center dot-). We have conjugated a mitochondria-targeting triphenylphosphonium (TPP) cation to a O-2(center dot-)-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 O-2(center dot-). The combination of mitochondrial uptake and O-2(center dot-) scavenging by MitoSOD decreased inactivation of the matrix enzyme aconitase caused by O-2(center dot-). MitoSOD is an effective mitochondria-targeted macrocyclic SOD mimetic that selectively protects mitochondria from O-2(center dot-) damage.