A Mitochondria-Targeted Macrocyclic Mn(II) Superoxide Dismutase Mimetic

SummarySuperoxide (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.

► A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic is described ► Pulse radiolysis showed that MitoSOD was an effective and selective SOD mimetic ► MitoSOD was rapidly accumulated within mitochondria driven by the membrane potential ► Mitochondrial damage due to superoxide was decreased by MitoSOD