A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic

Geoffrey Kelso, Andrej Maroz, Helena M Cocheme, Angela Logan, Tracy A Prime, Alexander V Peskin, Christine C Winterbourn, Andrew M James, Meredith F Ross, Sally Brooker, Carolyn M Porteous, Robert F Anderson, Michael P Murphy, Robin A J Smith

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41 Citations (Scopus)

Abstract

Superoxide (O(2)(-)) is the proximal mitochondrial reactive oxygen species underlying pathology and redox signaling. This central role prioritizes development ofa mitochondria-targeted reagent selective for controlling O(2)(-). We have conjugated a mitochondria-targeting triphenylphosphonium (TPP) cation to a O(2)(-)-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 ofMn and retained SOD activity. Pulse radiolysis measurements confirmed that MitoSOD wasa veryeffective catalytic SOD mimetic. MitoSOD also catalyzes the ascorbate-dependent reduction of O(2)(-). The combination of mitochondrial uptake and O(2)(-) scavenging by MitoSOD decreased inactivation of the matrix enzyme aconitase caused by O(2)(-). MitoSOD is an effective mitochondria-targeted macrocyclic SOD mimetic that selectively protects mitochondria from O(2)(-) damage.
Original languageEnglish
Pages (from-to)1237 - 1246
Number of pages10
JournalChemistry and Biology
Volume19
Issue number10
DOIs
Publication statusPublished - 2012

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