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

TitleA mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic.
Publication TypeJournal Article
Year of Publication2012
AuthorsKelso, GF, Maroz, A, Cochemé, HM, Logan, A, Prime, TA, Peskin, AV, Winterbourn, CC, James, AM, Ross, MF, Brooker, S, Porteous, CM, Anderson, RF, Murphy, MP, Smith, RAJ
JournalChem Biol
Volume19
Issue10
Pagination1237-46
Date Published2012 Oct 26
ISSN1879-1301
KeywordsAconitate Hydratase, Animals, Ascorbic Acid, Biomimetic Materials, Catalysis, Crystallography, X-Ray, Kinetics, Macrocyclic Compounds, Manganese, Microsomes, Liver, Mitochondria, Molecular Conformation, Organometallic Compounds, Oxidation-Reduction, Pulse Radiolysis, Rats, Superoxide Dismutase, Superoxides
Abstract

Superoxide (O(2)(·-)) 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)(·-). 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 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)(·-). 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.
DOI10.1016/j.chembiol.2012.08.005
Alternate JournalChem. Biol.
Citation Key10.1016/j.chembiol.2012.08.005
PubMed ID23102218
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom