Title | A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Kelso, 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 |
Journal | Chem Biol |
Volume | 19 |
Issue | 10 |
Pagination | 1237-46 |
Date Published | 2012 Oct 26 |
ISSN | 1879-1301 |
Keywords | Aconitate 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. |
DOI | 10.1016/j.chembiol.2012.08.005 |
Alternate Journal | Chem. Biol. |
Citation Key | 10.1016/j.chembiol.2012.08.005 |
PubMed ID | 23102218 |
Grant List | MC_U105663142 / / Medical Research Council / United Kingdom |