title: A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic.
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.
authors.affiliation: Centre for Green Chemistry, Monash University, Victoria 3800, Australia.
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Kelso
authors.forename: Andrej
authors.initials: A
authors.lastname: Maroz
authors.forename: Helena M
authors.initials: HM
authors.lastname: Cochemé
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Prime
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Peskin
authors.forename: Christine C
authors.initials: CC
authors.lastname: Winterbourn
authors.forename: Andrew M
authors.initials: AM
authors.lastname: James
authors.forename: Meredith F
authors.initials: MF
authors.lastname: Ross
authors.forename: Sally
authors.initials: S
authors.lastname: Brooker
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Porteous
authors.forename: Robert F
authors.initials: RF
authors.lastname: Anderson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
mesh_terms: D000154:Aconitate Hydratase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D018360:Crystallography, X-Ray; D007700:Kinetics; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011675:Pulse Radiolysis; D051381:Rats; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; D013481:Superoxides; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase; D000154:Aconitate Hydratase; D001205:Ascorbic Acid