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

doi:10.1016/j.chembiol.2012.08.005

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

School of Chemistry

Research output: Contribution to journal › Article › Research › peer-review

53 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 language	English
Pages (from-to)	1237 - 1246
Number of pages	10
Journal	Chemistry and Biology
Volume	19
Issue number	10
DOIs	https://doi.org/10.1016/j.chembiol.2012.08.005
Publication status	Published - 2012

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Kelso, G., Maroz, A., Cocheme, H. M., Logan, A., Prime, T. A., Peskin, A. V., Winterbourn, C. C., James, A. M., Ross, M. F., Brooker, S., Porteous, C. M., Anderson, R. F., Murphy, M. P., & Smith, R. A. J. (2012). A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic. Chemistry and Biology, 19(10), 1237 - 1246. https://doi.org/10.1016/j.chembiol.2012.08.005

@article{0fd273f376784d939b2729e89b8c0cf1,

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 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.",

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

year = "2012",

doi = "10.1016/j.chembiol.2012.08.005",

language = "English",

volume = "19",

pages = "1237 -- 1246",

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T1 - A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic

AU - Kelso, Geoffrey

AU - Maroz, Andrej

AU - Cocheme, Helena M

AU - Logan, Angela

AU - Prime, Tracy A

AU - Peskin, Alexander V

AU - Winterbourn, Christine C

AU - James, Andrew M

AU - Ross, Meredith F

AU - Brooker, Sally

AU - Porteous, Carolyn M

AU - Anderson, Robert F

AU - Murphy, Michael P

AU - Smith, Robin A J

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.sciencedirect.com/science/article/pii/S1074552112002815#

U2 - 10.1016/j.chembiol.2012.08.005

DO - 10.1016/j.chembiol.2012.08.005

M3 - Article

SN - 1074-5521

VL - 19

SP - 1237

EP - 1246

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 10

ER -

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

Abstract

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