Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria

Ivan Spasojević; Yumin Chen; Teresa J. Noel; Yiqun Yu; Marsha P. Cole; Lichun Zhang; Yunfeng Zhao; Daret K. St. Clair; Ines Batinić-Haberle

doi:10.1016/j.freeradbiomed.2007.01.019

Mn porphyrin-based superoxide dismutase (SOD) mimic, Mn^IIITE-2-PyP⁵⁺, targets mouse heart mitochondria

Ivan Spasojević, Yumin Chen, Teresa J. Noel, Yiqun Yu, Marsha P. Cole, Lichun Zhang, Yunfeng Zhao, Daret K. St. Clair, Ines Batinić-Haberle

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

108 Scopus citations

Abstract

The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, Mn^IIITE-2-PyP⁵⁺ (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP⁵⁺ are essential for its high antioxidant potency. The exceptional ability of Mn^IIITE-2-PyP⁵⁺ to dismute O₂^·- parallels its ability to reduce ONOO^- and CO₃^-. Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that ≥3 μM Mn^IIITE-2-PyP⁵⁺ was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of Mn^IIITE-2-PyP⁵⁺ are obtainable in vivo. For this study we have developed a new and sensitive method for Mn^IIITE-2-PyP⁵⁺ determination in tissues. The method is based on the exchange of porphyrin Mn²⁺ with Zn²⁺, followed by the HPLC/fluorescence detection of Zn^IITE-2-PyP⁴⁺. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of Mn^IIITE-2-PyP⁵⁺, the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol. 55:39-46; 1979). We found Mn^IIITE-2-PyP⁵⁺ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 μL/mg protein, the calculated Mn^IIITE-2-PyP⁵⁺ concentration is 5.1 μM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that Mn^IIITE-2-PyP⁵⁺, a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.

Original language	English
Pages (from-to)	1193-1200
Number of pages	8
Journal	Free Radical Biology and Medicine
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.freeradbiomed.2007.01.019
State	Published - Apr 15 2007

Bibliographical note

Funding Information:
Ivan Spasojević acknowledges NIH/NCI Duke Comprehensive Cancer Center Core Grant (5-P30-CA14236-29). Ines Batinić-Haberle appreciates financial support from NIH- IR21-ESO/3682, W19A167798-01, and NIH U19 AI67798-01. Yumin Chen, Marsha Cole, Yunfeng Zhao, Teresa Noel, and Daret St. Clair are thankful to the support of NIH Grants CA 49797, CA 73599, and CA 94853. Authors are also thankful to Rafael Radi and Gerardo Ferrer-Sueta for helpful discussions and to Irwin Fridovich for critical reading of the manuscript and for his continuous support.

Funding

Ivan Spasojević acknowledges NIH/NCI Duke Comprehensive Cancer Center Core Grant (5-P30-CA14236-29). Ines Batinić-Haberle appreciates financial support from NIH- IR21-ESO/3682, W19A167798-01, and NIH U19 AI67798-01. Yumin Chen, Marsha Cole, Yunfeng Zhao, Teresa Noel, and Daret St. Clair are thankful to the support of NIH Grants CA 49797, CA 73599, and CA 94853. Authors are also thankful to Rafael Radi and Gerardo Ferrer-Sueta for helpful discussions and to Irwin Fridovich for critical reading of the manuscript and for his continuous support.

Funders	Funder number
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01CA049797, CA 94853, U19 AI67798-01, 5-P30-CA14236-29, IR21-ESO/3682, W19A167798-01, CA 73599

Keywords

HPLC/fluorescence detection of Mn porphyrin in vivo
Heart mitochondria
Mn porphyrin/Zn porphyrin exchange
MnTE-2-PyP, AEOL-10113
SOD mimic targeting mitochondria

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.freeradbiomed.2007.01.019

Cite this

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title = "Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria",

abstract = "The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnIIITE-2-PyP5+ (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP5+ are essential for its high antioxidant potency. The exceptional ability of MnIIITE-2-PyP5+ to dismute O2·- parallels its ability to reduce ONOO- and CO3-. Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that ≥3 μM MnIIITE-2-PyP5+ was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of MnIIITE-2-PyP5+ are obtainable in vivo. For this study we have developed a new and sensitive method for MnIIITE-2-PyP5+ determination in tissues. The method is based on the exchange of porphyrin Mn2+ with Zn2+, followed by the HPLC/fluorescence detection of ZnIITE-2-PyP4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of MnIIITE-2-PyP5+, the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol. 55:39-46; 1979). We found MnIIITE-2-PyP5+ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 μL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 μM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that MnIIITE-2-PyP5+, a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.",

keywords = "HPLC/fluorescence detection of Mn porphyrin in vivo, Heart mitochondria, Mn porphyrin/Zn porphyrin exchange, MnTE-2-PyP, AEOL-10113, SOD mimic targeting mitochondria",

author = "Ivan Spasojevi{\'c} and Yumin Chen and Noel, \{Teresa J.\} and Yiqun Yu and Cole, \{Marsha P.\} and Lichun Zhang and Yunfeng Zhao and \{St. Clair\}, \{Daret K.\} and Ines Batini{\'c}-Haberle",

note = "Funding Information: Ivan Spasojevi{\'c} acknowledges NIH/NCI Duke Comprehensive Cancer Center Core Grant (5-P30-CA14236-29). Ines Batini{\'c}-Haberle appreciates financial support from NIH- IR21-ESO/3682, W19A167798-01, and NIH U19 AI67798-01. Yumin Chen, Marsha Cole, Yunfeng Zhao, Teresa Noel, and Daret St. Clair are thankful to the support of NIH Grants CA 49797, CA 73599, and CA 94853. Authors are also thankful to Rafael Radi and Gerardo Ferrer-Sueta for helpful discussions and to Irwin Fridovich for critical reading of the manuscript and for his continuous support.",

year = "2007",

month = apr,

day = "15",

doi = "10.1016/j.freeradbiomed.2007.01.019",

language = "English",

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T1 - Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria

AU - Spasojević, Ivan

AU - Chen, Yumin

AU - Noel, Teresa J.

AU - Yu, Yiqun

AU - Cole, Marsha P.

AU - Zhang, Lichun

AU - Zhao, Yunfeng

AU - St. Clair, Daret K.

AU - Batinić-Haberle, Ines

N1 - Funding Information: Ivan Spasojević acknowledges NIH/NCI Duke Comprehensive Cancer Center Core Grant (5-P30-CA14236-29). Ines Batinić-Haberle appreciates financial support from NIH- IR21-ESO/3682, W19A167798-01, and NIH U19 AI67798-01. Yumin Chen, Marsha Cole, Yunfeng Zhao, Teresa Noel, and Daret St. Clair are thankful to the support of NIH Grants CA 49797, CA 73599, and CA 94853. Authors are also thankful to Rafael Radi and Gerardo Ferrer-Sueta for helpful discussions and to Irwin Fridovich for critical reading of the manuscript and for his continuous support.

PY - 2007/4/15

Y1 - 2007/4/15

N2 - The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnIIITE-2-PyP5+ (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP5+ are essential for its high antioxidant potency. The exceptional ability of MnIIITE-2-PyP5+ to dismute O2·- parallels its ability to reduce ONOO- and CO3-. Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that ≥3 μM MnIIITE-2-PyP5+ was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of MnIIITE-2-PyP5+ are obtainable in vivo. For this study we have developed a new and sensitive method for MnIIITE-2-PyP5+ determination in tissues. The method is based on the exchange of porphyrin Mn2+ with Zn2+, followed by the HPLC/fluorescence detection of ZnIITE-2-PyP4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of MnIIITE-2-PyP5+, the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol. 55:39-46; 1979). We found MnIIITE-2-PyP5+ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 μL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 μM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that MnIIITE-2-PyP5+, a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.

AB - The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnIIITE-2-PyP5+ (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP5+ are essential for its high antioxidant potency. The exceptional ability of MnIIITE-2-PyP5+ to dismute O2·- parallels its ability to reduce ONOO- and CO3-. Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that ≥3 μM MnIIITE-2-PyP5+ was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of MnIIITE-2-PyP5+ are obtainable in vivo. For this study we have developed a new and sensitive method for MnIIITE-2-PyP5+ determination in tissues. The method is based on the exchange of porphyrin Mn2+ with Zn2+, followed by the HPLC/fluorescence detection of ZnIITE-2-PyP4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of MnIIITE-2-PyP5+, the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol. 55:39-46; 1979). We found MnIIITE-2-PyP5+ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 μL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 μM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that MnIIITE-2-PyP5+, a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.

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KW - Heart mitochondria

KW - Mn porphyrin/Zn porphyrin exchange

KW - MnTE-2-PyP, AEOL-10113

KW - SOD mimic targeting mitochondria

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