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>or=3 microM 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 microL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 microM, 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.

Mitochondrial Dysfunction in SOD1G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants

“…Accordingly, DMPO, L-NAME, Mito-Q, and MnTE-2-PyP restored mitochondrial respiration and also prevented astrocyte-derived neurotoxicity. It has been recently shown that MnTE-2-PyP in the Mn 3ϩ oxidation state is reduced by complex I and complex II of the mitochondrial ETC, and the reduced (Mn 2ϩ ) complex reacts and decomposes peroxynitrite, suggesting that Mn-porphyrins may act as peroxynitrite reduction catalysts in vivo and protect mitochondria from oxidative damage (Ferrer-Sueta et al, 2006;Spasojević et al, 2007). These results emphasize the key role of nitroxidative stress in astrocytes in the pathogenesis of neurodegenerative diseases.…”

Only one of a wide assortment of manganese-containing SOD mimicking compounds rescues the slow aerobic growth phenotypes of both Escherichia coli and Saccharomyces cerevisiae strains lacking superoxide dismutase enzymes

“…It is possible that in order to be effective these SOD mimics or manganese ions have to be in a particular cellular location(s) at sufficient concentration and be in a suitable chemical form to scavenge superoxide. It is interesting in this regard to note that MnTE-2-PyP has recently been demonstrated to target mouse heart mitochondria [43]. The differences in the efficacy observed for some SOD mimics, such as EUK compounds, that work in E. coli and not in yeast could be due to mislocalization or due to lack of sufficient concentration buildup of active species of these compounds in compartments where the radicals are present.…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Breast cancer. Because (a) MnSOD (the essential endogenous antioxidant) is reduced in many cancers; (b) increased expression of MnSOD inhibits cancer growth (152), and (c) SOD mimic, MnTE-2-PyP 5þ enters mitochondria (306), it is only logical that we tested the possible anticancer activity of MnTE-2-PyP 5þ . Three studies from our group were done within the last 8 years (with doses of MnTE-2-PyP 5þ ranging from 6 to 15 mg=kg) with the goal to prove if and why a catalytic SOD mimic=peroxynitrite scavenger would exert anticancer effects [i.e., to evaluate whether the attenuation of the oxidative stress by MnTE-2-PyP 5þ could suppress tumor growth in a 4T1 mouse breast tumor model (222,221,259)].…”