Faculty Collaboration Database

Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: role of mitochondrial superoxide. Free Radic Biol Med 2005 Sep 01;39(5):567-83

Date

08/09/2005

Pubmed ID

16085176

DOI

10.1016/j.freeradbiomed.2005.04.016

Scopus ID

2-s2.0-23444440170 (requires institutional sign-in at Scopus site)   184 Citations

Abstract

The purpose of this study was to test the hypothesis whether Mito-carboxy proxyl (Mito-CP), a mitochondria-targeted nitroxide, inhibits peroxide-induced oxidative stress and apoptosis in bovine aortic endothelial cells (BAEC). Glucose/glucose oxidase (Glu/GO)-induced oxidative stress was monitored by dichlorodihydrofluorescein oxidation catalyzed by intracellular H(2)O(2) and transferrin receptor-mediated iron transported into cells. Pretreatment of BAECs with Mito-CP significantly diminished H(2)O(2)- and lipid peroxide-induced intracellular formation of dichlorofluorescene and protein oxidation. Electron paramagnetic resonance (EPR) studies confirmed the selective accumulation of Mito-CP into the mitochondria. Mito-CP inhibited the cytochrome c release and caspase-3 activation in cells treated with peroxides. Mito-CP inhibited both H(2)O(2)- and lipid peroxide-induced inactivation of complex I and aconitase, overexpression of transferrin receptor (TfR), and mitochondrial uptake of (55)Fe, while restoring the mitochondrial membrane potential and proteasomal activity. In contrast, the "untargeted" carboxy proxyl (CP) nitroxide probe did not protect the cells from peroxide-induced oxidative stress and apoptosis. However, both CP and Mito-CP inhibited superoxide-induced cytochrome c reduction to the same extent in a xanthine/xanthine oxidase system. We conclude that selective uptake of Mito-CP into the mitochondria is responsible for inhibiting peroxide-mediated Tf-Fe uptake and apoptosis and restoration of the proteasomal function.

Author List

Dhanasekaran A, Kotamraju S, Karunakaran C, Kalivendi SV, Thomas S, Joseph J, Kalyanaraman B

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aconitate Hydratase
Animals
Antioxidants
Aorta
Apoptosis
Caspases
Catalysis
Cattle
Cell Survival
Cyclic N-Oxides
Cytochromes c
Cytosol
Electron Spin Resonance Spectroscopy
Endothelial Cells
Endothelium, Vascular
Flow Cytometry
Free Radicals
Gas Chromatography-Mass Spectrometry
Glucose Oxidase
Hydrogen Peroxide
Iron
Lipid Peroxidation
Lipids
Membrane Potentials
Microscopy, Fluorescence
Mitochondria
Models, Chemical
Nitric Oxide
Organophosphorus Compounds
Oxidative Stress
Oxygen
Peroxides
Proteasome Endopeptidase Complex
Receptors, Transferrin
Superoxide Dismutase
Superoxides
Time Factors
Transferrin
Xanthine
Xanthine Oxidase