Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis

Anuradha Dhanasekaran, Srigiridhar Kotamraju, Shasi V. Kalivendi, Toshiyuki Matsunaga, Tiesong Shang, Agnes Keszler, Joy Joseph, B. Kalyanaraman

Research output: Contribution to journalArticle

174 Citations (Scopus)

Abstract

The mitochondria-targeted drugs mitoquinone (Mito-Q) and mitovitamin E (MitoVit-E) are a new class of antioxidants containing the triphenylphosphonium cation moiety that facilitates drug accumulation in mitochondria. In this study, Mito-Q (ubiquinone attached to a triphenylphosphonium cation) and MitoVit-E (vitamin E attached to a triphenylphosphonium cation) were used. The aim of this study was to test the hypothesis that mitochondria-targeted antioxidants inhibit peroxide-induced oxidative stress and apoptosis in bovine aortic endothelial cells (BAEC) through enhanced scavenging of mitochondrial reactive oxygen species, thereby blocking reactive oxygen species-induced transferrin receptor (TfR)-mediated iron uptake into mitochondria. Glucose/glucose oxidase-induced oxidative stress in BAECs was monitored by oxidation of dichlorodihydrofluorescein that was catalyzed by both intracellular H 2O2 and transferrin iron transported into cells. Pretreatment of BAECs with Mito-Q (1 μM) and MitoVit-E (1 μM) but not untargeted antioxidants (e.g. vitamin E) significantly abrogated H 2O2- and lipid peroxide-induced 2′,7′- dichlorofluorescein fluorescence and protein oxidation. Mitochondria-targeted antioxidants inhibit cytochrome c release, caspase-3 activation, and DNA fragmentation. Mito-Q and MitoVit-E inhibited H2O2- and lipid peroxide-induced inactivation of complex I and aconitase, TfR overexpression, and mitochondrial uptake of 55Fe, while restoring the mitochondrial membrane potential and proteasomal activity. We conclude that Mito-Q or MitoVit-E supplementation of endothelial cells mitigates peroxide-mediated oxidant stress and maintains proteasomal function, resulting in the overall inhibition of TfR-dependent iron uptake and apoptosis.

Original languageEnglish (US)
Pages (from-to)37575-37587
Number of pages13
JournalJournal of Biological Chemistry
Volume279
Issue number36
DOIs
StatePublished - Sep 3 2004

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Mitochondria
Endothelial cells
Peroxides
Iron
Endothelial Cells
Antioxidants
Transferrin Receptors
Apoptosis
Cations
Oxidative stress
Lipid Peroxides
Reactive Oxygen Species
Oxidative Stress
Aconitate Hydratase
Oxidation
Glucose Oxidase
Ubiquinone
Tocopherols
Mitochondrial Membrane Potential
Scavenging

ASJC Scopus subject areas

  • Biochemistry

Cite this

Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. / Dhanasekaran, Anuradha; Kotamraju, Srigiridhar; Kalivendi, Shasi V.; Matsunaga, Toshiyuki; Shang, Tiesong; Keszler, Agnes; Joseph, Joy; Kalyanaraman, B.

In: Journal of Biological Chemistry, Vol. 279, No. 36, 03.09.2004, p. 37575-37587.

Research output: Contribution to journalArticle

Dhanasekaran, Anuradha ; Kotamraju, Srigiridhar ; Kalivendi, Shasi V. ; Matsunaga, Toshiyuki ; Shang, Tiesong ; Keszler, Agnes ; Joseph, Joy ; Kalyanaraman, B. / Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 36. pp. 37575-37587.
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