Sulforaphane inhibits mitochondrial permeability transition and oxidative stress |
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Authors: | Greco Tiffany Shafer Jonathan Fiskum Gary |
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Affiliation: | aDepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA;bUniversity of Maryland Baltimore County, Baltimore, MD 21201, USA |
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Abstract: | Exposure of mitochondria to oxidative stress and elevated Ca2+ promotes opening of the mitochondrial permeability transition pore (PTP), resulting in membrane depolarization, uncoupling of oxidative phosphorylation, and potentially cell death. This study tested the hypothesis that treatment of rats with sulforaphane (SFP), an activator of the Nrf2 pathway of antioxidant gene expression, increases the resistance of liver mitochondria to redox-regulated PTP opening and elevates mitochondrial levels of antioxidants. Rats were injected with SFP or drug vehicle and liver mitochondria were isolated 40 h later. Respiring mitochondria actively accumulated added Ca2+, which was then released through PTP opening induced by agents that either cause an oxidized shift in the mitochondrial redox state or directly oxidize protein thiol groups. SFP treatment of rats inhibited the rate of pro-oxidant-induced mitochondrial Ca2+ release and increased expression of the glutathione peroxidase/reductase system, thioredoxin, and malic enzyme. These results are the first to demonstrate that SFP treatment of animals increases liver mitochondrial antioxidant defenses and inhibits redox-sensitive PTP opening. This novel form of preconditioning could protect against a variety of pathologies that include oxidative stress and mitochondrial dysfunction in their etiologies. |
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Keywords: | Abbreviations: ARE, antioxidant response element CyD, cyclophilin D DMSO, dimethyl sulfoxide GPX1, glutathione peroxidase 1 GAPDH, glyceraldehyde-3-phosphate dehydrogenase GSH, reduced glutathione GSSG, oxidized glutathione IDH2, isocitrate dehydrogenase 2 ME3, malic enzyme 3 NQO1, NAD(P)H:quinone oxidoreductase 1 Nrf2, NF-E2-related factor 2 OAA, oxaloacetate PhAsO, phenylarsine oxide PTP, mitochondrial permeability transition pore SOD2, superoxide dismutase 2 SFP, sulforaphane tBOOH, tert-butylhydroperoxide Trx2, thioredoxin 2 VDAC, voltage-dependent anion channel |
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