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Int. J. Mol. Sci. 2017, 18(8), 1686; doi:10.3390/ijms18081686

Intramitochondrial Ascorbic Acid Enhances the Formation of Mitochondrial Superoxide Induced by Peroxynitrite via a Ca2+-Independent Mechanism

Dipartimento di Scienze Biomolecolari Università degli Studi di Urbino “Carlo Bo”, 61029 Urbino, Italy
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Received: 13 July 2017 / Revised: 30 July 2017 / Accepted: 30 July 2017 / Published: 2 August 2017
(This article belongs to the Special Issue Mitochondria Crosstalks with other Organelles in Pathophysiology)
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Abstract

Exposure of U937 cells to peroxynitrite promotes mitochondrial superoxide formation via a mechanism dependent on both inhibition of complex III and increased mitochondrial Ca2+ accumulation. Otherwise inactive concentrations of the oxidant produced the same maximal effects in the presence of either complex III inhibitors or agents mobilizing Ca2+ from the ryanodine receptor and enforcing its mitochondrial accumulation. l-Ascorbic acid (AA) produced similar enhancing effects in terms of superoxide formation, DNA strand scission and cytotoxicity. However, AA failed to enhance the intra-mitochondrial concentration of Ca2+ and the effects observed in cells supplemented with peroxinitrite, while insensitive to manipulations preventing the mobilization of Ca2+, or the mitochondrial accumulation of the cation, were also detected in human monocytes and macrophages, which do not express the ryanodine receptor. In all these cell types, mitochondrial permeability transition-dependent toxicity was detected in cells exposed to AA/peroxynitrite and, based on the above criteria, these responses also appeared Ca2+-independent. The enhancing effects of AA are therefore similar to those mediated by bona fide complex III inhibitors, although the vitamin failed to directly inhibit complex III, and in fact enhanced its sensitivity to the inhibitory effects of peroxynitrite. View Full-Text
Keywords: peroxynitrite; ascorbic acid; mitochondrial superoxide; DNA damage; mitochondrial dysfunction; complex III peroxynitrite; ascorbic acid; mitochondrial superoxide; DNA damage; mitochondrial dysfunction; complex III
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Guidarelli, A.; Cerioni, L.; Fiorani, M.; Cantoni, O. Intramitochondrial Ascorbic Acid Enhances the Formation of Mitochondrial Superoxide Induced by Peroxynitrite via a Ca2+-Independent Mechanism. Int. J. Mol. Sci. 2017, 18, 1686.

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