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Background: S-nitrosylation of mitochondrial enzymes involved in energy transfer under nitrosative stress may result in ATP deficiency. We investigated whether alpha-lipoic acid, a powerful antioxidant, could alleviate nitrosative stress by regulating S-nitrosylation, which could result in retaining the mitochondrial enzyme activity.

Methods: In this study, we have identified the S-nitrosylated forms of subunit 1 of dihydrolipoyllysine succinyltransferase (complex III), and subunit 2 of the alpha-ketoglutarate dehydrogenase complex by implementing a fluorescence-based differential quantitative proteomics method.

Results: We found that the activities of these two mitochondrial enzymes were partially but reversibly inhibited by S-nitrosylation in cultured endothelial cells, and that their activities were partially restored by supplementation of alpha-lipoic add. We show that protein S-nitrosylation affects the activity of mitochondrial enzymes that are central to energy supply, and that alpha-lipoic acid protects mitochondrial enzymes by altering S-nitrosylation levels.

Conclusions: Inhibiting protein S-nitrosylation with alpha-lipoic acid seems to be a protective mechanism against nitrosative stress.

General significance: Identification and characterization of these new protein targets should contribute to expanding the therapeutic power of alpha-lipoic acid and to a better understanding of the underlying antioxidant mechanisms. (C) 2015 Elsevier B.V. All rights reserved.