Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress

Authors

Sylvia Hiller, University of North Carolina at Chapel Hill
Robert DeKroon, University of North Carolina at Chapel Hill
Eric D. Hamlett, Medical University of South Carolina
Longquan Xu, University of North Carolina at Chapel Hill
Cristina Osorio, University of North Carolina at Chapel Hill
Jennifer Robinette, University of North Carolina at Chapel Hill
Witold Winnik, U.S. Environmental Protection Agency
Stephen Simington, University of North Carolina at Chapel Hill
Nobuyo Maeda, University of North Carolina at Chapel Hill
Oscar Alzate, Texas A&M Health Science CenterFollow
Xianwen Yi, University of North Carolina at Chapel HillFollow

Document Type

Article

Date of this Version

2016

Citation

Biochimica et Biophysica Acta 1860 (2016), pp. 36–45, http://dx.doi.org/10.1016/j.bbagen.2015.09.001.

Comments

U.S. government work.

Abstract

Background: S-nitrosylation of mitochondrial enzymes involved in energy transfer under nitrosative stress may result in ATP deficiency. We investigated whether α-lipoic acid, a powerful antioxidant, could alleviate nitrosative stress by regulating S-nitrosylation,which could result in retaining themitochondrial 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 α-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 α-lipoic acid. We show that protein S-nitrosylation affects the activity of mitochondrial enzymes that are central to energy supply, and that α-lipoic acid protectsmitochondrial enzymes by altering S-nitrosylation levels.

Conclusions: Inhibiting protein S-nitrosylation with α-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 α-lipoic acid and to a better understanding of the underlying antioxidant mechanisms.