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

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 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 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 protects mitochondrial 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.

Redox-Driven Signaling: 2-Oxo Acid Dehydrogenase Complexes as Sensors and Transmitters of Metabolic Imbalance

“…Although the sulfur-based radicals have not attracted such attention as ROS or RNS in biological studies, the ability of thiyl radicals to promote not only oxygen reduction but also nitrosylation and transnitrosylation reactions (98) certainly warrants more attention to production of these radicals in biological systems and their potential involvement in homeostatic mechanisms. This is supported by recent findings on production of thiyl radicals by 2-oxo acid dehydrogenase complexes (48), nitrosylation of lipoyl-bearing components of the complexes (90), transnitrosylating function of thioredoxins (TRXs) (208), and specific interaction of mitochondrial thioredoxin with 2-oxo acid dehydrogenase complexes, shown for both animal (33) and plant (16,211) proteins.…”

“…They include the superoxide-dependent mobilization of iron from proteins with iron/sulfur clusters, such as mitochondrial glutaredoxins and aconitase. Furthermore, the supramolecular structure supports the peroxynitrite reductase and nitrosylation reactions participating in the protection and damage, correspondingly, under nitrosative stress (26,55,90,122,208). Providing for the balance between the physiological and side reactions of 2-oxo acid dehydrogenase complexes, the complexbound thiyl radicals and associated ROS may thus be concertedly involved in signaling by ROS and RNS.…”

Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential

“…It has one chiral center that is denoted by an asterisk species (ROS) are reactive molecules derived from the natural byproduct of the oxygen metabolism and having significant roles in the homeostasis and in the cell-signaling. Nitric oxide (NO) is a soluble and highly diffusible gas generated by a wide variety of cell types including vascular endothelial cells [27]. Excess production of endogenous NO under inflammatory conditions can be toxic to vascular endothelial cells [54].…”

“…LA is also a pivotal component of mitochondrial complex of four important proteins participating in the synthesis and degradation of glycine molecule. LA is also a cofactor for several enzymes including pyruvate dehydrogenase complex (PDC) and a-ketoglutarate dehydrogenase complex (KDC), two mitochondrial enzymes involved in glucose metabolism and energy production [27].…”

Alpha-lipoic acid in treatment of diabetes mellitus complications

“…S-нітрозилювання цих мітохондріальних ферментів, залучених у процес переносу енергетичних субстратів, призводить до дефіциту аденозинтрифосфату (АТФ). α-ЛК відновлює активність ферментів, що сприяє підвищенню енергетичної безпеки клітин [7].…”