Role of Hydrogen Sulfide in NRF2- and Sirtuin-Dependent Maintenance of Cellular Redox Balance

Abstract

Hydrogen sulfide (H₂S) has arisen as a critical gasotransmitter signaling molecule modulating cellular biological events related to health and diseases in heart, brain, liver, vascular systems and immune response. Three enzymes mediate the endogenous production of H₂S: cystathione β-synthase (CBS), cystathione γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). CBS and CSE localizations are organ-specific. 3-MST is a mitochondrial and cytosolic enzyme. The generation of H₂S is firmly regulated by these enzymes under normal physiological conditions. Recent studies have highlighted the role of H₂S in cellular redox homeostasis, as it displays significant antioxidant properties. H₂S exerts antioxidant effects through several mechanisms, such as quenching reactive oxygen species (ROS) and reactive nitrogen species (RNS), by modulating cellular levels of glutathione (GSH) and thioredoxin (Trx-1) or increasing expression of antioxidant enzymes (AOE), by activating the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2). H₂S also influences the activity of the histone deacetylase protein family of sirtuins, which plays an important role in inhibiting oxidative stress in cardiomyocytes and during the aging process by modulating AOE gene expression. This review focuses on the role of H₂S in NRF2 and sirtuin signaling pathways as they are related to cellular redox homeostasis.

Keywords: NRF2; hydrogen sulfide; oxidative stress; redox; sirtuin.

Figure 1

Schematic description of intracellular synthesis and degradation of hydrogen sulfide H₂S. H₂S is produced by cytoplasmic and mitochondrial enzymes cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT) using cysteine or homocysteine as substrates. The intracellular non-toxic H₂S level is being actively maintained by oxidation in mitochondria by the enzyme sulfide:quinone reductase (SQR), together with rhodanese and sulfur dioxygenase, or by methylation in the cytoplasm using thiol S-methyltransferase (TMST). Free H₂S can also be bound by methemoglobin and by molecules with metallic or disulfide bonds and excreted with biological fluids. Reprinted with permission of the American Thoracic Society. Copyright © 2018 American Thoracic Society [14].

Figure 2

Schematic of H₂S mechanism related to glutathione GSH and nuclear factor (erythroid-derived 2)-like 2 NRF2 targets in oxidative cell-damage. The endogenous release of H₂S increases GSH synthesis and blocks reactive oxygen species ROS production. When the cellular level of H₂S is increased, Kelch-like ECH-associated protein 1 Keap1 protein is S-sulfhydrated SSH: which brings a conformational change of the protein and NRF2 release from Keap1. NRF2 translocates to the nucleus, binding to the promoter containing antioxidant response element (ARE) sequences and increased transcription of antioxidant genes as catalase CAT, superoxide dismutase SOD1, glutathione-S-transferase GST, glutathione peroxidase GPx. AOE: antioxidant enzyme.

Figure 3

Schematic of H₂S mechanism and sirtuins SIRT-1, SIRT-3 during oxidative stress. H₂S induces SIRT1 to regulate the levels of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate NAD/NADH to prevent ROS generation. SIRT-3 induces the expression of transcription factor FOXO3 and consequent ROS production. Additionally, H₂S has been shown to induce SOD2 through SIRT3 in mitochondria and regulate oxidative stress. SSH: S-sulfhydration; AP-1: activator protein-1.