Testosterone and Follicle Stimulating Hormone–Dependent Glyoxalase 1 Up-Regulation Sustains the Viability of Porcine Sertoli Cells through the Control of Hydroimidazolone– and Argpyrimidine-Mediated NF-κB Pathway

Abstract

Because Sertoli cells (SCs) play a central role in germ cell survival, their death may result in marked germ cell loss and infertility. SCs are the only somatic cells within the seminiferous tubules and are essential for regulating spermatogenesis. Factors that enhance or diminish the viability of SCs may have profound effects on spermatogenesis. Yet the mechanisms underlying the maintenance of SC viability remain largely unknown. Glyoxalase 1 (Glo1) detoxifies methylglyoxal (MG), a highly reactive carbonyl species mainly formed during glycolysis, which is a potent precursor of cytotoxic advanced glycation end products (AGEs). Hydroimidazolone (MG-H1) and argpyrimidine (ArgPyr) are AGEs resulting from MG-mediated post-translational modification of arginine residues in various proteins. The role of Glo1 and MG-derived AGEs in regulating the fate of SCs has never been investigated. By using gene silencing and the specific MG scavenger, aminoguanidine, the authors demonstrate that Glo1, under testosterone and follicle-stimulating hormone control, sustains viability of porcine neonatal SCs through a mechanism involving the NF-κB pathway. Glo1 knockdown induces a mitochondrial apoptotic pathway driven by the intracellular accumulation of MG-H1 and ArgPyr that desensitizes NF-κB signaling by modifying the inhibitor of NF-κB kinase, IKKß. This is the first report describing a role for Glo1 and MG-derived AGEs in SC biology, providing valuable new insights into the potential involvement of this metabolic axis into spermatogenesis.

Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells

“…Short-term treatment with high concentrations of MG has been reported to induce intracellular damage similar to that of hyperglycemia [ 15 ]. Therefore, via the glyoxalase pathway, the cellular detoxification of the reactive dicarbonyl metabolite, MG is essentially implemented [ 16 , 17 ]. In this pathway, Glo-1, a major MG detoxifying enzyme, catalyzes the first and the rate-limiting step in the removal of MG, and is crucial in protecting cells against oxidative stress [ 18 , 19 ].…”

Methylglyoxal Acts as a Tumor-Promoting Factor in Anaplastic Thyroid Cancer

“…MG-derived dicarbonyl adducts exert complex pleiotropic effects on normal and pathologic processes in cells, including modulation of protein biological activity [3] and stability [4], and generation of reactive oxygen species (ROS) and oxidative stress [5], which may culminate in distinct biological outcomes [6,7,8,9,10,11]. In particular, supra-physiological accumulation of hydroimidazolone (MG-H1) and argpyrimidine (AP), AGEs originating from MG-mediated post-translational modification of proteins at arginine residues, has been shown to induce oxidative DNA damage and apoptosis [6,9,10,11]. However, post-translational modifications by MG-derived AP can also enhance the functionality of fundamental stress-inducible proteins implicated in cellular recovery after exposure to damaging stimuli and protection against apoptosis, including heat shock protein 27 (Hsp27), thus playing an important role in cell survival [12,13].…”

Redox-Sensitive Glyoxalase 1 Up-Regulation Is Crucial for Protecting Human Lung Cells from Gold Nanoparticles Toxicity

“…In order to investigate possible mechanisms contributing to maintaining the BEAS-2B and A549 cell viability upon AuNPs exposure, we focused on Glo1, a cytoprotective enzyme whose function is to limit the intracellular accumulation of the potent pro-apoptotic agent, methylglyoxal (MG) [ 20 ]. In fact, when MG accumulates in cells at supra-physiological concentrations, it induces important post-translational modifications (PTM) that generates advanced glycation end-products (AGEs), such as hydroimidazolone (MG-H1), a heterogeneous family of compounds known to induce oxidative DNA damage and apoptosis [ 18 , 19 , 23 , 24 , 36 ]. We found that AuNPs exposure induced a significant increase of Glo1 enzyme activity, already at 3 h post-exposure, compared to the control cells in both cell lines ( Figure 3 a,b).…”

“…Apoptosis was detected by measuring the activation of caspase-3, using an enzyme-linked immunosorbent assay (ELISA) (Thermo Fisher Scientific, Monza, Italy), specific for activated human caspase-3, following the manufacturer’s instructions [ 24 , 25 ].…”

“…As such, MG reacts spontaneously with amino residues of proteins, lipids, and nucleic acids, leading to the formation of advanced glycation end products (AGEs). MG-derived dicarbonyl adducts exert complex pleiotropic effects in cells, culminating in distinct biological outcomes [ 21 , 22 ], including apoptosis [ 18 , 19 , 23 , 24 ] and cell transformation, through epithelial to mesenchymal transition (EMT) [ 17 , 25 ]. MG glycation of proteins is mainly directed to arginine residues, forming the hydroimidazolone MG-H1, while the major DNA adduct of MG is the imidazopurinone, MGdG [ 20 ].…”