Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells

Abstract

Arsenic exposure has been implicated as a risk factor for cardiovascular diseases, metabolic disorders, and cancer, yet the role mitochondrial dysfunction plays in the cellular mechanisms of pathology is largely unknown. To investigate arsenic-induced mitochondrial dysfunction in vascular smooth muscle cells (VSMCs), we exposed rat aortic smooth muscle cells (A7r5) to inorganic arsenic (iAs(III)) and its metabolite monomethylarsonous acid (MMA(III)) and compared their effects on mitochondrial function and oxidative stress. Our results indicate that MMA(III) is significantly more toxic to mitochondria than iAs(III). Exposure of VSMCs to MMA(III), but not iAs(III), significantly decreased basal and maximal oxygen consumption rates and concomitantly increased compensatory extracellular acidification rates, a proxy of glycolysis. Treatment with MMA(III) significantly increased hydrogen peroxide and superoxide levels compared to iAs(III). Exposure to MMA(III) resulted in significant decreases in mitochondrial ATP, aberrant perinuclear clustering of mitochondria, and decreased mitochondrial content. Mechanistically, we observed that mitochondrial superoxide and hydrogen peroxide contribute to mitochondrial toxicity, as treatment of cells with MnTBAP (a mitochondrial superoxide dismutase mimetic) and catalase significantly reduced mitochondrial respiration deficits and cell death induced by both arsenic compounds. Overall, our data demonstrates that MMA(III) is a mitochondria-specific toxicant that elevates mitochondrial and non-mitochondrial sources of ROS.

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

“…OCRs in transfected HeLa cells were analyzed at baseline and following the sequential addition of 1 M oligomycin, 300 nM FCCP, and 1 M rotenone/antimycin A to determine the ATP-linked OCRs, maximal OCRs, and mitochondrially derived OCRs, respectively, as published previously (28). Spare respiratory capacity was calculated as described previously (56,57). In brief, the basal OCRs were subtracted from the maximal OCRs induced by FCCP by applying the formula, spare respiratory capacity ϭ FCCP-induced maximal OCR Ϫ basal OCR.…”

Subcellular Organelle Toxicity Caused by Arsenic Nanoparticles in Isolated Rat Hepatocytes

“…Monomethylarsonous acid, one of the metabolites, which distrib- Arsenic Nanoparticles-induced Hepatotoxicity ute irregularly in different tissues (RBC, liver, and kidney), is an ultimate toxicant to mitochondria. 43 On the other hand, the pattern of metabolism and methylation, and accumulation and retaining of metabolites in tissues are not the same among distinct animals. 44 Thiol groups, residing in the inner mitochondrial membrane upon the oxidation, presumably lead to conformational changes in mitochondrial permeability transition pore (MPT) and collapse of ΔѰm, which are generally considered potential end-points in various insults associated with oxidative stress.…”

Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation

“…We began with a 10 µM concentration of sodium arsenite used in prior in vitro models with aortic endothelial [10, 11] and vascular smooth muscle cell cultures [12, 13], a concentration 50–75% less than that used in prior studies of arsenic and thrombosis [9]. P-selectin expression (CD62P) is a cell surface marker primarily expressed by activated platelets and involved in platelet adhesion.…”