Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells.
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 for 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.
Department of Environmental Sciences and Health, University of Nevada, Reno, NV 89557, USA.
Clare
C
Pace
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Tania Das
TD
Banerjee
School of Community Health Sciences, University of Nevada, Reno, NV 89557, USA.
Barrett
B
Welch
Department of Environmental Sciences and Health, University of Nevada, Reno, NV 89557, USA.
Roxana
R
Khalili
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA. Electronic address: rdagda@medicine.nevada.edu.
Ruben K
RK
Dagda
School of Community Health Sciences, University of Nevada, Reno, NV 89557, USA. Electronic address: jangermann@medicine.nevada.edu.
Jeff
J
Angermann
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009942:Organometallic Compounds / Q000633:toxicity*; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D009942:Organometallic Compounds; C406082:monomethylarsonous acid; D013481:Superoxides; D000255:Adenosine Triphosphate; D001151:Arsenic
Antioxidant; Arsenic; Methyliiodoarsine; Mitochondria; Superoxide; Vascular smooth muscle cells