Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells.

Dos Santos AA, López-Granero C, Farina M, Rocha JBT, Bowman AB, Aschner M
Food Chem Toxicol. 2018 113: 328-336

PMID: 29428217 · DOI:10.1016/j.fct.2018.01.057

Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 μM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD/NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA.

Copyright © 2018. Published by Elsevier Ltd.

MeSH Terms (15)

Animals Astrocytes Caspase 3 Caspase 9 Cell Death Cells, Cultured Enzyme Activation Lim Kinases Methylmercury Compounds Mice, Inbred C57BL Myosin-Light-Chain Phosphatase Oxidative Stress Phosphorylation Proteolysis rho-Associated Kinases

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