Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Abstract

Arsenic and antimony are metalloids with profound effects on biological systems and human health. Both elements are toxic to cells and organisms, and exposure is associated with several pathological conditions including cancer and neurodegenerative disorders. At the same time, arsenic- and antimony-containing compounds are used in the treatment of multiple diseases. Although these metalloids can both cause and cure disease, their modes of molecular action are incompletely understood. The past decades have seen major advances in our understanding of arsenic and antimony toxicity, emphasizing genotoxicity and proteotoxicity as key contributors to pathogenesis. In this review, we highlight mechanisms by which arsenic and antimony cause toxicity, focusing on their genotoxic and proteotoxic effects. The mechanisms used by cells to maintain proteostasis during metalloid exposure are also described. Furthermore, we address how metalloid-induced proteotoxicity may promote neurodegenerative disease and how genotoxicity and proteotoxicity may be interrelated and together contribute to proteinopathies. A deeper understanding of cellular toxicity and response mechanisms and their links to pathogenesis may promote the development of strategies for both disease prevention and treatment.

Multilevel Regulation of Membrane Proteins in Response to Metal and Metalloid Stress: A Lesson from Yeast

“…For instance, they can interact with various cellular macromolecules, such as DNA, proteins, and membranes. As a result, they induce serious cellular disturbances, including DNA damage [10][11][12], oxidative stress [13][14][15], and proteotoxicity [16,17]. To cope with these challenges, in the course of evolution, cells have developed distinct mechanisms of detoxification and adaptation involving the regulation of specific transporters and enzymes involved in the uptake, sequestration, metabolism, or export of these toxic compounds.…”

“…Additionally, the mechanisms of metal and metalloid detoxification in yeast are relatively well-described in relation to other eukaryotic organisms, including humans. They are also somewhat resistant to toxic agents, surviving a comparably deadly dosage of arsenic or antimony, counted in milli-molar concentrations [10,19]. Those dissimilarities in sensitivity may result from various differences, including the presence of the cell wall, simpler metabolic requirements, as well as other, additional systems like specific transporters, which are not present in the mammalian cells.…”