Genetic Determinants of Mitochondrial Response to Arsenic in YeastSaccharomyces cerevisiae

Abstract

We have used yeast Saccharomyces cerevisiae as a tool to identify the importance of mitochondrial processes involved in arsenic-induced carcinogenicity in humans. We screened 466 single-gene knockout strains of yeast S. cerevisiae known to be involved in biogenesis of mitochondria for sodium arsenite (AsIII) and sodium arsenate (AsV) sensitivity. We identified 72 arsenite-sensitive and 81 arsenate-sensitive mutants. We categorized the identified mutants based on the various mitochondrial processes, including nucleic acid metabolism, oxidative phosphorylation, protein synthesis, and vacuolar acidification. We have identified 65 human orthologues to proteins involved in arsenite sensitivity and 3 human orthologues to arsenite resistance. Furthermore, 23 human orthologues to arsenate sensitivity and 20 human orthologues to arsenate-resistant proteins, including MSH3, COX10, GCSH, PPOX, and MTHFD1, were also identified. Using PathwayAssist software, we did cellular network analysis between identified mitochondrial proteins. Three types of interactions, (a) protein-protein interactions, (b) common transcriptional regulators, and (c) common target genes, were identified. We found that RTG (retrograde) genes involved in mitochondria-to-nucleus signaling regulate both arsenite sensitivity and resistance. Furthermore, our study revealed that ABF1, a multifunctional transcriptional factor, regulates genes involved in both arsenite and arsenate sensitivity and resistance. However, REB1 and RAP1 transcriptional regulators were common to only arsenate-and arsenite-sensitive genes, respectively. These studies indicate that multiple pathways involved in mitochondrial biogenesis protect yeast S. cerevisiae from arsenic-induced toxicity. Together, our studies suggest that evolutionary conserved mitochondrial networks identified in yeast S. cerevisiae must play an important role in arsenic-induced carcinogenesis in humans.

Global Transcriptome and Deletome Profiles of Yeast Exposed to Transition Metals

“…These responses may reduce the intracellular levels of the metal by decreasing the number of metal-importing transporters and increasing metal efflux through major facilitators. The processes identified in this study are similar to adaptations in yeast exposed to other environmental stressors, as well as in human fibroblasts exposed to arsenic [15], [38]–[40].…”

Contribution of Yap1 towards Saccharomyces cerevisiae adaptation to arsenic-mediated oxidative stress

“…Yap1, the best-characterized member of the Yap family and the major regulator in oxidative stress, is involved in arsenic stress responses. As recently pointed by other investigators [14], tolerance to either arsenate or arsenite also involves specific sets of mitochondrial genes. It is indeed known that arsenite [As(III)] can react with the thiol groups of proteins, inhibiting many biological pathways, whereas the pentavalent form [As(V)] of arsenic is a phosphate analogue interfering with phosphorylation reactions [1].…”

A genome-wide screen in Saccharomyces cerevisiae reveals pathways affected by arsenic toxicity

“…Nucleic acid metabolism, oxidative phosphorylation, protein synthesis and vacuolar acidification were involved in either arsenite sensitivity or resistance as determined by screening single gene knockout strains of S. cerevisiae in mitochondrial biogenesis and function [22]. The strains whose deletion confers sensitivity to arsenic trioxide were found to be significantly enriched in the biological processes of osmoregulation, stress-related transcription regulation, cytoskeletal assembly and maintenance, signal transduction, DNA repair, oxidative stress, glutathione synthesis, secretory pathways and vacuole function, and general defense mechanisms [23].…”