Single cells in genetically homogeneous microbial cultures exhibit marked phenotypic individuality, a biological phenomenon that is considered to bolster the fitness of populations. Major phenotypes that are characterized by heterogeneity span the breadth of microbiology, in fields ranging from pathogenicity to ecology. The cell cycle, cell ageing and epigenetic regulation are proven drivers of heterogeneity in several of the best-known phenotypic examples. However, the full contribution of factors such as stochastic gene expression is yet to be realized.

Aerobic life requires organisms to resist the damaging effects of ROS (reactive oxygen species), particularly during stress. Extensive research has established a detailed picture of how cells respond to oxidative stress. Attention is now focusing on identifying the key molecular targets of ROS, which cause killing when resistance is overwhelmed. Experimental criteria used to establish such targets have differing merits. Depending on the nature of the stress, ROS cause loss of essential cellular functions or gain of toxic functions. Essential targets on which life pivots during ROS stress include membrane lipid integrity and activity of ROS-susceptible proteins, including proteins required for faithful translation of mRNA. Protein oxidation also triggers accumulation of toxic protein aggregates or induction of apoptotic cell death. This burgeoning understanding of the principal ROS targets will offer new possibilities for therapy of ROS related diseases.

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Reactive oxygen species (ROS) are linked to various degenerative conditions, but it is unclear which molecular target(s) may be the cell's primary “Achilles’ heel,” accounting for inhibition by ROS. Our results indicate that the FeS protein Rli1p, with essential and conserved functions in protein synthesis, is an important target of ROS toxicity.

Increased cellular levels of reactive oxygen species are known to arise during exposure of organisms to elevated metal concentrations, but the consequences for cells in the context of metal toxicity are poorly characterized. Using two-dimensional gel electrophoresis, combined with immunodetection of protein carbonyls, we report here that exposure of the yeast Saccharomyces cerevisiae to copper causes a marked increase in cellular protein carbonyl levels, indicative of oxidative protein damage. The response was time dependent, with total-protein oxidation peaking approximately 15 min after the onset of copper treatment. Moreover, this oxidative damage was not evenly distributed among the expressed proteins of the cell. Rather, in a similar manner to peroxide-induced oxidative stress, copperdependent protein carbonylation appeared to target glycolytic pathway and related enzymes, as well as heat shock proteins. Oxidative targeting of these and other enzymes was isoformspeci¢c and, in most cases, was also associated with a decline in the proteins' relative abundance. Our results are consistent with a model in which copper-induced oxidative stress disables the £ow of carbon through the preferred glycolytic pathway, and promotes the production of glucose-equivalents within the pentose phosphate pathway. Such re-routing of the metabolic £ux may serve as a rapid-response mechanism to help cells counter the damaging e¡ects of copper-induced oxidative stress. ß

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Chromium toxicity

Competitive growth between over 6,000 heterozygous yeast mutants in the presence of chromium together with microarray-based screens showed that proteasomal activity is crucial for cellular chromium resistance.

The continued release of caesium radioisotopes into the environment has led to a resurgence of interest in microbe-Cs interactions. Caesium exists almost exclusively as the monovalent cation Cs+ in the natural environment. Although Cs+ is a weak Lewis acid that exhibits a low tendency to form complexes with ligands, its chemical similarity to the biologically essential alkali cation K+ facilitates high levels of metabolism-dependent intracellular accumulation. Microbial Cs+ (K+) uptake is generally mediated by monovalent cation transport systems located on the plasma membrane. These differ widely in specificity for alkali cations and consequently microorganisms display large differences in their ability to accumulate Cs+; Cs+ appears to have an equal or greater affinity than K+ for transport in certain microorganisms. Microbial Cs+ accumulation is markedly influenced by the presence of external cations, e.g. K+, Na+, NH4+ and H+, and is generally accompanied by an approximate stoichiometric exchange for intracellular K+. However, stimulation of growth of K(+)-starved microbial cultures by Cs+ is limited and it has been proposed that it is not the presence of Cs+ in cells that is growth inhibitory but rather the resulting loss of K+. Increased microbial tolerance to Cs+ may result from sequestration of Cs+ in vacuoles or changes in the activity and/or specificity of transport systems mediating Cs+ uptake. The precise intracellular target(s) for Cs(+)-induced toxicity has yet to be clearly defined, although certain internal structures, e.g. ribosomes, become unstable in the presence of Cs+ and Cs+ is known to substitute poorly for K+ in the activation of many K(+)-requiring enzymes.