Cross-talk between iron and cobalt has been long recognized in biological systems. This is due to the capacity of cobalt to interfere with proper iron utilization.
Co2+ induces the increase of the labile-Fe pool (LIP) by Fe-S cluster damage, heme synthesis inhibition and “naked” iron import, which turns cell viability cumbersome. The N2-fixating bacteria Sinorhizobium meliloti is a suitable model to determine the roles of Co2+-transporting Cation diffusion facilitator exporters (Co-eCDF) in Fe2+ homeostasis because it presents a putative member of this sub-familiy, AitP, and two specific Fe2+-export systems. An insertional mutant of AitP showed Co2+ sensitivity and accumulation but not Fe2+ sensitivity, despite AitP being a bona fide low affinity Fe2+ exporter as demonstrated by the kinetic analyses of Fe2+ uptake into everted membrane vesicles. Co2+ sensitivity was increased in double mutants lacking AitP and Fe2+ exporters but this did not correlate with the Co2+ accumulation, suggesting a concomitant Fe2+-dependent induced stress. Growth in presence of sub-lethal Fe2+ and Co2+ concentrations suggested that naked Fe-import might contribute to Co2+ toxicity. Supporting this Co2+ induced transcription of Fe-import system and genes associated to Fe homeostasis. Analyses of total protoporphyrin content point to Fe-S cluster attack as the major source for LIP. AitP mediated Fe2+-export is likely countered via a non-futile Fe2+-import pathway. Two lines of evidence support this: i) an increased hemin uptake in presence of Co2+ was observed in WT vs. AitP mutant and ii) hemin reversed the Co2+ sensitivity in the last. Thus simultaneous detoxification mediated by AitP, aid cells to orchestrate an Fe-S cluster salvage response avoiding the increase in the LIP caused by disassembly of Fe-S clusters or naked iron uptake.
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