Interkingdom competition for Fe(III) revealed by a synthetic lethal interaction between Caenorhabditis elegans mitochondrial electron transport and Escherichia coli siderophore iron release mutations

C. elegans consumes bacteria which can supply essential vitamins and cofactors especially for mitochondrial functions ancestrally related to bacteria. Therefore, we screened the Keio E. coli knockout library for mutations that induce a C. elegans mitochondrial damage response gene. We identified 45 E. coli mutations that induce a the C. elegans hsp-6::gfp response gene. Surprisingly, four of these E. coli mutations that disrupt the import or removal of iron from the bacterial siderophore enterobactin were lethal in combination with C. elegans mutations that disrupt particular iron-sulfur proteins of the electron transport chain. Bacterial mutations that fail to synthesize enterobactin are not synthetic lethal with these C. elegans mitochondrial mutants; it is the enterobactin-iron complex that is lethal in combination with the C. elegans mitochondrial mutations. Antioxidants suppress this inviability, suggesting that reactive oxygen species (ROS) are produced by the mutant mitochondria in combination with the bacterial enterobactin-iron complex.\n\nSignificance StatementThe animal mitochondrion has a bacterial origin and continues to have a dialogue with the bacterial metabolisms of their microbiome. We identified 45 E. coli gene disruptions that induce a C. elegans mitochondrial damage response gene. Four of these E. coli mutations that disrupt the import or retrieval of iron from the siderophore enterobactin were synthetic lethal with C. elegans mitochondrial mutants. Antioxidants strongly suppressed the inviability of C. elegans mitochondrial mutants grown on the E. coli enterobactin siderophore utilization or import mutants. We hypothesize that reactive oxygen species are produced by C. elegans mitochondrial mutations and that this non-lethal ROS triggers ferric-chelated enterobactin to induce dramatically increased ROS, which leads to lethality.