Mass Spectrometry-Based Lipidomics Reveals a Strong Connection Between Lipid Homeostasis and Iron Acquisition in...

Iron is a critical determinant in the development of drug tolerance in Candida albicans . Several genes essential for iron acquisition, transport, and regulation have been studied. Previous studies have shown that growth in an iron-limited medium alters the lipid compositions of C. albicans cells. In the present study, we performed a mass spectrometry-based lipid analysis of two major iron acquisition pathway proteins: an iron transporter, Ftr1 (ferrous permease), and a closely linked copper transporter, Ccc2. Deletions of FTR1 or CCC2 lead to significant changes in the lipid profile of C. albicans , especially the phospholipid and sphingolipid metabolism. For example, both Δftr1 and Δccc2 mutants showed depleted sphingolipid and steryl ester contents, but not much change in their DAG and TAG contents. The phospholipid profile of Δccc2 cells was quite unique with a much elevated PG content. The overall phospholipid profile of Δftr1 was not much different from the wild type. Both Δftr1 and Δccc2 cells showed significant differences in their molecular lipid species compositions. These lipid perturbations correlated with the susceptible response towards the drugs targeting lipid biogenesis and iron acquisition in Δftr1 and Δccc2 mutants. Taken together, this study shows that iron pathway proteins such as Ftr1 and Ccc2 are closely linked to lipid metabolism and iron acquisition in C. albicans . Understanding the mechanism of this lipid-iron association should be useful in exploring the two pathways for understanding the mechanism of iron uptake and designing the combinatorial drug therapies.