Lactic Acid Influences Iron Assimilation by a Fungal Pathogen via the Iron Reductive Uptake Pathway
Gomes-Gonçalves, Alexandra (Universidade do Minho)
Van Genechten, Wouter (Katholieke Universiteit te Leuven (1970- ))
Ataíde, Patrícia (Universidade do Minho)
Barata-Antunes, Cláudia (Universidade do Minho)
Ghasemi, Faezeh (Universidade do Minho)
Casal, Margarida (Universidade do Minho)
Teixeira, Miguel C. (Universidade de Lisboa)
Ariño Carmona, Joaquín (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Brown, Alistair J. P. (University of Exeter)
Van Dijck, Patrick (Katholieke Universiteit te Leuven (1970- ))
Paiva, Sandra (Universidade do Minho)

Data:	2025
Resum:	Candida albicans is a fungal commensal of humans that often causes mucosal infections in otherwise healthy individuals and also serious infections in immunocompromised patients. The capacity of this fungus to colonize and cause disease relies on its ability to grow within the host, adapting to various nutrient restrictions and physicochemical conditions. The presence of alternative carbon sources, such as the lactate produced by the local microbiota, influences C. albicans antifungal drug resistance and immune evasion. In this study, we used genome-wide transcriptomic analysis to investigate the effect of lactate exposure upon metabolic rewiring. We provide evidence that C. albicans cells respond to growth in the presence of lactate at pH 5 by regulating genes encoding micronutrient transporters, notably iron transporters. More specifically, lactate triggers the downregulation of genes on the reductive iron uptake pathway, inferring a diminished requirement for high-affinity iron uptake. This is supported by the observation that lactate promotes the intracellular accumulation of iron by C. albicans cells. Lactate even enhances the growth of iron-transport defective C. albicans cells under iron-limited conditions. Lactate is known to activate protein kinase A (PKA) signaling. However, lactate-induced iron assimilation is PKA-independent. This study provides new insights into the role of lactate in iron homeostasis-two important factors that promote C. albicans virulence in the mammalian host, where nutritional immunity is a key antimicrobial strategy. Lactate modulates iron homeostasis in Candida albicans by repressing the reductive iron uptake pathway, reducing reliance on high-affinity iron transport. This process promotes intracellular iron accumulation and enhances growth, even in iron-transport-deficient strains under iron-limited conditions. Notably, this effect is independent of protein kinase A signaling, despite lactate's known activation of this pathway. These findings illustrate lactate's role in iron homeostasis, emphasizing its contribution to C. albicans adaptation and virulence in the host environment.
Ajuts:	Agencia Estatal de Investigación PID2020-113319RB-I00 Ministerio de Ciencia e Innovación PID2023-150535OB-I00
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Candida albicans ; Fungal pathogenesis ; Iron homeostasis ; Lactate
Publicat a:	MicrobiologyOpen, Vol. 14 (December 2025) , art. e70167, ISSN 2045-8827

DOI: 10.1002/mbo3.70167
PMID: 41400135

11 p, 1.6 MB

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