Metabolic plasticity of lipid storage and utilization governs fungal persister formation within macrophages

ABSTRACT: The ability of Candida glabrata to survive within macrophages creates a reservoir for recurrent infections and antifungal failure, yet the underlying mechanisms remain elusive. Here, using a host-mimicking in vitro evolution model, we identify asparagine synthetase (ASN2) as a critical genetic determinant of intracellular persistence. We show that ASN2 deficiency confers a significant fitness advantage in vivo under echinocandin pressure by inducing a state of metabolic dormancy. Integrated multi-omics analyses reveal that asparagine starvation in ΔASN2 mutants causes a bottleneck in the tricarboxylic acid (TCA) cycle, rewiring carbon flux toward the accumulation of intracellular lipids. This lipid accumulation strategy is coupled with growth arrest, thereby protecting the fungus from echinocandins. In stark contrast, we find that wild-type prototrophic persisters rely on the mobilization of lipid reserves via peroxisomal fatty acid β-oxidation to fuel their survival. Disruption of ACAA1, encoding a peroxisomal 3-ketoacyl-CoA thiolase, impairs lipid utilization and attenuates the prototrophic persister state. Our study delineates a metabolic bifurcation where C. glabrata exploits either passive lipid storage for dormancy or active lipid oxidation for endurance to survive the hostile phagosomal environment and echinocandin pressure, highlighting metabolic checkpoints as potential therapeutic targets.

INSTRUMENT(S): Gas Chromatography MS - alternating - normal-phase, Liquid Chromatography MS - positive - normal-phase, Liquid Chromatography MS - negative - normal-phase

PROVIDER: MTBLS14351 | MetaboLights | 2026-04-22

REPOSITORIES: MetaboLights