Antifungal Mechanism of Action of Lactoferrin: Identification of H + -ATPase (P 3A -Type) as a New Apoptotic-Cell Membrane Receptor
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Human lactoferrin (hLf) is a protein of the innate immune system which induces an apoptotic-like process in yeast. Determination of the susceptibility to lactoferrin of several yeast species under different metabolic conditions, respiratory activity, cytoplasmic ATP levels, and external medium acidification mediated by glucose assays suggested plasma membrane Pma1p (P 3A -type ATPase) as the hLf molecular target. The inhibition of plasma membrane ATPase activity by hLf and the identification of Pma1p as the hLf-binding membrane protein confirmed the previous physiological evidence. Consistent with this, cytoplasmic ATP levels progressively increased in hLf-treated Candida albicans cells. However, oligomycin, a specific inhibitor of the mitochondrial F-type ATPase proton pump (mtATPase), abrogated the antifungal activity of hLf, indicating a crucial role for mtATPase in the apoptotic process. We suggest that lactoferrin targeted plasma membrane Pma1p H + -ATPase, perturbing the cytoplasmic ion homeostasis (i.e., cytoplasmic H + accumulation and subsequent K + efflux) and inducing a lethal mitochondrial dysfunction. This initial event involved a normal mitochondrial ATP synthase activity responsible for both the ATP increment and subsequent hypothetical mitochondrial proton flooding process. We conclude that human lactoferrin inhibited Pma1p H + -ATPase, inducing an apoptotic-like process in metabolically active yeast. Involvement of mitochondrial H + -ATPase (nonreverted) was essential for the progress of this programmed cell death in which the ionic homeostasis perturbation seems to precede classical nonionic apoptotic events.
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Similar salt protection, but not sorbitol protection, has been reported for hLf and human defensins.
“Similar salt protection, but not sorbitol protection, has been reported for hLf and human defensins [27,30]”
From Ovotransferrin and Its γ-Core-Containing Peptides Impair Pma1-Dependent Proton Homeostasis in Candida albicans (2026) · cites this paper as [27]
The Results (p. 6) report that hLf did not reduce cell viability under conditions containing 50 mM KCl, supporting salt protection for hLf. Our copy does not report a sorbitol-protection test or establish the comparison with human defensins; a search for sorbitol found no relevant passage. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn C. albicans, human lactoferrin exerts in vitro candidacidal activity through a non-permeabilizing mechanism associated with impaired Pma1 function, disruption of ion homeostasis, intracellular ATP accumulation, and mitochondrial participation in downstream regulated cell death.
“In C. albicans, human lactoferrin exerts in vitro candidacidal activity through a non-permeabilizing mechanism associated with impaired plasma membrane H+-ATPase Pma1 function, disruption of ion homeostasis, intracellular ATP accumulation, and mitochondrial participation in downstream regulated cell death [27,28,29].”
From Ovotransferrin and Its γ-Core-Containing Peptides Impair Pma1-Dependent Proton Homeostasis in Candida albicans (2026) · cites this paper as [27]
Comparable ATP accumulation and mitochondrial participation have been reported in C. albicans exposed to hLf, defensins, the BM2 peptide, and pharmacological inhibitors of Pma1.
“Comparable ATP accumulation and mitochondrial participation have been reported in C. albicans exposed to hLf, defensins, the BM2 peptide, and pharmacological inhibitors of Pma1 [27,28,30,31,37].”
From Ovotransferrin and Its γ-Core-Containing Peptides Impair Pma1-Dependent Proton Homeostasis in Candida albicans (2026) · cites this paper as [27]
K+ may reduce the downstream ionic imbalance that converts defective proton extrusion into lethal damage.
“Rather, K+ may reduce the downstream ionic imbalance that converts defective proton extrusion into lethal damage, as previously proposed for hLf and γ-core-containing peptides [27,30,31].”
From Ovotransferrin and Its γ-Core-Containing Peptides Impair Pma1-Dependent Proton Homeostasis in Candida albicans (2026) · cites this paper as [27]
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“Rather, K + may reduce the downstream ionic imbalance that converts defective proton extrusion into lethal damage, as previously proposed for hLf and γ -core-containing peptides [27,30,31].”
InfluentialSelf-citation
- Authors
- Andrés, M. T., Acosta-Zaldívar, M., & Fierro, J. F.
- Affiliations
- Universidad de Oviedo (ES)
- Laboratory of Oral Microbiology, School of Stomatology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2016-07
- Volume
- 60
- Issue
- 7
- Pages
- 4206-4216
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4914641
- OpenAlex
- W2345789896
- Semantic Scholar
- 287111f5ed16ccd7c12c5cd5e3f59a2b8fa58e87
- Cited by
- 41
- References
- 52
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 5
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- lactoferrin, antifungal mechanism, H+-ATPase, Candida albicans, yeast, mitochondrial ATP synthase, mitochondrial H+-ATPase, ion homeostasis, programmed cell death, innate immunity
- MeSH terms
- Antifungal Agents, Candida albicans, Cell Membrane, Proton-Translocating ATPases, Lactoferrin, Apoptosis
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