With age comes resilience: how mitochondrial modulation drives age-associated fluconazole tolerance in Cryptococcus neoformans .

Autor:	Yoo K; Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA., Bhattacharya S; Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, New York, USA., Oliveira NK; Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA., Pereira de Sa N; Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA., Matos GS; Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA., Del Poeta M; Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA.; Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.; Veterans Administration Medical Center, Northport, New York, USA.; Institute of Chemical Biology and Drug Discovery, Stony Brook, New York, USA., Fries BC; Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA.; Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.; Veterans Administration Medical Center, Northport, New York, USA.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2024 Sep 11; Vol. 15 (9), pp. e0184724. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1128/mbio.01847-24
Abstrakt:	Cryptococcus neoformans ( Cn ) is an opportunistic fungal microorganism that causes life-threatening meningoencephalitis. During the infection, the microbial population is heterogeneously composed of cells with varying generational ages, with older cells accumulating during chronic infections. This is attributed to their enhanced resistance to phagocytic killing and tolerance of antifungals like fluconazole (FLC). In this study, we investigated the role of ergosterol synthesis, ATP-binding cassette (ABC) transporters, and mitochondrial metabolism in the regulation of age-dependent FLC tolerance. We find that old Cn cells increase the production of ergosterol and exhibit upregulation of ABC transporters. Old cells also show transcriptional and phenotypic characteristics consistent with increased metabolic activity, leading to increased ATP production. This is accompanied by increased production of reactive oxygen species, which results in mitochondrial fragmentation. This study demonstrates that the metabolic changes occurring in the mitochondria of old cells drive the increase in ergosterol synthesis and the upregulation of ABC transporters, leading to FLC tolerance. Importance: Infections caused by Cryptococcus neoformans cause more than 180,000 deaths annually. Estimated 1-year mortality for patients receiving care ranges from 20% in developed countries to 70% in developing countries, suggesting that current treatments are inadequate. Some fungal cells can persist and replicate despite the usage of current antifungal regimens, leading to death or treatment failure. Aging in fungi is associated with enhanced tolerance against antifungals and resistance to killing by host cells. This study shows that age-dependent increase in mitochondrial reactive oxygen species drive changes in the regulation of membrane transporters and ergosterol synthesis, ultimately leading to the heightened tolerance against fluconazole in old C. neoformans cells. Understanding the underlying molecular mechanisms of this age-associated antifungal tolerance will enable more targeted antifungal therapies for cryptococcal infections. Competing Interests: Maurizio Del Poeta, M.D., is a co-founder and chief scientific officer of MicroRid Technologies Inc. The goal of MicroRid Technologies Inc is to discover and develop new antifungals for the treatment of invasive fungal infections. All other authors declare no competing interests.
Databáze:	MEDLINE
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