Aspergillus fumigatus infections cause high levels of morbidity and mortality in immunocompromised patients. Gliotoxin (GT), a secondary metabolite, is cytotoxic for mammalian cells, but the molecular basis and biological relevance of this toxicity remain speculative. We show that GT induces apoptotic cell death by activating the proapoptotic Bcl-2 family member Bak, but not Bax, to elicit the generation of reactive oxygen species, the mitochondrial release of apoptogenic factors, and caspase-3 activation. Activation of Bak by GT is direct, as GT triggers in vitro a dose-dependent release of cytochrome c from purified mitochondria isolated from wild-type and Bax- but not Bak-deficient cells. Resistance to A. fumigatus of mice lacking Bak compared to wild-type mice demonstrates the in vivo relevance of this GT-induced apoptotic pathway involving Bak and suggests a correlation between GT production and virulence. The elucidation of the molecular basis opens new strategies for the development of therapeutic regimens to combat A. fumigatus and related fungal infections.
The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice
Abbreviations used in this paper: 2-HE, 2-hydroxiethidine; AIF, apoptosis-inducing factor; ANT, adenine nucleotide transporter; FDM, factor-dependent myeloid; GT, gliotoxin; IA, invasive aspergilloses; MEF, mouse embryonic fibroblast; MnTBAP, Mn(III) tetrakis(4-benzoic acid) porphyrin chloride; MPTP, mitochondrial permeability transition pore; NAC, N-acetylcysteine; PI, propidium iodide; PS, phosphatidylserine; ROS, reactive oxygen species; wt, wild-type.
Julian Pardo, Christin Urban, Eva M. Galvez, Paul G. Ekert, Uwe Müller, June Kwon-Chung, Mario Lobigs, Arno Müllbacher, Reinhard Wallich, Christoph Borner, Markus M. Simon; The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice . J Cell Biol 14 August 2006; 174 (4): 509–519. doi: https://doi.org/10.1083/jcb.200604044
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