The ER-mitochondria encounter structure contributes to hyphal growth, mitochondrial morphology and virulence of the pathogenic mold Aspergillus fumigatus

Geißel, Bernadette; Penka, Mirjam; Neubauer, Michael; Wagener, Johannes

doi:10.1016/j.ijmm.2016.11.005

Cited by 21 publications

(13 citation statements)

References 24 publications

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“…Mitochondria are important for many cellular processes in eukaryotes. In A. fumigatus, genes involved in mitochondrial dynamics and in the endoplasmic reticulummitochondria encounter structure (ERMES) were shown to play a role in virulence and antifungal resistance (15,16). However, little is known about the role of MRC.…”

Section: Discussionmentioning

confidence: 99%

Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus

Aruanno

Bachmann

Sanglard

et al. 2019

Antimicrob Agents Chemother

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Aspergillus fumigatus is an opportunistic mold responsible for invasive aspergillosis. Triazoles (e.g., voriconazole) represent the first-line treatment, but emerging resistance is of concern. The echinocandin drug caspofungin is used as second-line treatment but has limited efficacy. The heat shock protein 90 (Hsp90) orchestrates the caspofungin stress response and is the trigger of an adaptive phenomenon called the paradoxical effect (growth recovery at increasing caspofungin concentrations). The aim of this study was to elucidate the Hsp90-dependent mechanisms of the caspofungin stress response. Transcriptomic profiles of the wild-type A. fumigatus strain (KU80) were compared to those of a mutant strain with substitution of the native hsp90 promoter by the thiA promoter (pthiA-hsp90), which lacks the caspofungin paradoxical effect. Caspofungin induced expression of the genes of the mitochondrial respiratory chain (MRC), in particular, NADH-ubiquinone oxidoreductases (complex I), in KU80 but not in the pthiA-hsp90 mutant. The caspofungin paradoxical effect could be abolished by rotenone (MRC complex I inhibitor) in KU80, supporting the role of MRC in the caspofungin stress response. Fluorescent staining of active mitochondria and measurement of oxygen consumption and ATP production confirmed the activation of the MRC in KU80 in response to caspofungin, but this activity was impaired in the pthiA-hsp90 mutant. Using a bioluminescent reporter for the measurement of intracellular calcium, we demonstrated that inhibition of Hsp90 by geldanamycin or MRC complex I by rotenone prevented the increase in intracellular calcium shown to be essential for the caspofungin paradoxical effect. In conclusion, our data support a role of the MRC in the caspofungin stress response which is dependent on Hsp90.

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Section: Discussionmentioning

confidence: 99%

Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus

Aruanno

Bachmann

Sanglard

et al. 2019

Antimicrob Agents Chemother

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“…ERMIONE is proposed to be a central hub for orchestrating mitochondrial biogenesis, lipid homeostasis, organelle dynamics and inter-organellar interactions. Based on our studies of Gem1 (this study), as well as the SAM and ERMES complexes in C. albicans (Qu et al, 2012 ; Tucey et al, 2016 ), and the study of ERMES in A. fumigatus (Geißel et al, 2017 ), we propose that ERMIONE plays a crucial role in the environmental adaptation of pathogenic fungi, which ultimately drives their virulence by controlling stress responses and invasive growth. Therefore, disruption of ERMIONE holds promise as antifungal therapy.…”

Section: Discussionmentioning

confidence: 65%

“…Genetic and cell biology data support the existence of an ERMES complex in C. albicans that is of equivalent composition as in S. cerevisiae , with four core subunits: Mmm1, Mdm10, Mdm34, and Mdm12 (Kornmann et al, 2009 ; Tucey et al, 2016 ). ERMES is conserved within fungi (Wideman et al, 2013 ), and a recent study of ERMES in the pathogenic mold Aspergillus fumigatus supports the idea that targeting ER-Mitochondria interactions might be promising as a therapeutic strategy against multiple, divergent pathogenic fungal species (Geißel et al, 2017 ).…”

Section: Introductionmentioning

confidence: 92%

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

Koch

Tucey

et al. 2017

Front. Microbiol.

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The interactions of mitochondria with the endoplasmic reticulum (ER) are crucial for maintaining proper mitochondrial morphology, function and dynamics. This enables cells to utilize their mitochondria optimally for energy production and anabolism, and it further provides for metabolic control over developmental decisions. In fungi, a key mechanism by which ER and mitochondria interact is via a membrane tether, the protein complex ERMES (ER-Mitochondria Encounter Structure). In the model yeast Saccharomyces cerevisiae, the mitochondrial GTPase Gem1 interacts with ERMES, and it has been proposed to regulate its activity. Here we report on the first characterization of Gem1 in a human fungal pathogen. We show that in Candida albicans Gem1 has a dominant role in ensuring proper mitochondrial morphology, and our data is consistent with Gem1 working with ERMES in this role. Mitochondrial respiration and steady state cellular phospholipid homeostasis are not impacted by inactivation of GEM1 in C. albicans. There are two major virulence-related consequences of disrupting mitochondrial morphology by GEM1 inactivation: C. albicans becomes hypersusceptible to cell wall stress, and is unable to grow invasively. In the gem1Δ/Δ mutant, it is specifically the invasive capacity of hyphae that is compromised, not the ability to transition from yeast to hyphal morphology, and this phenotype is shared with ERMES mutants. As a consequence of the hyphal invasion defect, the gem1Δ/Δ mutant is drastically hypovirulent in the worm infection model. Activation of the mitogen activated protein (MAP) kinase Cek1 is reduced in the gem1Δ/Δ mutant, and this function could explain both the susceptibility to cell wall stress and lack of invasive growth. This result establishes a new, respiration-independent mechanism of mitochondrial control over stress signaling and hyphal functions in C. albicans. We propose that ER-mitochondria interactions and the ER-Mitochondria Organizing Network (ERMIONE) play important roles in adaptive responses in fungi, in particular cell surface-related mechanisms that drive invasive growth and stress responsive behaviors that support fungal pathogenicity.

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“…Furthermore, F-box domain proteins have been reported to play crucial roles in regulating various developmental processes and stress responses [ 51 ]. A study in A. fumigatus showed that the MMM1 protein is important in maintaining mitochondrial morphology; the ER–mitochondria structure accelerates hyphal growth and is involved in virulence of the pathogenic mold [ 50 ]. Therefore, it is probable that FBO and MMM1 have an active influence on growth and development in fungi.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals Genes Mediating Salt Tolerance through Calcineurin/CchA-Independent Signaling inAspergillus nidulans

Wang

Jun²,

Jiang-yu

et al. 2017

BioMed Research International

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Adaptation to changes in the environment is crucial for the viability of all organisms. Although the importance of calcineurin in the stress response has been highlighted in filamentous fungi, little is known about the involvement of ion-responsive genes and pathways in conferring salt tolerance without calcium signaling. In this study, high-throughput RNA-seq was used to investigate salt stress-induced genes in the parent, ΔcnaB, and ΔcnaBΔcchA strains of Aspergillus nidulans, which differ greatly in salt adaption. In total, 2,884 differentially expressed genes including 1,382 up- and 1,502 downregulated genes were identified. Secondary transporters, which were upregulated to a greater extent in ΔcnaBΔcchA than in the parent or ΔcnaB strains, are likely to play important roles in response to salt stress. Furthermore, 36 genes were exclusively upregulated in the ΔcnaBΔcchA under salt stress. Functional analysis of differentially expressed genes revealed that genes involved in transport, heat shock protein binding, and cell division processes were exclusively activated in ΔcnaBΔcchA. Overall, our findings reveal that secondary transporters and stress-responsive genes may play crucial roles in salt tolerance to bypass the requirement for the CchA-calcineurin pathway, contributing to a deeper understanding of the mechanisms that influence fungal salt stress adaption in Aspergillus.

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The ER-mitochondria encounter structure contributes to hyphal growth, mitochondrial morphology and virulence of the pathogenic mold Aspergillus fumigatus

Cited by 21 publications

References 24 publications

Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus

Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus

The Mitochondrial GTPase Gem1 Contributes to the Cell Wall Stress Response and Invasive Growth of Candida albicans

Transcriptomic Analysis Reveals Genes Mediating Salt Tolerance through Calcineurin/CchA-Independent Signaling inAspergillus nidulans

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