Abstract
The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases. Hyphal morphogenesis contributes to virulence of the human fungal pathogen Candida albicans. Koch et al. show that mdivi-1, a putative inhibitor of mitochondrial division, represses hyphal growth of Candida and implicate regulation of endogenous nitric oxide levels in the mechanism of action of mdivi-1 and the regulation of hyphal morphogenesis.
| Original language | English |
|---|---|
| Pages (from-to) | 2244-2258 |
| Number of pages | 15 |
| Journal | Cell Reports |
| Volume | 25 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 20 Nov 2018 |
Keywords
- Candida albicans
- fungal pathogenesis
- hyphae
- mdivi-1
- metabolism
- mitochondria
- morphogenesis
- mycology
- nitric oxide
Cite this
}
A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling. / Koch, Barbara; Barugahare, Adele A.; Lo, Tricia L.; Huang, Cheng; Schittenhelm, Ralf B.; Powell, David R.; Beilharz, Traude H.; Traven, Ana.
In: Cell Reports, Vol. 25, No. 8, 20.11.2018, p. 2244-2258.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling
AU - Koch, Barbara
AU - Barugahare, Adele A.
AU - Lo, Tricia L.
AU - Huang, Cheng
AU - Schittenhelm, Ralf B.
AU - Powell, David R.
AU - Beilharz, Traude H.
AU - Traven, Ana
PY - 2018/11/20
Y1 - 2018/11/20
N2 - The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases. Hyphal morphogenesis contributes to virulence of the human fungal pathogen Candida albicans. Koch et al. show that mdivi-1, a putative inhibitor of mitochondrial division, represses hyphal growth of Candida and implicate regulation of endogenous nitric oxide levels in the mechanism of action of mdivi-1 and the regulation of hyphal morphogenesis.
AB - The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases. Hyphal morphogenesis contributes to virulence of the human fungal pathogen Candida albicans. Koch et al. show that mdivi-1, a putative inhibitor of mitochondrial division, represses hyphal growth of Candida and implicate regulation of endogenous nitric oxide levels in the mechanism of action of mdivi-1 and the regulation of hyphal morphogenesis.
KW - Candida albicans
KW - fungal pathogenesis
KW - hyphae
KW - mdivi-1
KW - metabolism
KW - mitochondria
KW - morphogenesis
KW - mycology
KW - nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=85056202475&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.10.080
DO - 10.1016/j.celrep.2018.10.080
M3 - Article
VL - 25
SP - 2244
EP - 2258
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 8
ER -