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F1Fo-ATP synthase subunit determines lethal pathogenic fungi infection

ABSTRACT: Fungal infections, especially candidiasis and aspergillosis, claim an unacceptably high fatality rate. The energy ATP that is necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation, with the key enzyme being F1Fo-ATP synthase. But it remains unknown how this enzyme affects fungal pathogenicity. Here, we show that F1Fo-ATP synthase δ subunit deletion abrogates lethal Candida albicans infection without affecting intracellular ATP concentrations or growth. Mechanistically, δ subunit deletion reduces Pfk1 activity by interrupting Pfk1 phosphorylation to trigger its conformation shifts, decreases downstream FBP level, blocks Ras1-dependent and -independent cAMP-PKA pathways, and curtails virulence factors. Based on these findings, we engineer a small molecule compound targeting δ subunit that effectively protects mice from succumbing to invasive candidiasis. In summary, our findings reveal that F1Fo-ATP synthase δ subunit determines lethal infection from pathogenic fungi and represents a potential therapeutic target.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic

SUBMITTER: æ°´ç§ æ

PROVIDER: MTBLS3332 | MetaboLights | 2021-10-08

REPOSITORIES: MetaboLights

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F1Fo-ATP synthase subunit determines lethal infection in pathogenic fungi

Project description:Fungal infections, especially for candidiasis and aspergillosis, claim an unacceptably high fatality. However, the determining mechanism that promote fungal lethal infections are still elusive. The energy ATP necessary for fungal cell growth and function is synthesized mainly through oxidative phosphorylation, whose key enzyme is F1Fo-ATP synthase. Nonetheless, it remians unknown how this enzyme affects fungal pathogenicity. Here we show that F1Fo-ATP synthase subunit deletion completely abrogates C. albicans lethal infection rather than leading to remarkable intracellular ATP concentration and growth defect. Mechanically, subunit deletion reduces PFK1 activity via interrupting PFK1 phosphorylation to trigger its conformational change, decreases downstream FBP level, blocks Ras1-dependent and -independent cAMP-PKA pathway, and curtails virulence factors. Based on these findings, we engineer a small molecule compound aimed at subunit that effectively protects mice from succumbing to invasive candidiasis. In summary, our findings reveal that F1Fo-ATP synthase δ subunit determines the lethal infection of pathogenic fungi and represents a potential new therapeutic target.

2021-09-16 | PXD024729 | Pride

atpd_vs_WT

Project description:Series of 4 repetitions of hybridization of treatment (atpd) and control (WT) each. Comparison of Arabidopsis atpd mutant lacking ATP synthase delta subunit versus WT. D. Maiwald et al., Plant Physiol 133 (2003), pp. 191-202 Keywords: repeat sample

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atpd_vs_WT

2005-01-01 | GSE1178 | GEO

Acetate Fermentation facilitates survival of Mtb when respiration is inhibited

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2012-12-31 | GSE35484 | GEO

Acetate Fermentation facilitates survival of Mtb when respiration is inhibited

2012-12-31 | E-GEOD-35484 | biostudies-arrayexpress

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Project description:Microarray analysis was carried out on human MOH cells exposed to fb-PMT (10e-6 M tetrac equivalent) for 24 h. fb-PMT significantly downregulated electron transport chain genes ATP5A1 (ATP synthase A1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase [ubiquinone] FA8), NDUFV2 and other NDUF genes, SLC25A6 (solute carrier group 2), UCP2 ([mitochondrial] uncoupling protein 2) and COX5A. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Six additional NDUF genes linked to oxidative phosphorylation were affected. Conclusions. fb-PMT caused downregulation of expression of a panel of genes involved in electron transport, oxidative phosphorylation, and cytoplasmic ribosomal protein generation in MOH cells. A key component of the anticancer activity of fb-PMT relates to disordering of ATP generation mechanisms in tumor cells.

2022-07-01 | GSE180889 | GEO

Anticancer Agent Fb-Pmt Links The Thyroid Hormone Receptor On Integrin Αvβ3 To Cancer Cell Metabolism/Atp Generation [Suit2-fbPMT]

Project description:Microarray analysis was carried out on human SUIT2 cells, cells exposed to fb-PMT (10-6 M tetrac equivalent) for 24 h. fb-PMT significantly downregulated electron transport chain genes ATP5A1 (ATP synthase A1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase [ubiquinone] FA8), NDUFV2 and other NDUF genes, SLC25A6 (solute carrier group 2), UCP2 ([mitochondrial] uncoupling protein 2) and COX5A. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Six additional NDUF genes linked to oxidative phosphorylation were affected. Conclusions. fb-PMT caused downregulation of expression of a panel of genes involved in electron transport, oxidative phosphorylation, and cytoplasmic ribosomal protein generation in SUIT2 cells, cells. A key component of the anticancer activity of fb-PMT relates to disordering of ATP generation mechanisms in tumor cells.

2022-07-01 | GSE180895 | GEO

ANTICANCER AGENT P-bi-TAT LINKS THE THYROID HORMONE RECEPTOR ON INTEGRIN αvβ3 TO CANCER CELL METABOLISM/ATP GENERATION II

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2020-08-28 | GSE140449 | GEO

ANTICANCER AGENT P-bi-TAT LINKS THE THYROID HORMONE RECEPTOR ON INTEGRIN αvβ3 TO CANCER CELL METABOLISM/ATP GENERATION

2020-08-28 | GSE140272 | GEO

Anticancer Agent P-Bi-Tat Links The Thyroid Hormone Receptor On Integrin Αvβ3 To Cancer Cell Metabolism/Atp Generation [Suit2-P-biTAT]

Project description:Microarray analysis was carried out on human SUIT2 cells exposed to P-bi-TAT (10-6 M tetrac equivalent) for 24 h. P-bi-TAT significantly downregulated electron transport chain genes ATP5A1 (ATP synthase A1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase [ubiquinone] FA8), NDUFV2 and other NDUF genes, SLC25A6 (solute carrier group 2), UCP2 ([mitochondrial] uncoupling protein 2) and COX5A. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Six additional NDUF genes linked to oxidative phosphorylation were affected. Conclusions. P-bi-TAT caused downregulation of expression of a panel of genes involved in electron transport, oxidative phosphorylation, and cytoplasmic ribosomal protein generation in GBM cells. A key component of the anticancer activity of P-bi-TAT relates to disordering of ATP generation mechanisms in tumor cells.

2022-04-27 | GSE180896 | GEO

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