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Johansson, Annika I.ORCID iD iconorcid.org/0000-0001-5000-1288
Publications (5 of 5) Show all publications
Green, A. C., Marttila, P., Kiweler, N., Chalkiadaki, C., Wiita, E., Cookson, V., . . . Meiser, J. (2023). Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature Metabolism, 5(4), 642-659
Open this publication in new window or tab >>Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
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2023 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 5, no 4, p. 642-659Article in journal (Refereed) Published
Abstract [en]

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cell Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-206656 (URN)10.1038/s42255-023-00771-5 (DOI)000962791100003 ()37012496 (PubMedID)2-s2.0-85151482683 (Scopus ID)
Funder
Novo Nordisk Foundation, 17OC0029972Swedish Cancer Society, 2018/600Swedish Cancer Society, 2021/1490Swedish Childhood Cancer Foundation, 2018-0095Swedish Childhood Cancer Foundation, 2021-0030Swedish Research Council, 2015-00162Swedish Research Council, 2017-06095Vinnova, 2018-00257Vinnova, 2021-04817Torsten Söderbergs stiftelse
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-09-05Bibliographically approved
Garkava-Gustavsson, L., Sätra, J. S., Odilbekov, F., Abreu, I., Johansson, A. I., van de Weg, E. & Zhebentyayeva, T. (2023). Resistance to Neonectria ditissima in apple: insights from metabolomics and lipidomics analyses. In: V. Bus; M. Causse (Ed.), Xxxi international horticultural congress (ihc2022): International symposium on breeding and effective use of biotechnology and molecular tools in horticultural crops. Paper presented at XXXI International Horticultural Congress (IHC2022), International Symposium on Breeding and Effective Use of Biotechnology and Molecular Tools in Horticultural Crops, Angers, France, august 14-20, 2022. (pp. 329-335). International Society for Horticultural Science
Open this publication in new window or tab >>Resistance to Neonectria ditissima in apple: insights from metabolomics and lipidomics analyses
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2023 (English)In: Xxxi international horticultural congress (ihc2022): International symposium on breeding and effective use of biotechnology and molecular tools in horticultural crops / [ed] V. Bus; M. Causse, International Society for Horticultural Science , 2023, p. 329-335Conference paper, Published paper (Refereed)
Abstract [en]

European canker, caused by the necrotrophic fungus Neonectria ditissima, is the most serious disease in apple production in Sweden. The disease is favored by a relatively cool and rainy climate. The canker damages have a significant economic impact due to reduced bearing surface and increased orchard management costs. The possibilities for chemical and biological control are very limited. Therefore, directed breeding for new resistant cultivars is urgently needed. Knowledge of inheritance of canker resistance and understanding of molecular mechanisms involved in resistant and susceptible responses to fungal attacks would facilitate breeding. In this study, we evaluated the tempo-spatial differences in plant-pathogen interactions in a set of partially resistant and susceptible cultivars by conducting metabolomic and lipidomic analyses. The major trends in metabolomics and lipidomic profiles were common among cultivars, irrespective of the degree of susceptibility. Several metabolites and lipids varied with time point and cultivar under N. ditissima infection. Putative key metabolites such as suberic acid and jasmonic acid were upregulated in all cultivars upon infection. Additionally, several lipids exhibited changes 30 to 45 days post-inoculation. Thus, the approach used seems to have resulted in a rich data set to be further analyzed in light of ongoing QTL-mapping efforts.

Place, publisher, year, edition, pages
International Society for Horticultural Science, 2023
Series
Acta Horticulturae, ISSN 05677572, E-ISSN 24066168 ; 1362
Keywords
fruit tree canker, Malus × domestica, metabolites, susceptibility
National Category
Genetics and Breeding in Agricultural Sciences Plant Biotechnology
Identifiers
urn:nbn:se:umu:diva-208059 (URN)10.17660/ActaHortic.2023.1362.44 (DOI)2-s2.0-85153494693 (Scopus ID)978-94-62613-61-4 (ISBN)
Conference
XXXI International Horticultural Congress (IHC2022), International Symposium on Breeding and Effective Use of Biotechnology and Molecular Tools in Horticultural Crops, Angers, France, august 14-20, 2022.
Available from: 2023-06-09 Created: 2023-06-09 Last updated: 2023-11-07Bibliographically approved
Diamanti, R., Srinivas, V., Johansson, A. I., Nordström, A., Griese, J. J., Lebrette, H. & Högbom, M. (2022). Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase. FEBS Letters, 596(12), 1600-1610
Open this publication in new window or tab >>Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase
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2022 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 596, no 12, p. 1600-1610Article in journal (Refereed) Published
Abstract [en]

R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese–iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine–valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
aldehyde deformylating oxygenase, ferritin-like protein, hydroxy fatty acids, long-chain fatty acids, R2-like ligand-binding oxidase, R2lox
National Category
Biochemistry and Molecular Biology Structural Biology
Identifiers
urn:nbn:se:umu:diva-193164 (URN)10.1002/1873-3468.14319 (DOI)000764082200001 ()35175627 (PubMedID)2-s2.0-85126047671 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2017.0275Knut and Alice Wallenberg Foundation, 2019.0436Swedish Research Council, 2017-0401EU, European Research Council, 724394
Available from: 2022-03-18 Created: 2022-03-18 Last updated: 2022-11-24Bibliographically approved
Long, M., Sanchez-Martinez, A., Longo, M., Suomi, F., Stenlund, H., Johansson, A. I., . . . McWilliams, T. G. (2022). DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion. EMBO Journal, 41, Article ID e109390.
Open this publication in new window or tab >>DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion
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2022 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 41, article id e109390Article in journal (Refereed) Published
Abstract [en]

Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
DGAT1, iron, lipid droplet, metabolism, mitophagy
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-193974 (URN)10.15252/embj.2021109390 (DOI)000780832100001 ()35411952 (PubMedID)2-s2.0-85128030914 (Scopus ID)
Funder
Novo Nordisk
Available from: 2022-05-02 Created: 2022-05-02 Last updated: 2023-03-24Bibliographically approved
Hubert, M., Larsson, E., Vegesna, N. V., Ahnlund, M., Johansson, A. I., Moodie, L. W. K. & Lundmark, R. (2020). Lipid accumulation controls the balance between surface connection and scission of caveolae. eLIFE, 9, Article ID e55038.
Open this publication in new window or tab >>Lipid accumulation controls the balance between surface connection and scission of caveolae
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2020 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e55038Article in journal (Refereed) Published
Abstract [en]

Caveolae are bulb-shaped invaginations of the plasma membrane (PM) that undergo scission and fusion at the cell surface and are enriched in specific lipids. However, the influence of lipid composition on caveolae surface stability is not well described or understood. Accordingly, we inserted specific lipids into the cell PM via membrane fusion and studied their acute effects on caveolae dynamics. We demonstrate that sphingomyelin stabilizes caveolae to the cell surface, whereas cholesterol and glycosphingolipids drive caveolae scission from the PM. Although all three lipids accumulated specifically in caveolae, cholesterol and sphingomyelin were actively sequestered, whereas glycosphingolipids diffused freely. The ATPase EHD2 restricts lipid diffusion and counteracts lipid-induced scission. We propose that specific lipid accumulation in caveolae generates an intrinsically unstable domain prone to scission if not restrained by EHD2 at the caveolae neck. This work provides a mechanistic link between caveolae and their ability to sense the PM lipid composition.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd, 2020
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-172503 (URN)10.7554/eLife.55038 (DOI)000537207600001 ()32364496 (PubMedID)2-s2.0-85084964804 (Scopus ID)
Funder
Swedish Research Council, 2017-04028Swedish Cancer Society, CAN 2017/735Swedish Cancer Society, CAN2014/746The Kempe Foundations
Available from: 2020-07-02 Created: 2020-07-02 Last updated: 2020-07-02Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5000-1288

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