Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

H. Furkan Alkan, Katharina E. Walter, Alba Luengo, Corina T. Madreiter-Sokolowski, Sarah Stryeck, Allison N. Lau, Wael Al-Zoughbi, Caroline A. Lewis, Craig J. Thomas, Gerald Hoefler, Wolfgang F. Graier, Tobias Madl, Matthew G. Vander Heiden, Juliane G. Bogner-Strauss

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

Originalspracheenglisch
Seiten (von - bis)706-720.e6
FachzeitschriftCell metabolism
Jahrgang28
Ausgabenummer5
DOIs
PublikationsstatusVeröffentlicht - 6 Nov 2018

Fingerprint

Glutaminase
Glutamine
Aspartic Acid
Cell Survival
Oxidation-Reduction
Homeostasis
Growth
Cell Proliferation
Carbon Cycle
Neoplasms
Allografts
Cell Death
aspartate-glutamate carrier

Schlagwörter

    ASJC Scopus subject areas

    • Physiologie
    • !!Molecular Biology
    • Zellbiologie

    Kooperationen

    • BioTechMed-Graz

    Dies zitieren

    Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. / Alkan, H. Furkan; Walter, Katharina E.; Luengo, Alba; Madreiter-Sokolowski, Corina T.; Stryeck, Sarah; Lau, Allison N.; Al-Zoughbi, Wael; Lewis, Caroline A.; Thomas, Craig J.; Hoefler, Gerald; Graier, Wolfgang F.; Madl, Tobias; Vander Heiden, Matthew G.; Bogner-Strauss, Juliane G.

    in: Cell metabolism, Jahrgang 28, Nr. 5, 06.11.2018, S. 706-720.e6.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Alkan, HF, Walter, KE, Luengo, A, Madreiter-Sokolowski, CT, Stryeck, S, Lau, AN, Al-Zoughbi, W, Lewis, CA, Thomas, CJ, Hoefler, G, Graier, WF, Madl, T, Vander Heiden, MG & Bogner-Strauss, JG 2018, 'Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting' Cell metabolism, Jg. 28, Nr. 5, S. 706-720.e6. https://doi.org/10.1016/j.cmet.2018.07.021
    Alkan HF, Walter KE, Luengo A, Madreiter-Sokolowski CT, Stryeck S, Lau AN et al. Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. Cell metabolism. 2018 Nov 6;28(5):706-720.e6. https://doi.org/10.1016/j.cmet.2018.07.021
    Alkan, H. Furkan ; Walter, Katharina E. ; Luengo, Alba ; Madreiter-Sokolowski, Corina T. ; Stryeck, Sarah ; Lau, Allison N. ; Al-Zoughbi, Wael ; Lewis, Caroline A. ; Thomas, Craig J. ; Hoefler, Gerald ; Graier, Wolfgang F. ; Madl, Tobias ; Vander Heiden, Matthew G. ; Bogner-Strauss, Juliane G. / Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting. in: Cell metabolism. 2018 ; Jahrgang 28, Nr. 5. S. 706-720.e6.
    @article{ed24d8250a384fb69aec3ba268c30ff5,
    title = "Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting",
    abstract = "Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.",
    keywords = "AGC1, Aralar, aspartate-glutamate carrier, cancer metabolism, glutamine metabolism, SLC25A12",
    author = "Alkan, {H. Furkan} and Walter, {Katharina E.} and Alba Luengo and Madreiter-Sokolowski, {Corina T.} and Sarah Stryeck and Lau, {Allison N.} and Wael Al-Zoughbi and Lewis, {Caroline A.} and Thomas, {Craig J.} and Gerald Hoefler and Graier, {Wolfgang F.} and Tobias Madl and {Vander Heiden}, {Matthew G.} and Bogner-Strauss, {Juliane G.}",
    year = "2018",
    month = "11",
    day = "6",
    doi = "10.1016/j.cmet.2018.07.021",
    language = "English",
    volume = "28",
    pages = "706--720.e6",
    journal = "Cell metabolism",
    issn = "1550-4131",
    publisher = "Cell Press",
    number = "5",

    }

    TY - JOUR

    T1 - Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting

    AU - Alkan, H. Furkan

    AU - Walter, Katharina E.

    AU - Luengo, Alba

    AU - Madreiter-Sokolowski, Corina T.

    AU - Stryeck, Sarah

    AU - Lau, Allison N.

    AU - Al-Zoughbi, Wael

    AU - Lewis, Caroline A.

    AU - Thomas, Craig J.

    AU - Hoefler, Gerald

    AU - Graier, Wolfgang F.

    AU - Madl, Tobias

    AU - Vander Heiden, Matthew G.

    AU - Bogner-Strauss, Juliane G.

    PY - 2018/11/6

    Y1 - 2018/11/6

    N2 - Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

    AB - Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

    KW - AGC1

    KW - Aralar

    KW - aspartate-glutamate carrier

    KW - cancer metabolism

    KW - glutamine metabolism

    KW - SLC25A12

    UR - http://www.scopus.com/inward/record.url?scp=85056422003&partnerID=8YFLogxK

    U2 - 10.1016/j.cmet.2018.07.021

    DO - 10.1016/j.cmet.2018.07.021

    M3 - Article

    VL - 28

    SP - 706-720.e6

    JO - Cell metabolism

    JF - Cell metabolism

    SN - 1550-4131

    IS - 5

    ER -