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Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function. / Raja, Vaishnavi; Salsaa, Michael; Joshi, Amit S.; Li, Yiran; van Roermund, Carlo W. T.; Saadat, Nadia; Lazcano, Pablo; Schmidtke, Michael; Hüttemann, Maik; Gupta, Smiti V.; Wanders, Ronald J. A.; Greenberg, Miriam L.

In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, Vol. 1864, No. 5, 2019, p. 654-661.

Research output: Contribution to journalArticleAcademicpeer-review

Harvard

Raja, V, Salsaa, M, Joshi, AS, Li, Y, van Roermund, CWT, Saadat, N, Lazcano, P, Schmidtke, M, Hüttemann, M, Gupta, SV, Wanders, RJA & Greenberg, ML 2019, 'Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function', BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, vol. 1864, no. 5, pp. 654-661. https://doi.org/10.1016/j.bbalip.2019.02.001

APA

Raja, V., Salsaa, M., Joshi, A. S., Li, Y., van Roermund, C. W. T., Saadat, N., ... Greenberg, M. L. (2019). Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1864(5), 654-661. https://doi.org/10.1016/j.bbalip.2019.02.001

Vancouver

Raja V, Salsaa M, Joshi AS, Li Y, van Roermund CWT, Saadat N et al. Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS. 2019;1864(5):654-661. https://doi.org/10.1016/j.bbalip.2019.02.001

Author

Raja, Vaishnavi ; Salsaa, Michael ; Joshi, Amit S. ; Li, Yiran ; van Roermund, Carlo W. T. ; Saadat, Nadia ; Lazcano, Pablo ; Schmidtke, Michael ; Hüttemann, Maik ; Gupta, Smiti V. ; Wanders, Ronald J. A. ; Greenberg, Miriam L. / Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function. In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS. 2019 ; Vol. 1864, No. 5. pp. 654-661.

BibTeX

@article{2f57f931f7b749f795e15392bc1fc78f,
title = "Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function",
abstract = "Previous studies have shown that the cardiolipin (CL)-deficient yeast mutant, crd1Δ has decreased levels of acetyl-CoA and decreased activities of the TCA cycle enzymes aconitase and succinate dehydrogenase. These biochemical phenotypes are expected to lead to defective TCA cycle function. In this study, we report that signaling and anaplerotic metabolic pathways that supplement defects in the TCA cycle are essential in crd1Δ mutant cells. The crd1Δ mutant is synthetically lethal with mutants in the TCA cycle, retrograde (RTG) pathway, glyoxylate cycle, and pyruvate carboxylase 1. Glutamate levels were decreased, and the mutant exhibited glutamate auxotrophy. Glyoxylate cycle genes were up-regulated, and the levels of glyoxylate metabolites succinate and citrate were increased in crd1Δ. Import of acetyl-CoA from the cytosol into mitochondria is essential in crd1Δ as deletion of the carnitine-acetylcarnitine translocase led to lethality in the CL mutant. β-oxidation was functional in the mutant, and oleate supplementation rescued growth defects. These findings suggest that TCA cycle deficiency caused by the absence of CL necessitates activation of anaplerotic pathways to replenish acetyl-CoA and TCA cycle intermediates. Implications for Barth syndrome, a genetic disorder of CL metabolism, are discussed.",
author = "Vaishnavi Raja and Michael Salsaa and Joshi, {Amit S.} and Yiran Li and {van Roermund}, {Carlo W. T.} and Nadia Saadat and Pablo Lazcano and Michael Schmidtke and Maik H{\"u}ttemann and Gupta, {Smiti V.} and Wanders, {Ronald J. A.} and Greenberg, {Miriam L.}",
year = "2019",
doi = "10.1016/j.bbalip.2019.02.001",
language = "English",
volume = "1864",
pages = "654--661",
journal = "BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS",
issn = "1388-1981",
publisher = "Elsevier",
number = "5",

}

RIS

TY - JOUR

T1 - Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function

AU - Raja, Vaishnavi

AU - Salsaa, Michael

AU - Joshi, Amit S.

AU - Li, Yiran

AU - van Roermund, Carlo W. T.

AU - Saadat, Nadia

AU - Lazcano, Pablo

AU - Schmidtke, Michael

AU - Hüttemann, Maik

AU - Gupta, Smiti V.

AU - Wanders, Ronald J. A.

AU - Greenberg, Miriam L.

PY - 2019

Y1 - 2019

N2 - Previous studies have shown that the cardiolipin (CL)-deficient yeast mutant, crd1Δ has decreased levels of acetyl-CoA and decreased activities of the TCA cycle enzymes aconitase and succinate dehydrogenase. These biochemical phenotypes are expected to lead to defective TCA cycle function. In this study, we report that signaling and anaplerotic metabolic pathways that supplement defects in the TCA cycle are essential in crd1Δ mutant cells. The crd1Δ mutant is synthetically lethal with mutants in the TCA cycle, retrograde (RTG) pathway, glyoxylate cycle, and pyruvate carboxylase 1. Glutamate levels were decreased, and the mutant exhibited glutamate auxotrophy. Glyoxylate cycle genes were up-regulated, and the levels of glyoxylate metabolites succinate and citrate were increased in crd1Δ. Import of acetyl-CoA from the cytosol into mitochondria is essential in crd1Δ as deletion of the carnitine-acetylcarnitine translocase led to lethality in the CL mutant. β-oxidation was functional in the mutant, and oleate supplementation rescued growth defects. These findings suggest that TCA cycle deficiency caused by the absence of CL necessitates activation of anaplerotic pathways to replenish acetyl-CoA and TCA cycle intermediates. Implications for Barth syndrome, a genetic disorder of CL metabolism, are discussed.

AB - Previous studies have shown that the cardiolipin (CL)-deficient yeast mutant, crd1Δ has decreased levels of acetyl-CoA and decreased activities of the TCA cycle enzymes aconitase and succinate dehydrogenase. These biochemical phenotypes are expected to lead to defective TCA cycle function. In this study, we report that signaling and anaplerotic metabolic pathways that supplement defects in the TCA cycle are essential in crd1Δ mutant cells. The crd1Δ mutant is synthetically lethal with mutants in the TCA cycle, retrograde (RTG) pathway, glyoxylate cycle, and pyruvate carboxylase 1. Glutamate levels were decreased, and the mutant exhibited glutamate auxotrophy. Glyoxylate cycle genes were up-regulated, and the levels of glyoxylate metabolites succinate and citrate were increased in crd1Δ. Import of acetyl-CoA from the cytosol into mitochondria is essential in crd1Δ as deletion of the carnitine-acetylcarnitine translocase led to lethality in the CL mutant. β-oxidation was functional in the mutant, and oleate supplementation rescued growth defects. These findings suggest that TCA cycle deficiency caused by the absence of CL necessitates activation of anaplerotic pathways to replenish acetyl-CoA and TCA cycle intermediates. Implications for Barth syndrome, a genetic disorder of CL metabolism, are discussed.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85061341244&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30731133

U2 - 10.1016/j.bbalip.2019.02.001

DO - 10.1016/j.bbalip.2019.02.001

M3 - Article

C2 - 30731133

VL - 1864

SP - 654

EP - 661

JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

SN - 1388-1981

IS - 5

ER -

ID: 5996431