Cardiolipin-deficient cells depend on anaplerotic pathways to ameliorate defective TCA cycle function.
Biochim Biophys Acta Mol Cell Biol Lipids
; 1864(5): 654-661, 2019 05.
Article
en En
| MEDLINE
| ID: mdl-30731133
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. ß-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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Saccharomyces cerevisiae
/
Cardiolipinas
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Regulación Fúngica de la Expresión Génica
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Ciclo del Ácido Cítrico
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Proteínas de Saccharomyces cerevisiae
Idioma:
En
Revista:
Biochim Biophys Acta Mol Cell Biol Lipids
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos