Glutaminolysis and Transferrin Regulate Ferroptosis

By Minghui Gao, Prashant Monian, N. Quadri, R. Ramasamy, Xuejun Jiang. Molecules and Cells, 2015

1,843 citations recorded by the source corpus.

SUMMARY Ferroptosis has emerged as a new form of regulated necrosis that is implicated in various human diseases. However, the mechanisms of ferroptosis are not well defined. This study reports the discovery of multiple molecular components of ferroptosis and its intimate interplay with cellular metabolism and redox machinery. Nutrient starvation often leads to sporadic apoptosis. Strikingly, we found that upon deprivation of amino acids, a more rapid and potent necrosis process can be induced in a serum-dependent manner, which was subsequently determined to be ferroptosis. Two serum factors, the iron-carrier protein transferrin and amino acid glutamine, were identified as the inducers of ferroptosis. We further found that the cell surface transferrin receptor and the glutamine-fueled intracellular metabolic pathway, glutaminolysis, played crucial roles in the death process. Inhibition of glutaminolysis, the essential component of ferroptosis, can reduce heart injury triggered by ischemia-reperfusion, suggesting a potential therapeutic approach for treating related diseases.

Subfields: Immunology, Pulmonary and Respiratory Medicine, Surgery

View Paper: https://www.semanticscholar.org/paper/3998b1bf37fba3fef9269f1d76513a66919e888e

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Citations in the corpus

The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, positive): “Glutamine is required for the induction of ferroptosis during seruminduced injury after amino acid starvation [72].”
Ferroptosis: process and function (2016, background): “Inhibiting glutaminolysis and ferroptosis by compound 968, DFO, or ferrastatin-1 limits ischemia/reperfusion-induced heart injury ex vivo.(30) Process and function of ferroptosis Y Xie et al”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “import by the circulating iron carrier transferrin (TF) [571, 572], degradation of ferritin (a cellular iron storage com-”
Ferroptosis: mechanisms and links with diseases (2021, background): “Conversely, inhibition of glutaminolysis and cell surface transferrin receptor can reduce heart injury triggered by ischemia/reperfusion (I/R) against ferroptosis.(19) On the oxidation pathway, lipoxygenases (Lox) catalyze PUFA oxidation via a phosphorylase kinase G2 (PHKG2)-dependent iron pool,(19)”
The Development of the Concept of Ferroptosis (2018, positive): “Moreover, addition of iron to the growth medium [25], as well as of iron-bound transferrin [117], were shown to accelerate erastin-induced ferroptosis, and administration of a bioavailable iron form enhances ferroptotic death in mouse models defective in system Xc [125].”
Role of Mitochondria in Ferroptosis (2018, background): “Furthermore, glutamine metabolism, known as glutaminolysis, is required for cysteine deprivation-induced ferroptosis (Gao et al., 2015a; Gao et al., 2015b), and one of the major functions of glutaminolysis is to fuel the mitochondrial tricarboxylic acid (TCA) cycle.”