Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity

Tarangelo, Amy; Rodencal, Jason; Kim, Joon Tae; Magtanong, Leslie; Long, Jonathan Z.; Dixon, Scott J.

doi:10.26508/lsa.202101157

Cited by 31 publications

(22 citation statements)

References 53 publications

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“…Of the top ten processes, nine have previously been associated with AD (Figure A). , This included the dysregulated metabolism of processes associated with mitochondrial dysfunction via the serine/threonine metabolism, oxidative phosphorylation, and TCA cycle. Additionally, branched amino acid metabolism, tryptophan metabolism, glycolysis, inositol phosphate metabolism, purine metabolism, and pyruvate metabolism have all been linked to aging, loss of neuroprotective function, and increased Aβ deposition. , The drug metabolism pathway that lacked association to AD had a notable overlap of enzymes involved in glutathione, purine, and pyrimidine metabolic pathways that have been implicated in AD . Furthermore, in the AD pathway, we continued to observe associations across both regions (Figure B).…”

Section: Resultsmentioning

confidence: 64%

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Odenkirk,

Zheng,

Kyle

et al. 2024

J. Proteome Res.

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Alzheimer's disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 AD and 29 controls (Ctrl) were studied to balance the number of ε4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, ε4 allele carriers (APOE4+ for those carrying 1 or 2 ε4s and APOE4− for non-ε4 carriers), and differences in ε3ε3 and ε3ε4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). The region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology.

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Section: Resultsmentioning

confidence: 64%

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Odenkirk,

Zheng,

Kyle

et al. 2024

J. Proteome Res.

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“…Our findings indicated that erastin remarkably reduced the proliferative activity of PCa cells. In addition, Fe 2+ is one of the essential factors of DNA replication, which is vital for cell survivability [38][39][40]. Consequently, we believed that erastin primarily transforms PCa cell proliferation by altering DNA replication.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of ferroptosis related genes in prostate cancer cells under erastin exposure

Huang

Jiang

et al. 2023

Preprint

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Few studies are focusing on the mechanism of erastin acts on prostate cancer(PCa) cells, and essential ferroptosis-related genes (FRGs) that can be PCa treatment targets are rarely known. In the current study, in vitro assays were performed to evaluate the ferroptotic levels of PCa cells under erastin treatment. RNA-seq was used to measure the expression of differentially expressed genes (DEGs) in erastin-induced PCa cells. A series of bioinformatic analyses were applied to analyze the pathways, module, transcription factors, and expression levels of DEGs. Erastin inhibited the expression of ferroptosis marker SLC7A11 and cell survivability in both PCa cells. After treatment with erastin, the concentration level of MDA and Fe2+ significantly increased, whereas GSH and GSSG significantly decreased in PCa cells. A total of 295 overlapping DEGs were screened and identified in two cells under erastin exposure and significantly enriched for association with some pathways. The expression levels of four hub FRGs, including TMEFF2, CLU, NRXN3, and UNC5B, were significantly different in PCa and normal tissues. TMEFF2 was the gene co-expressed with SLC7A11 and GPX4. In both PCa cells, the expression levels of SLC7A11 and cell growth were inhibited after the knockdown of TMEFF2. The concentration of Fe2+ significantly increased in two TMEFF2 downregulated cells. In conclusion, FRGs and their correlations with ferroptosis in PCa were identified and validated. Our results showed that these FRGs play a crucial role in PCa, and offered the potential therapeutic target genes for the investigation and treatment of PCa.

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“…Previous studies have linked ferroptosis to nucleotide metabolism through dihydroorotate dehydrogenase (DHODH) 40 and through ribonucleotide reductase (RNR) 41 . Here, we show that alterations in nucleotide metabolism account for some of the largest changes in the metabolome of cells treated with ferroptosis inducers erastin and RSL3.…”

Section: Discussionmentioning

confidence: 99%

Nucleotide metabolism is linked to cysteine availability

Allen

Sun

Wei

et al. 2022

Preprint

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The small molecule erastin inhibits the cystine-glutamate antiporter, system xc-, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied. To this end, we investigated how erastin impacts global metabolism in cultured cells and compared this metabolic profile to that caused by the ferroptosis inducer RSL3 or in-vivo cysteine deprivation. Common among the metabolic profiles were alterations in nucleotide and central carbon metabolism. Supplementing nucleosides to cysteine-deprived cells rescued cell proliferation in certain contexts, showing that these alterations to nucleotide metabolism can affect cellular fitness. While GPX4 inhibition caused a similar metabolic profile as cysteine deprivation, nucleoside treatment did not rescue cell viability or proliferation under RSL3 treatment, suggesting that these metabolic changes have varying importance in different scenarios of ferroptosis. Together, our study shows how global metabolism is affected during ferroptosis, and points to nucleotide metabolism as an important target of cysteine deprivation.

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Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity

Cited by 31 publications

References 53 publications

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Identification and validation of ferroptosis related genes in prostate cancer cells under erastin exposure

Nucleotide metabolism is linked to cysteine availability

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