ArticleScientific reports2021
The acute transcriptional responses to dietary methionine restriction are triggered by inhibition of ternary complex formation and linked to Erk1/2, mTOR, and ATF4.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 29 citations in OpenAlex.
- Sulfur amino acid restriction and caloric restriction induce divergent redox metabolism-related adaptations in male F344 rats.Redox report : communications in free radical research · 2026Article
- Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.Molecular metabolism · 2026Article
- IDH-mutant inhibitors enhance the sensitivity of IDH1-mutant gliomas to cysteine-methionine deprivation and ferroptosis.bioRxiv : the preprint server for biology · 2026Article
- Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.Frontiers in cell and developmental biology · 2026Review
- Dietary sulfur amino acid restriction improves glucose homeostasis through hepaticbioRxiv : the preprint server for biology · 2025Article
- Dietary methionine depletion and hydrogen sulfide-producing genes in perivascular adipose tissue of male Wistar rats.Physiological reports · 2025Article
- Methionine deficiency causes spermatogonial apoptosis via oxidative stress and DNA damage response pathway.Biological research · 2025Article
- Manipulating dietary protein and amino acids in the common marmoset Callithrix jacchus impacts circulating metabolites and FGF21 levels.Scientific reports · 2025Article
- Methionine Restriction Attenuates Scar Formation in Fibroblasts Derived from Patients with Post-Burn Hypertrophic Scar.International journal of molecular sciences · 2025Article
- Minimum methionine requirement in adult cats as determined by indicator amino acid oxidation.Journal of animal science · 2024Article
- Kinetic proteomics identifies targeted changes in liver metabolism and the ribo-interactome by dietary sulfur amino acid restriction.GeroScience · 2023Article
- Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism.Aging cell · 2022Article
- The Origins, Evolution, and Future of Dietary Methionine Restriction.Annual review of nutrition · 2022Review
- mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity.International journal of molecular sciences · 2022Review
- Article
- Review
- Targeting the methionine addiction of cancer.American journal of cancer research · 2022Review
- Rates of protein synthesis are maintained in brain but reduced in skeletal muscle during dietary sulfur amino acid restriction.Frontiers in aging · 2022Article
- The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein.Nutrients · 2021Article
- HepaticNutrients · 2021Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The initial sensing of dietary methionine restriction (MR) occurs in the liver where it activates an integrated stress response (ISR) that quickly reduces methionine utilization. The ISR program is regulated in part by ATF4, but ATF4's prototypical upstream regulator, eIF2α, is not acutely activated by MR. Bioinformatic analysis of RNAseq and metabolomics data from liver samples harvested 3 h and 6 h after initiating MR shows that general translation is inhibited at the level of ternary complex formation by an acute 50% reduction of hepatic methionine that limits formation of initiator methionine tRNA. The resulting ISR is induced by selective expression of ATF4 target genes that mediate adaptation to reduced methionine intake and return hepatic methionine to control levels within 4 days of starting the diet. Complementary in vitro experiments in HepG2 cells after knockdown of ATF4, or inhibition of mTOR or Erk1/2 support the conclusion that the early induction of genes by MR is partially dependent on ATF4 and regulated by both mTOR and Erk1/2. Taken together, these data show that initiation of dietary MR induces an mTOR- and Erk1/2-dependent stress response that is linked to ATF4 by the sharp, initial drop in hepatic methionine and resulting repression of translation pre-initiation.
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