mTORC1 promotes purine synthesis via ATF4-driven mitochondrial tetrahydrofolate metabolism.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Science |
| Year | 2016 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.aad0489 · PMID 26912861 · Free full text (PMC4786372) |
In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2alpha phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.
| Intervention | Genetic/pharmacologic (mTORC1) |
| Target | mTORC1 / ATF4 / mitochondrial folate (THF) cycle |
| Model | Mammalian cells |
| Effect | mTORC1 induces de novo purine synthesis through control of the mitochondrial tetrahydrofolate cycle |