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Dihydroxyacetone phosphate signals glucose availability to mTORC1.
Jose M Orozco1,2,3,4, Patrycja A Krawczyk1,2,3,4, Sonia M Scaria1,2,3,4
1Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Nature Metabolism
|July 29, 2020
Summary
Mechanistic target of rapamycin complex 1 (mTORC1) activation by glucose was mysterious. Researchers identified dihydroxyacetone phosphate (DHAP) as the key metabolite, revealing how cells sense glucose for growth.
Area of Science:
- Cellular metabolism
- Molecular biology
- Biochemistry
Background:
- Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth, requiring amino acids and glucose for activation.
- The precise mechanism of glucose sensing by mTORC1 remains largely unknown.
- AMP-activated protein kinase is a known cellular energy sensor, but its role in direct glucose sensing by mTORC1 is unclear.
Purpose of the Study:
- To elucidate the mechanism by which glucose activates mTORC1 independent of cellular energy levels.
- To identify specific glucose metabolites responsible for mTORC1 activation.
- To understand the role of glycolysis intermediates in mTORC1 signaling.
Main Methods:
- Utilized metabolically engineered human cells lacking AMP-activated protein kinase.
- Investigated glucose metabolism and its downstream metabolites.
- Assayed mTORC1 activity in response to specific metabolite manipulations.
Main Results:
- Identified a key metabolite, dihydroxyacetone phosphate (DHAP), required for mTORC1 activation by glucose.
- Demonstrated that DHAP acts downstream of aldolase and upstream of GAPDH in glycolysis.
- Showed that DHAP synthesis from dihydroxyacetone (DHA) is sufficient to activate mTORC1, even without glucose.
Conclusions:
- Dihydroxyacetone phosphate (DHAP) is the critical metabolite sensed by mTORC1 for glucose-dependent activation.
- This finding clarifies a missing link in cellular nutrient sensing pathways.
- DHAP's role as a precursor for mTORC1-controlled lipid synthesis provides a functional link for this sensing mechanism.
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