The prediction method
Identify the limiting resource. Ask which sensor reads that resource: AMPK reads the ATP:AMP ratio, mTORC1 reads amino acid and growth factor availability, PHD enzymes read oxygen. Follow that sensor's output to the transcriptional and post-translational changes it produces. Then ask whether the limitation is transient or sustained, because duration determines whether the response remains reversible or becomes a new set-point.
Three limitations, three predicted responses
Low glucose, normal oxygen
- ATP:AMP ratio falls, AMPK activated
- Fatty acid synthesis off, fatty acid oxidation on
- mTORC1 inhibited, translation slowed
- Autophagy induced through ULK1
- Reversible if glucose returns
Low oxygen, normal glucose
- PHD enzymes lose substrate, HIF-alpha accumulates
- Glycolytic enzymes and glucose transporters induced
- VEGF secreted, lactate production rises
- ATP maintained by glycolysis at high glucose cost
- Reversible if oxygen returns
Chronic intermittent limitation of both
- HIF chronically active, glycolytic program fixed
- Oxidative capacity lost
- Autophagy runs continuously
- Cell becomes dependent on the stress program
- Not reversible; blocking the program can kill the cell
Duration is the deciding variable
The same sensors and the same programs operate in all three scenarios. What changes is how long they stay on. Acute activation is a reversible adjustment. Sustained activation resets the cell's metabolic set-point and creates a dependence on the stress program itself. This is the same duration-dependent logic established for the ER unfolded protein response and for mitochondrial quality control.