Itaconate Trap Study
This project aims to look at metabolic traps in central carbon metabolism that lead to observed altered energy production pathways in ME/CFS.
Christopher Armstrong, PhD
Rob Phair, PhD
- Constructed the differential equation model for the TCA cycle.
- Developed the itaconate trap hypothesis.
- Itaconate cycle is initiated by pathogens.
- Only amino acids can efficiently replace fuel carbons lost to itaconate.
- Itaconate cycle metabolites sequester CoA and inactivate Vitamin B12.
STUDY HYPOTHESIS AND DESCRIPTION
One of the key metabolic theses aiming to explain ME/CFS symptoms is the dysregulated nitrogen metabolism theory proposed by Armstrong and colleagues. Three features of this theory make it attractive:
1) it is consistent with the observed shift from carbohydrate to alternative sources of energy (amino acids and fatty acids),
2) it predicts a reduction in oxygen consumption consistent with a hypometabolic state, and
3) it predicts overproduction of ammonia, a known neurotoxin that could explain ME/CFS neurological symptoms. One underdeveloped aspect of the nitrogen metabolism theory of ME/CFS is the mechanistic chain of events connecting the initial infectious or traumatic trigger to a chronically altered state of central carbon and mitochondrial metabolism.
This computational proposal aims to fill that gap by testing mechanisms that have the potential for switch-like or bistable behavior.
- Explore the itaconate trap and other potential traps in central carbon metabolism.
- Build pathways of central carbon metabolism.
- Develop kinetic models to try predict potential “weakness” points.
- Test the hypothesis experimentally.