Alternate energy switch in the cells identified!

Alternate energy switch in the cells identified!

A scientific collaboration between researchers in Scotland and China has uncovered a new kind of `energy sensor' in our cells, changing our understanding of how the body monitors glucose levels and switches on the supply of alternative `fuels'.

It is thought the research, published in the journal Nature, could have particular implications for diabetes, in which the level of glucose in the blood is abnormally high.

The research focused on the activity of a protein called AMPK. The AMPK enzyme is switched on when energy levels in the cell fall, and drives processes which stimulate energy production, while preventing energy-consuming processes.

AMPK is important because it enables the body to start burning other `fuels'. For example, during exercise, when the demand for energy is dramatically increased in muscle, AMPK switches on the uptake and metabolism of glucose and fats to provide the required energy.

It has been known for years that starving cells of glucose switches on AMPK, but everyone had assumed that this worked via the known ability of AMPK to sense changes in the cell's energy status.  It is unclear whether activation of AMPK occurs solely via changes in AMP or ADP, the classical activators of AMPK.

Authors show an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation.

Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation.

Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation.

These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

"We have now shown that cells can actually sense glucose by a completely different mechanism, in which AMPK is recruited to structures called lysosomes. It is by doing this that cells can switch on pathways for metabolism of alternative fuels, such as fats, when glucose becomes scarce but before cellular energy declines."

Senior author said more work would be needed to understand the full implications of this for human health. However, given the extremely prominent role of glucose in diabetes it is likely to be of significant value in understanding more about the disease.

AMPK is thought to be implicated in other conditions and diseases, including obesity and cancer.