Inside Salk; Salk Insitute

Recycling cellular fuel

Recycling cellular fuel

When the process of autophagy is defective, cells are unable to recycle cellular organelles such as mitochondria (shown in red) to generate molecular building blocks when needed. Cell nuclei shown in blue.
Image: Courtesy of Daniel Egan

If you exercise regularly, feel good about drinking red wine, take diabetes meds and/or starve yourself in hope of a long life, then you have a personal stake in AMPK signaling.

AMPK is a metabolic master switch that springs into gear when cells run low on energy. Now researchers in the lab of Reuben Shaw have uncovered one of its principal secrets: how it revs up a cellular recycling program to free up essential molecular building blocks in times of need.

In a study published in Science, Shaw and his team report that AMPK triggers a cellular recycling function known as autophagy by activating an enzyme known as ATG1, which jumpstarts the process. The newly uncovered direct molecular connection between AMPK and ATG1 is significant because dysfunctions in both AMPK signaling and autophagy are implicated in a plethora of aging-related diseases, including type 2 diabetes, cancer and neurodegerative diseases such Parkinson's and Alzheimer's.

Add to that the possibility that AMPK itself may have anti-tumor activity, and it is no wonder that pharmaceutical companies are keenly interested in what proteins AMPK "talks to" and how drugs that stimulate that conversation work.

Despite its ominous name—derived from "self" (auto) and "eating" (phagy)—cells use autophagy to dispose of debris before it becomes toxic enough to kill a cell. "Autophagy is an ancient process that evolved to break down components cells don't need to create things they do need," explains Dan Egan, a graduate student in Shaw's lab.

Previously, Shaw's lab had not only demonstrated that AMPK is deregulated in certain forms of cancer but also that the enzyme is a critical target of the type 2 diabetes drug metformin. "Taking a drug that activates this pathway, like metformin, is the equivalent of taking several different drugs," says Shaw, reeling off a list of anti-tumor and anti-diabetes pathways activated by AMPK. "Now we can add regulation of autophagy to that l ist."