Exercise is good for you! AMPK role in cell recycling may explain why AMPK plays an important role in metabolic disorders

AMPK (Adenosine monophosphate – activated protein kinase) is an amazing enzyme. It plays critical role in cellular energy homeostasis – maintaining balance of energy production and consumption in the cell by regulating ATP generation.

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 are shown in blue. Credit: Daniel Egan, Salk Institute for Biological Studies
As muscles contract, ATP is hydrolyzed, forming ADP. ADP then helps to replenish cellular ATP by donating a phosphate group to another ADP, forming an ATP and an AMP. As more AMP is produced during muscle contraction, the AMP:ATP ratio dramatically increases, leading to the allosteric activation of AMPK.

Researchers at the Salk Institute for Biological Studies have discovered how AMPK, a metabolic master switch that springs into gear when cells run low on energy, revs up a cellular recycling program to free up essential molecular building blocks in times of need. In a paper published in the Dec. 23, 2010 edition of Science Express, a team led by Reuben Shaw, PhD., Howard Hughes Medical Institute Early Career Scientist and Hearst Endowment assistant professor in the Salk’s Molecular and Cell Biology Laboratory, reports that AMPK activates a cellular recycling process known as autophagy by activating an enzyme known as ATG1, that 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 II diabetes, cancer, and neurodegenerative diseases such Parkinson’s and Alzheimer’s.

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 list.”

His team initiated the study by defining a unique targeting sequence used by AMPK to transmit its signals and then using bioinformatics and biochemistry to identify proteins that act as AMPK targets. One of the prime suspects identified in that that effort was the protein Atg1/ULK1, a factor that triggers autophagy in yeast.

To test the effects on autophagy of deregulating these enzymes, the group focused on large intracellular structures called mitochondria, whose role is to generate energy. “Mitochondria are easily damaged in detoxifying tissues like liver,” explains Shaw. “A critical way that defective mitochondria are turned over is through a special form of autophagy called mitophagy.”

In that case, cells would envelope their unhealthy mitochondria in a membrane, dump them in a cellular acid pit, and recycle the remains. If AMPK initiated the process, cells genetically engineered to lack AMPK might show altered mitochondrial turnover compared to normal cells.

And that is precisely what the researchers saw: liver cells in which AMPK had been eliminated contained too many mitochondria, many of which looked spindly, indicating they were moribund, and confirming that AMPK was directing autophagic waste disposal. “We found that the ability to recycle their defective mitochondria allowed cells to survive starvation better,” says Shaw.

But if you aren’t an evolutionary biologist, you still have a personal stake in AMPK signaling if you: exercise regularly, feel good about drinking red wine, take diabetes meds, and/or starve yourself in hopes of a long life—all of which reportedly stimulate AMPK signals.

Add to that the possibility that AMPK 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.

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