How the cell's power station survives attacks

How the cell's power station survives attacks
In an average human cell, anywhere from 100 to 500 mitochondria churn out energy in the form of ATP molecules, which act like batteries to carry power to the rest of the cell. At any given time, one or two mitochondria fragment (fission) or reform (fusion) to cycle out any damaged parts. But when a poison--like cyanide or arsenic--or other dangers threaten the mitochondria, a mass fragmentation takes place.

Researchers have known for years that mitochondria undergo this fragmentation when treated with drugs that affect the mitochondria, but the biochemical details of how the mitochondria damage is sensed and how that triggers the rapid fission response has not been clear until now.

In the new work, the Salk team found that when cells are exposed to mitochondria damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to mitochondria instructing them to break apart into many tiny mitochondrial fragments. Interestingly, AMPK is activated by the widely used diabetes therapeutic metformin, as well as exercise and a restricted diet. The new findings suggest that some of the benefits from these therapies may result from their effects in promoting mitochondrial health.

To uncover exactly what happens in those first few minutes, the team used the gene editing technique CRISPR to delete AMPK in cells and showed that, even when poison or other threats are introduced to the mitochondria, they do not fragment without AMPK. This indicates that AMPK somehow directly acts on mitochondria to induce fragmentation.

The group then looked at a way to chemically turn on AMPK without sending attacks to mitochondria. To their surprise, they found that activating AMPK alone was enough to cause the mitochondria to fragment, even without the damage.

The team discovered why this was: when the cell's power stations are disrupted, the amount of energy floating around a cell--ATP--is lowered. After just a few minutes, AMPK detects this reduction of energy in the cell and hurries to the mitochondria. Like a guard pulling a fire alarm, AMPK activates a receptor on the outside membrane of a mitochondrion to signal it to fragment.

Drilling down further, the researchers found that AMPK actually acts on two areas of a mitochondrial receptor, called mitochondrial fission factor (MFF), to start the process. MFF calls over a protein, Drp1, that binds and wraps around the mitochondrion like a beaded noose to twist and break it apart.

"We discovered that the modification of MFF by AMPK is needed for MFF to call over more Drp1 to the mitochondria," says one of the first authors of the paper published in the journal Science. "Without AMPK sending the alarm, MFF cannot call over to Drp1 and there is no new fragmentation of mitochondria after damage."

In the future, the team is interested in addressing what other consequences this signaling pathway has for specific cell types.  
"On one hand, AMPK is known to be important for type 2 diabetes, immune disease and cancer. On the other hand, mitochondrial dysfunction is becoming increasing connected to metabolic diseases and neurodegenerative diseases. We're making some of the first steps in connecting these two things that have major disease implications."


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