Mitochondria, the energy generators of our cells, are essential for life. When they are under attack - from a combination of stress, environmental toxins, and genetic mutations – our cells tear these power stations apart, strip out the damaged pieces and reassemble them into new mitochondria.
Now, scientists at the Salk Institute in La Jolla, California, have uncovered an unexpected way in which cells trigger this critical response to threats, offering insight into disorders such as cancer, diabetes, genetic mitochondrial diseases and neurodegenerative disease including Alzheimer’s and Parkinson’s disease - which are linked to dysfunctional mitochondria.
Researchers have known for years that mitochondria undergo fragmentation when treated with drugs that affect the mitochondria (including antibiotics, statins, and chemotherapy), but the biochemical details of how this mitochondrial damage is sensed and how it triggers the mitochondria to break up has not been clear until now.
In this new work, the Salk team found that when cells are exposed to mitochondrial damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to the mitochondria instructing them to break apart into tiny mitochondrial fragments so they can be recycled into new, healthy mitochondria. Interestingly, AMPK is known to be activated by the widely used diabetes drug metformin, as well as intense exercise and a restricted diet.
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 damage. “I could not believe how black and white the results were. Just turning on AMPK by itself gives you as much fragmentation as a mitochondrial poison,” says Shaw.
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 and prepare for recycling.
Mitochondrial dysfunction has been increasingly linked to Type 2 diabetes, cancer, and neurodegenerative diseases including Alzheimer’s, Parkinson’s, and ALS. Identifying ways to positively intervene and promote improved mitochondrial health holds enormous promise for the development of future therapies.
Publication: AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Erin Quan Toyama et al. Science 2016.
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