When the cells are stressed, chemical alarms are set off that set off a range of activities that protect the cell’s key actors. During the onslaught, a protein called Parkin rushes to protect the mitochondria, the powerhouses that generate energy for the cell.
Now Salk researchers have discovered a direct link between a master cell stress sensor and Parkin himself. The same pathway is also linked to type 2 diabetes and cancer, which could open a new avenue for treating all three diseases.
“Our results represent the earliest step in Parkin’s alarm response anyone has ever found by far. All other known biochemical events occur in an hour. We have now found something that happens within five minutes,” says Professor Reuben Shaw, Director of the NCI-designated Salk Cancer Center and senior author of the new work described in Science Advances on April 7, 2021. “Unraveling this important step in the way cells dispose of defective mitochondria has implications for a number of diseases.”
Parkin’s job is to clear out mitochondria that have been damaged by cellular stress so that new ones can take their place, a process known as mitophagy. However, Parkin is mutated in familial Parkinson’s disease, which means that the protein is unable to clear damaged mitochondria.
While scientists have known for some time that Parkin somehow senses mitochondrial stress and initiates the process of mitophagy, no one understood exactly how Parkin first perceived problems with mitochondria – Parkin somehow knew that after mitochondrial damage it migrated into mitochondria, but there was they No known signal to Parkin until it got there.
Shaw’s lab, known for its work on metabolism and cancer, has spent years studying how the cell regulates a more general process of cell purification and recycling called autophagy.
About ten years ago, they discovered that an enzyme called AMPK, which is very sensitive to cellular stress of all kinds, including mitochondrial damage, controls autophagy by activating an enzyme called ULK1.
Following this discovery, Shaw and PhD student Portia Lombardo began looking for autophagy-related proteins that were directly activated by ULK1. They examined about 50 different proteins and expected that about 10 percent would fit.
They were shocked when Parkin was top of the list. Biochemical pathways are usually very confused and involve up to 50 participants, each of which activates the next. To find that a process as important as mitophagy was only initiated by three participants – first AMPK, then ULK1, then Parkin – was so surprising that Shaw could hardly believe it.
To confirm the results were correct, the team used mass spectrometry to show exactly where ULK1 attached a phosphate group to Parkin. They found that it ended up in a new region that other researchers recently found critical for Parkin activation but didn’t know why. A postdoctoral fellow in Shaw’s lab, Chien-Min Hung, then conducted precise biochemical studies to prove every aspect of the timeline, describing which proteins were doing what and where.
Shaw’s research is now beginning to explain this important first step in Parkin activation, which Shaw suspects could serve as a “heads-up” signal from AMPK down the chain of command via ULK1 to Parkin to after a first wave at the entrance to examine the mitochondria cause damage and possibly trigger the destruction of mitochondria that are too damaged to regain their function.
The results have far-reaching implications. AMPK, the central sensor of cell metabolism, is itself activated by a tumor suppressor protein called LKB1, which is implicated in a number of cancers, as noted by Shaw in previous work, and activated by a type 2 diabetes drug called metformin.
Meanwhile, numerous studies show that diabetic patients who take metformin have a lower risk of cancer and aging comorbidities. In fact, metformin is currently being used as one of the first “anti-aging” therapeutic agents in clinical trials.
“The big takeaway for me is that metabolism and changes in the health of your mitochondria are critical in cancer, diabetes and neurodegenerative diseases,” said Shaw, who holds the William R. Brody Chair.
Our finding is that a diabetes drug that activates AMPK, which we previously demonstrated to suppress cancer, can also help restore function in patients with neurodegenerative diseases. This is because the general mechanisms that support the health of the cells in our body are much more integrated than anyone could ever have imagined. “
Reuben Shaw, professor and director of the NCI-designated Salk Cancer Center
Hung, CM., Et al. (2021) AMPK / ULK1-mediated phosphorylation of the Parkin ACT domain mediates an early step in mitophagy. Advances in science. doi.org/10.1126/sciadv.abg4544.