When cells are under stress, chemical alarms are activated, triggering a series of activities that protect the most important players in the cell. During the rush, a protein called Parkin rushes to protect the mitochondria, the power plants that generate energy for the cell.
Now, Salk researchers have discovered a direct connection between the main sensor of cellular stress and Parkin himself. The same pathway is associated with diabetes and type 2 cancer, which could open a new pathway for the treatment of all three diseases.
“Our findings represent the earliest step in Parkin’s response to an alarm that anyone has ever found with a long stroke. All other known biochemical events happen in one hour; we have now found something that happens within five minutes,” says Professor Reuben Shaw, director The Salk Cancer Center appointed by the NCI and the senior author of the new work, described in detail in Scientific progress April 7, 2021. “Decoding this big step in the way cells deposit damaged mitochondria has implications for a number of diseases.”
Parkin’s job is to cleanse mitochondria damaged by cellular stress so that they can be replaced by a new one, a process called mitophagy. However, Parkin is mutated in familial Parkinson’s disease, due to which the protein cannot clean the damaged mitochondria.
Although scientists have known for some time that Parkin somehow feels mitochondrial stress and triggers the mitochondrial process, no one understood exactly how Parkin first experienced mitochondrial problems – Parkin somehow knew how to migrate to mitochondria after mitochondrial damage, but there was no known signal Parkin until he got there.
Shaw’s lab, known for its work in the field of metabolism and cancer, has spent years intensively researching how the cell regulates a more general cell cleansing and recycling process called autophagy.
Ten years ago, they discovered that an enzyme called AMPK, which is very sensitive to cellular stress of many species, including mitochondrial damage, controls autophagy by activating an enzyme called ULK1.
Following that discovery, Shaw and graduate student Portia Lombardo began a search for autophagy-related proteins directly activated by ULK1. They reviewed about 50 different proteins, expecting about 10 percent to fit.
They were shocked when Parkin was at the top of the list. Biochemical pathways are usually very intricate, involving up to 50 participants, each activating the next. The discovery that a procedure as important as mythophagy was initiated by only three participants — first AMPK, then ULK1, then Parkin — was so surprising that Shaw could hardly believe it.
To confirm that the findings were accurate, the team used mass spectrometry to pinpoint where ULK1 binds the phosphate group to Parkin. They discovered that he landed in a new region that other researchers recently determined was critical for Parkin activation, but that they did not know why. A postdoctoral fellow at Shaw’s Chien-Min Hung lab, he then performed precise biochemical studies to prove every aspect of the timeline and determine which proteins do what and where.
Shaw’s research is now beginning to explain this crucial first step in Parkin’s activation, which Shaw hypothesizes may serve as a “heads-up” signal from the AMPK down the chain of command across ULK1 to Parkin to go check mitochondria after the first wave of incoming damage and, if it is necessary to cause the destruction of those mitochondria that are too severely damaged to regain function.
The findings have broad implications. AMPK, the central sensor of cell metabolism, itself is activated by a tumor suppressor protein called LKB1 that is involved in a number of cancers, as Shaw found in a previous paper, and is activated by a type 2 diabetes drug called metformin.
Meanwhile, numerous studies show that patients with diabetes who take metformin have a lower risk of cancer and comorbid aging. In fact, metformin is currently being implemented as one of the first anti-aging therapies in clinical trials.
“The big exception for me is that metabolism and changes in the health of your mitochondria are crucial in cancer, they are critical in diabetes, and they are critical in neurodegenerative diseases,” says Shaw, chairman William R. Brody.
Our finding says that a drug for diabetes that activates AMPK, which we have previously shown can suppress cancer, can also help restore function in patients with neurodegenerative disease. This is because the general mechanisms that support cell health in our body are much more integrated than anyone could have imagined. “
Reuben Shaw, Professor and Director, Salk Cancer Center designated by NCI
Hung, CM., and others. (2021) AMPK / ULK1-mediated phosphorylation of the Parkin ACT domain mediates early-stage mitophagy. Scientific progress. doi.org/10.1126/sciadv.abg4544.